Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04103216 |
| Other study ID # |
PR-19079 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
February 1, 2020 |
| Est. completion date |
August 31, 2023 |
Study information
| Verified date |
September 2023 |
| Source |
International Centre for Diarrhoeal Disease Research, Bangladesh |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Background:
1. Burden:
Cryptosporidiosis among the top 10 causes of diarrhea in the 1st year of life in low and
middle-income countries (LMICs), with an estimated total of 48,000 annual deaths and
accounting for 4.2 million disability-adjusted life years lost.
2. Knowledge gap:
The only approved drug for the treatment of diarrhea caused by Cryptosporidium infection is
Nitazoxanide (NTZ) but NTZ has a higher failure rate in malnourished children. The lack of
effective therapy for cryptosporidiosis remains an immense knowledge gap in the efforts to
improve childhood health worldwide.
Hypothesis:
NTZ treatment failure in malnourished infants is due to a secondary immune deficiency that
can be reversed by the appropriate therapeutic treatment. Lactobacillus reuteri DSM 17938 can
have a potential immune modulating effect by altering gut microbiome promoting NTZ action.
Objectives:
Primary:
• To develop new approaches to treat and prevent cryptosporidiosis
Secondary:
- Determination of the treatment outcome of NTZ against cryptosporidiosis in Bangladeshi
children.
- Determination of the change in effectiveness of NTZ treatment in conjunction with the
administration of probiotics in malnourished Bangladeshi children with cryptosporidiosis
Methods:
This will be a prospectively conducted randomized pilot study with 2 arms in children in the
Mirpur (Dhaka, Bangladesh) slum area, where cryptosporidium infected children will receive
Nitazoxanide treatment with or without the probiotic, Lactobacillus reuteri DSM 17938.
Outcome measures/variables:
The significance of the work lies in the ability of the study to provide new approaches to
treat and prevent Cryptosporidiosis. The goal of this work is to assess the efficacy of NTZ
drug in a low socioeconomic Bangladeshi population and establish new supportive therapeutic
measures to the already established treatment with NTZ against in cryptosporidiosis.
Description:
Background: Reports from longitudinal birth cohort study at Bangladesh show that 77% of
children experience at least one incidence of cryptosporidiosis in the first two years of
life. Cryptosporidiosis is also associated with the development of malnutrition leading to an
estimate of an additional 4.2 million disability adjusted life years lost. A number of
studies on cryptosporidiosis conducted at icddr,b showed that Cryptosporidium sp. was one of
the most important causative agents of diarrhea associated with morbidity and mortality.
Previous studies at icddr,b also made a number of other intriguing elucidations, which
include:
1. Cryptosporidium sp. infected most children in the 1st year of life in a cohort at
Mirpur, Dhaka. Investigators observed that up to 64% of infants were diagnosed with
cryptosporidiosis in the 1st year of life while 26% of these cases had accompanying
co-infections.
2. Cryptosporidium sp. was established as a top 10 diarrheal pathogen, with infections
occurring with multiple other enteropathogens. Investigators discovered that infection
and diarrhea with multiple entero-pathogens in infants in an LMIC setting was the norm,
without any exception. On average each infant in Mirpur, Bangladesh had 3-5 enteric
pathogens present in their stool at any a single time point.The importance of
Cryptosporidium as a leading cause of infant diarrhea was validated by the MAL-ED study
conducted across 8 different low to middle income sites.
3. Diarrhea due to Cryptosporidium in the first year of life was independently associated
with the future development of malnutrition.
4. Impaired neurocognitive development at two years of age for infants with history of
cryptosporidiosis as measure using the Bayley's scales of infant development.
Currently, there is no effective vaccine for cryptosporidiosis and the only approved drug for
the treatment of diarrhea caused by Cryptosporidium infection is nitazoxanide (NTZ)(U.S.
DEPARTMENT OF HEALTH AND HUMAN SERVICES 2003). NTZ is the only treatment but its efficacy in
controlled clinical trials has varied widely. While this drug has been generally shown to
have an efficacy of >80%, in previous studies involving malnourished Zambian children it was
shown to have an efficacy of only 56%. An effective therapy would be appealing for
cryptosporidiosis in children in the developing world where the burden of infection is high
and where persistence of the enteropathogen in the absence of diarrhea is associated with
malnutrition.
Although the exact reason for NTZ exhibiting a higher failure rate in malnourished children
is unclear, this drug has been shown to inhibit the pyruvate-ferredoxin oxidoreductase of
parasites and anaerobic bacteria but its effectiveness in combating cryptosporidiosis is
dependent on the host immune competence. The gut micro-environment is a key component of the
host response to environmental challenge, with the gut microbiota being postulated to mediate
integral roles in promoting and calibrating all aspects of the immune system. Fermented
products (such as yogurt) have long been thought to promote health. However, in most
commercial food products the levels of the beneficial microorganisms or probiotics are not
consistent and at lower levels than required for the desired biological effect. Lactobacillus
reuteri DSM 17938 has been one of the most extensively studied probiotic in children and
adults with functional gastrointestinal disorders. Lactobacillus reuteri DSM 17938 in
particular would be effective against cryptosporidiosis due to the presence of both
microorganisms at duodenum of human. A recent study at icddr, b has shown this commonly used
probiotic appeared safe and well-accepted by Bangladeshi families. Lactobacillus reuteri has
been tested in clinical trials and has attained the "GRAS (generally regarded as safe)"
status for use in both children and adults and has additionally demonstrated immunomodulatory
activities. This probiotic is thus hypothesized to act as a beneficial supplement to the NTZ
treatment in cryptosporidiosis through a potential reduction in the gut inflammation
resulting from Cryptosporidium infection. Additionally, if the microbiota treatment promotes
parasite clearance and decrease the burden, it will be associated with faster disease
resolution and better clinical outcomes. Lactobacillus reuteri DSM 17938 has been reported to
inhibit the RORa/y activity to suppress Th17 cells, thus promoting an appropriate immune
response in improving the efficacy of the drug treatment. The Probiotic VSL#3 which contains
Lactobacillus reuteri DSM 17938 as well as other bacteria with anti-inflammatory activities
has been shown to reduce the severity of inflammatory diarrhea in animal models and has been
included as one of the treatment options for pouchitis by the British Society of
Gastroenterology. Investigator's goal in this study is to undertake an iterative approach to
improve and optimize the currently used most effective treatment regime against
cryptosporidiosis.
Experimental Design and Methodology:
The objectives of the study are to investigate 1) Determine the incidence of
Cryptosporidiosis 2) Assessment of the acquired immune response to Cryptosporidiosis and 3)
Analyze the human genes influencing susceptibility to Cryptosporidiosis. The proposed study
will utilize the field setting of the parent study. This proposed pilot study will help to
elucidate the effective treatment for cryptosporidiosis which will not only help the study
participants of the parent study, but also help other individuals with cryptosporidiosis from
similar settings. Later on the parent study findings will provide information which will help
to investigate host immune mechanism and permit the design of new strategies incorporating
host-directed therapies that could optimize an appropriate immune response improving the
efficacy of the NTZ with probiotics treatment.
Study products: Nitazoxanide will be purchased from local commercial Square pharmaceuticals
Ltd. and probiotics will be purchased from Bio Gaia a Swedish health care company.
Study details: This will be a randomized clinical trial to be conducted prospectively in a
pilot scale. The study will be conducted at Mirpur (Dhaka, Bangladesh) slum areas. The parent
organization maintains a field site for studies on cryptosporidiosis. This is an area with a
high incidence of both cryptosporidiosis and child malnutrition. Identified participants will
be screened by strict maintenance and following of the inclusion and exclusion criteria. The
study staff will take consent from the patient's legal guardian to enroll the child.
Investigators will screen 975 children presenting age 12 months to 36 months, of either sex
and having no history of antibiotic use in the last month before enrollment. The prevalence
of Cryptosporidium infection in the proposed age group in that community is approximately 8%.
Investigators will enroll 78 participants with cases of Cryptosporidiosis, diagnosed using
animmune assay from stool. Investigators will enroll both symptomatic and asymptomatic
children. Study physician will collect all the demographic, socioeconomic, anthropometric,
clinical and treatment information. A random number generator will be used to determine which
treatment group to which the child will be assigned. Stool and anthropometric information
will be collected from all groups onenrollment, on day 4 (day after NTZ treatment), on day 8
(day after Probiotics treatment), on day 90 (follow-up on 3 months) and on day 180 (follow-up
on 6 months). Rate of decrease of oocyst load by qPCR in stools at Days 4 and day 8 will be
tested.
Study Schedule: Complete study schedule details listed by study visit are described below.
Enrollment
- Taking of informed consent
- Anthropometric measurement
- Enrollment questionnaire
- Stool collection for immune assay of the detection of cryptosporidiosis and quantitative
PCR for the baseline parasites load
Start of Intervention (Day 1)
- Review of eligibility of enrollment
- Anthropometric measurement
- Start the intervention
Visit Day 2 and 3
- Administration of intervention
- Screening for adverse events
Visit Day 4
- Administration of intervention
- Screening for adverse events
- Stool collection for q PCR
Visit Day 5, 6 and 7
- Administration of intervention
- Screening for adverse events
Visit Day 8
- Screening for adverse events
- Stool collection for q PCR
Visit Day 20
- Screening for adverse events
- Stool collection for q PCR
Follow up visit day 90 and 180
- Anthropometric measurement
- Stool collection
Intervention:Child will be randomly selected to receive either the NTZ treatment for 3 days
with probiotics for 7days or the NTZ treatment for 3 days with placebo for 7days or to
receive the standard supportive care normally provided for Cryptosporidium infections. The
doses of NTZ will be twice a day for 3 days and L reuteri DSM 17938 will be 2×10^8 CFU will
be taken orally. Treatment group will receive 5 drops probiotic twice daily for a consecutive
7 days and placebo group will receive NTZ for 3 days without probiotic. The NTZ dosage will
be 5 ml every 12 hours with food. The NTZ oral suspension contain 100mg/5ml.
This drug NTZ and probiotics usually has no side effects. Prior study suggests no adverse
event or serious adverse event.
Expected drop-out: From previous experience the drop-out rate is very low. Investigator
considered 10% drop out in each group.
Sample size: This will be a pilot study with a total of 105 patients distributed equally
across the three above mentioned study arms. A sample size of N = 105 individuals (35 in each
of the groups) will be sufficient to detect a clinically important difference of the
proportion (at least) 24% between the groups, using a two-sided Z-test of the difference
between proportions with 80 % power and a 5 % level of significance and a precision of 0.10.
This 24 % difference represents the difference between the prevalence of 56% in the
NTZ+placebo group and 80 % in the NTZ+probiotics group. With consideration of 10% attrition
rate, the total sample size is 117 individual (39 in each group). Since this is a pilot study
and due to small funding, the precision value considered 0.10.
Data analysis plan: Database will be created after getting the lab test values. Data will be
analyzed using SPSS (version 16). Treatment efficacy will be measured in three groups. Nature
of data distribution will be checked whether it is normally distributed or not. Using two
sample mean test among group will be compared using parametric (t-test) or non-parametric
(Mann-Whitney test) where applicable. Investigator will be examined, if there is any
difference in cryptosporidium infection outcome of treatment with NTZ+placebo in comparison
NTZ+probiotics treatment in children and then paired parametric-test or paired non-parametric
test will be done depending on data distribution. Investigator will also examine the
treatment effectiveness in malnourished children. Multivariate logistic regression will be
performed to examine the effect of socioeconomic condition, nutrition and other clinical
conditions associated with different treatment on cryptosporidiosis.
