Impact of Two Alternative Dosing Strategies for Trachoma Control in Niger

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Brief Title

Impact of Two Alternative Dosing Strategies for Trachoma Control in Niger

Official Title

Impact of Two Alternative Dosing Strategies for Trachoma Control in Niger

Brief Summary

      Trachoma is a disease of poverty, which in the hyperendemic areas affects all individuals by
      the time they are two years old. Active disease is concentrated in children and occurs
      sporadically in adults. Infection is more widespread. It is anticipated that 25% of the
      children will be blinded by this disease if they live to be 60 years of age. The blindness
      rates are higher in women, presumably because of their closer contact with children who can
      infect them and add to damage from infections the women had while young.

      This proposal is to better define how azithromycin in community-based treatment can be used
      to eliminate blinding trachoma. We will also take the opportunity to join these field studies
      with genetic epidemiologic studies to better understand the dynamic epidemiology of Chlamydia
      trachomatis infection in a trachoma endemic area. The empiric data generated from the
      treatment/follow-up studies, together with the information on sources and spread patterns
      from genetic epidemiology will be used to generate more robust models to guide future
      treatment/re-treatment protocols.

      We propose to conduct a randomized, community based trial in the Maradi region of Niger to
      test the hypothesis that two community wide azithromycin treatments, spaced one month apart,
      are significantly more effective in reducing ocular C. trachomatis infection and trachoma at
      one year compared to a single mass azithromycin treatment.
    

Detailed Description

      Population

      We will take advantage of the ongoing work in the ten villages currently being studied in
      Kornaka West. They have never had mass treatment with azithromycin, and the baseline trachoma
      and infection rates are greater than 20%. The final survey for that current study will occur
      in January, 2008. Within villages, we will use the updated complete village census lists
      generated in the January 2008 survey. The children for that survey were randomly selected
      from the baseline census to provide a sample of approximately 50-60 children in the village
      ages 0 to five years. They are now a cohort of children ages 2 to 7 years. We propose to add
      approximately 15 children ages 0-2 from the updated census list for a total of 65-70 children
      per village.

      Sample

      We propose to re-randomize the villages, stratified by baseline trachoma rates and former
      intervention, into treatment intervention (2 rounds of mass treatment) and control (one round
      of mass treatment) arms. The villages will be balanced by baseline trachoma rates and the
      original randomization to water and sanitation interventions. Within villages, we propose to
      use the same sample of children ages 2-7 years and add a random sample of 15 children ages 0
      to 2 years.

      It will also be important to determine the effect of the two mass drug administration arms on
      infection in adults, so we propose to randomly select one adult from each household where
      there is an index child. If the adult is out of the village at the time of the survey, then
      the next randomly assigned adult will be selected for the study.

      Statistical plan including sample size justification and interim data analysis

      We intend to analyze the data starting by determining comparability of sample children and
      adults in intervention and control villages. Village characteristics, household
      characteristics, and age and gender distributions will be compared by intervention and
      control status. Importantly, baseline assessment of trachoma, and C. trachomatis infection,
      will be used to assure comparability. Variables that differ will be used as potentially
      confounding factors. We will determine the change from baseline to one month and one year in
      the trachoma prevalence and prevalence of C. trachomatis in the sentinel sample, stratified
      by children and adults. We will compare the average prevalence in the intervention villages
      compared to the control villages, by way of preserving the unit of randomization. We will
      then use logistic regression models to predict trachoma/infection at each time point,
      adjusting for clustering within villages and other confounding factors. Coverage of mass
      treatment will also be included as a predictor of trachoma/infection.

      We use our sample of children to estimate power, as they are the risk group with highest
      rates of infection and trachoma. With our sample size of 350 children per group, we have 80%
      power (at α=0.5) to detect a 15% difference in decline in active trachoma or infection,
      assuming modest village level clustering.

      We will sample 140 subjects per village (70 children plus one randomly selected adult from
      the same household) for a total of 1400 subjects. Subjects will be sampled at baseline,
      one-month post-treatment, and at one-year post-treatment.

      Prior to the surveys, a training program will take place to accomplish the following
      objectives for the survey team:

        -  All persons who will be grading trachoma are standardized against a senior grader, with
           reliability of kappa=0.65 for TF and for TI, at least. Consistency across graders is
           essential so that differences are not attributable to grader variations. In any case,
           all graders must work in all villages, so that the effect of variation by grader does
           not confound the effect of variation by village.

        -  All persons who will be taking or assisting with laboratory specimens are trained in
           proper techniques for taking and storing specimens in the field.

        -  Proper completion of the survey form, "Examen Oculaire" for each child and adult in the
           sample, and the completion of the census list on treatment receipt for all persons in
           the village

      The Baseline survey for trachoma in the sample of children and adults will take place prior
      to any antibiotic intervention. The surveys will consist of the following steps:

        1. Prior to the survey in the village, a member of the team will alert the village
           leadership that the survey team is coming, that mass treatment for all members of the
           community, as part of the Niger Trachoma Control Program will be part of the survey.

        2. The day of the baseline survey, all members of the household will be asked to stay in
           their concession for the examination and mass treatment, which is done house to house.
           As they come, the name will be checked on the list of those in the sample survey, and
           those who are in need of treatment only. If the person in the house is part of the
           trachoma survey, a form is prepared and a single specimen label filled out for the
           examiner and the laboratory technician. The label consists of the type of visit
           (b=baseline, 1=one month, 2=one year) and the full study identification number of the
           sample person: (village number)-(concession number)-(person number). Thus, during the
           baseline survey, a person who lives in village number 2, in concession number A-034 and
           who is on the census list as person 16 would have a study identification number of
           02-A-034-16, and a label for the vial of B-02-A-034-16

        3. The trachoma grader will be everting the eyelids. Therefore, his fingers are the primary
           source of contamination for the laboratory specimen. He will change gloves between each
           exam (or wash his gloves with soap and water) between each child, even children in the
           same house and even if the child does not appear to have trachoma. This is because about
           20% of children without trachoma can still have infection with C. trachomatis
           (sub-clinical infection). The trachoma grader, wearing 2.5X loupes and using a torche
           (or in sunlight), will assess the trachoma status of the tarsal plate, using the WHO
           Simplified grading scheme. The assistant will first evert the right eyelid, grade the
           tarsal plate, then evert the left eyelid and grade the trachoma status of the tarsal
           plate. A scribe will record the trachoma assessment on the "Examen Oculaire" form.

        4. While the left eyelid is still everted, the laboratory technician, following careful
           procedures described in the training manual, will roll the swab three times across the
           tarsal plate to obtain a specimen. The swab must not touch anything other than the
           tarsal plate. The lab technician can also not touch anything other than the swab and the
           vial. Once the swab has been taken, it is inserted in an open NUC vial, broken off, and
           the NUC vial is closed. The sealed vial is labeled with a pre-printed label and placed
           in a cold box with ice packs while in the field. The scribe will record that the
           specimen has been taken, or any reason why it was not taken.

        5. At this point, the sample person is eligible for azithromycin, which is administered at
           20mg/kg. A height stick will be used to estimate dose. For children younger than 2
           months, topical tetracycline will be used for 4-6 weeks. The form is reviewed for
           completeness, and stored safely for eventual data entry. Please note: The first
           azithromycin treatment in each study arm is administered as part of Niger's trachoma
           control program; only the second azithromycin treatment is provided to Arm 2 as part of
           the experimental protocol

        6. The concession is then checked to see if all members of the sample have been examined
           and a swab obtained. If so, the remainder of the concession is treated with azithromycin
           in accordance with program guidelines.

        7. The second treatment team assigned to the village will be providing azithromycin
           treatment to households who do NOT have anyone in the sample, in order to expedite
           treatment of the entire village.

        8. At the end of each day in the field, all specimens are transferred to a freezer in World
           Vision in Maradi, awaiting return to the freezer in Niamey. During the drive to Niamey,
           specimens must be kept frozen as well, with ice packs.

        9. The data entry clerk will enter the survey form into the "baseline" database if the
           survey is the baseline survey, or the "one month" or "one year" database, depending on
           the follow-up survey. The data entry clerk will also enter the data on those who
           received treatment at baseline, and at two months into the treatment data base.

      The same sample of children and adults will be surveyed for trachoma and infection at one
      month post the last treatment, and at one year. No additional persons will be added to the
      sample to replace any who have died or moved away, as we will not have baseline data for any
      replacements. The procedures for the one month and one year follow up surveys are exactly the
      same as for the baseline survey, except the following: the laboratory label is changed from a
      "B" to a "1" or a "2" as the first part of the label, and the survey forms are entered into
      the one month or one year data bases.

      All positive specimens will have the major outer membrane gene amplified and sequenced. The
      genovars will be mapped for location within villages and families and then their distribution
      will be followed over time, after treatment to provide a better understanding of the
      epidemiology of the infection. Results of the study will be used as data input for the
      generation of mathematical models to predict whether community-wide retreatment (or alternate
      strategies) will be needed, and the optimal timing for such retreatment.
    

Study Phase

Phase 4

Study Type

Interventional


Primary Outcome

Infection With Chlamydia Trachomatis Diagnosed by Use of NAATs [Nucleic Acid Amplification Test]


Condition

Trachoma

Intervention

Azithromcyin

Study Arms / Comparison Groups

 Arm 2
Description:  Subjects residing in villages assigned to treatment arm 2 will receive a clinical evaluation for trachoma and provide a swab specimen of conjunctivae of the R eye at enrollment (Day 0), as well as receive an initial treatment with 1 gm oral dose of Azithromycin; receive a second 1 gm oral dose of Azithromycin at Day 30; be re-screened (clinical evaluation and swab specimen of R eye collected) at Day 60 and Day 360.

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

1139

Start Date

January 2008

Completion Date

August 2009

Primary Completion Date

May 2009

Eligibility Criteria

        Subjects live in a village in Niger that exhibits a high prevalence of clinically active
        trachoma (>15%) amongst the children living in that village. This prevalence of clinical
        disease is a marker for much higher infection rates, thus justifying community wide
        treatment.

        Inclusion Criteria:

          -  To be eligible to participate in this study the subject must live in one of the
             villages selected for this study.

        Exclusion Criteria:

          -  All subjects meeting any of the exclusion criteria will be excluded from study
             participation. Exclusion criteria include:

               -  history of allergy to ANY macrolide antibiotic

               -  severe nausea or diarrhea after the first dose of azithromycin

               -  inability to tolerate oral therapy

               -  pre-existing serious illness
      

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Julius Schachter, PhD, , 

Location Countries

Niger

Location Countries

Niger

Administrative Informations


NCT ID

NCT00618449

Organization ID

H1079-31932

Secondary IDs

5R01AI048789

Responsible Party

Sponsor

Study Sponsor

University of California, San Francisco

Collaborators

 National Institute of Allergy and Infectious Diseases (NIAID)

Study Sponsor

Julius Schachter, PhD, Principal Investigator, University of California, San Francisco


Verification Date

April 2012