+--------------------+-------------------------------------------------+
| **Summary of       | We will conduct prospective surveillance for    |
| Project:**         | diarrheal diseases at ICDDR,B's Matlab hospital |
|                    | and perform microbiologic tests to define       |
|                    | etiology of diarrheal disease in children       |
|                    | \<5years old as a component of a prospective,   |
|                    | double-blind, randomized evaluation in Matlab   |
|                    | of the efficacy of RIX4414 (GSK) rotavirus      |
|                    | vaccine. This is consistent with the primary    |
|                    | objective of the trial to evaluate the efficacy |
|                    | of vaccination on severe diarrhea (requiring    |
|                    | hospitalization). We are requesting support     |
|                    | from NVPO unmet needs for this component of the |
|                    | trial.                                          |
|                    |                                                 |
|                    | We will perform active surveillance (via home   |
|                    | visits) for diarrheal disease (and rotavirus    |
|                    | specific diarrheal disease) on a 10% subsample  |
|                    | of study participants of the vaccine trial to   |
|                    | provide the basis for evaluation of impact of   |
|                    | vaccination on overall diarrheal incidence.     |
|                    |                                                 |
|                    | We will continue surveillance for               |
|                    | intussusception implemented with NVPO funding   |
|                    | before the trial at the 3 hospitals serving     |
|                    | Matlab, all 7 District Health Centers and       |
|                    | private clinics serving people living in the    |
|                    | Matlab area. Prospective surveillance for       |
|                    | intussusception will include clinical and       |
|                    | radiographic (ultrasound) approaches, followed  |
|                    | by transfer of patients meeting a case          |
|                    | definition for intussusception to a tertiary    |
|                    | care facility for management. This process is   |
|                    | needed to ensure that the phase III trial fully |
|                    | assesses this safety concern.                   |
+--------------------+-------------------------------------------------+
| **Specific Aims:** | 1\. Carry out comprehensive surveillance to     |
|                    | document potentially severe cases (reaching     |
|                    | hospital) of diarrheal disease and              |
|                    | rotavirus-documented diarrheal disease as a     |
|                    | component for evaluation of the efficacy of     |
|                    | RIX4414 rotavirus vaccine within a prospective, |
|                    | randomized, double-blinded trial..              |
|                    |                                                 |
|                    | 2\. Document incidence of non-severe diarrhea   |
|                    | (via home visits) on an approximate 10% sample  |
|                    | of participants in the rotavirus vaccine        |
|                    | efficacy trial.                                 |
|                    |                                                 |
|                    | 3\. Enhance capacity for rapid detection of     |
|                    | potential cases of IS, diagnostic confirmation, |
|                    | and non-surgical and surgical management of IS  |
|                    | among participants of the rotavirus vaccine     |
|                    | efficacy trial                                  |
+--------------------+-------------------------------------------------+
| **Statement of the | Rotavirus is the leading cause for diarrhea     |
| Problem:**         | morbidity and mortality among children in       |
|                    | developing countries. Vaccination holds the key |
|                    | to reducing disease burden. A licensed vaccine  |
|                    | against rotavirus, while effective was removed  |
|                    | from use after it was found to be associated    |
|                    | with intussception. A new vaccine, a human      |
|                    | derived vaccine, based on the G1 serotype (RIX  |
|                    | 4414 from Glaxo Smith Kline), has shown promise |
|                    | in clinical trials to date. Evaluation of this  |
|                    | vaccine is proceeding first in developing       |
|                    | countries (before evaluation in developed       |
|                    | countries) where the benefits of vaccination    |
|                    | (in terms of disease and mortality prevention)  |
|                    | can be directly considered in the context of    |
|                    | any risks identified. Existing data suggest     |
|                    | that infection with a single serotype of        |
|                    | rotavirus results in heterologous protection    |
|                    | (especially against severe disease) against     |
|                    | infection due to other serotypes.               |
|                    |                                                 |
|                    | Phase II trials in Bangladesh, supported in     |
|                    | part with NVPO unmet needs funding, have been   |
|                    | completed and will now be followed by a phase   |
|                    | III trial. The phase II trials included a total |
|                    | of 430 children (90 toddlers and 340 infants).  |
|                    | No increase in adverse events were identified   |
|                    | among children participating. While             |
|                    | immunogenicity data from the trial in infants   |
|                    | are pending, data from other sites show that    |
|                    | the vaccine is immunogenic. The phase III trial |
|                    | will be a prospective, blinded, randomized      |
|                    | trial which will assess the efficacy of the     |
|                    | vaccine against severe diarrhea and             |
|                    | rotavirus-specific severe diarrhea (requiring   |
|                    | hospitalization and using a validated diarrhea  |
|                    | severity score) and non-severe diarrhea, as     |
|                    | well as assessing the adverse event profile,    |
|                    | including whether there is any observable       |
|                    | association with intussusception. This          |
|                    | component will also help to ensure protection   |
|                    | of human subjects during the trial---it will    |
|                    | include methods for rapid transfer of patients  |
|                    | suspected to have intussusception to a          |
|                    | pediatric hospital in Dhaka where a surgeon     |
|                    | experienced in intussusception management will  |
|                    | be on call and available.                       |
+--------------------+-------------------------------------------------+
| **Background:**    | Rotavirus is responsible for an estimated       |
|                    | 600,000 deaths in children globally; 40% of all |
|                    | hospitalizations of children \<5 years old are  |
|                    | due to rotavirus in Bangladesh. Because         |
|                    | rotavirus is transmitted through interpersonal  |
|                    | contact, improved water sanitation will not     |
|                    | impact this disease---vaccination holds the key |
|                    | to reducing disease burden. Hopes were high for |
|                    | dramatic global health impact when rhesus       |
|                    | rotavirus vaccine, Rotashield, was licensed in  |
|                    | the United States in 1998; however, hopes were  |
|                    | deferred when the vaccine was found to be       |
|                    | highly linked to intussusception (IS). While    |
|                    | the risks were relatively low, the seriousness  |
|                    | of the adverse events created an unacceptable   |
|                    | balance between risk and benefits for use of    |
|                    | the vaccine in the United States.               |
|                    |                                                 |
|                    | In developing countries, the rates of severe    |
|                    | disease and death from rotavirus results in     |
|                    | different risk versus benefit considerations.   |
|                    | At ICDDR,B, rotavirus accounts for about 40% of |
|                    | diarrheal illnesses in patients \<5 years old,  |
|                    | as determined by surveillance at both the Dhaka |
|                    | and Matlab hospitals. Deaths due to rotavirus   |
|                    | in these settings are extremely rare because    |
|                    | rehydration is provided; however, in many areas |
|                    | of Bangladesh, adequate treatment may not be    |
|                    | given, resulting in an estimated 20,000         |
|                    | rotavirus deaths annually (Unicomb et al.,      |
|                    | 1997). Rotavirus is common among children \<2   |
|                    | years old. About one-third of infants \<6       |
|                    | months old and 41% of children \<2 years old,   |
|                    | admitted to the Dhaka hospital with diarrhea    |
|                    | had rotavirus. Since most severe infections     |
|                    | occur between the ages of 4 months and 2 years  |
|                    | of age, it would be ideal to use and effective  |
|                    | rotavirus vaccine early in life with completion |
|                    | of immunization series by 6 months.             |
|                    |                                                 |
|                    | We have been evaluating in Bangladesh (in a     |
|                    | phase I and phase II trial completed recently   |
|                    | according to strict GCP), the first involving   |
|                    | 90 toddlers and the second involving 340        |
|                    | infants) RIX 4414, a G1 serotype rotavirus      |
|                    | vaccine, developed by Glaxo Smith Kline, which  |
|                    | thus far, has been immunogenic with cross       |
|                    | protection against severe heterologous          |
|                    | rotavirus disease (i.e. rotavirus illness       |
|                    | caused by other serotypes). Given that the      |
|                    | serotype distribution of rotavirus strains is   |
|                    | quite diverse in Bangladesh, capacity for       |
|                    | heterologous protection will be crucial for the |
|                    | success of this vaccine candidate.              |
|                    |                                                 |
|                    | The primary objective of the phase III trial    |
|                    | will be to evaluate the ability of RIX 4414 to  |
|                    | prevent severe rotavirus diarrhea (regardless   |
|                    | of serotype) and overall diarrhea rates (some   |
|                    | diarrheal disease may be due to undetectable    |
|                    | rotavirus). We will assess the efficacy of the  |
|                    | vaccine in children infected with different     |
|                    | strains of rotavirus, in different seasons, for |
|                    | different levels of severity and at different   |
|                    | times post vaccination. Importantly, the trial  |
|                    | will also monitor for safety and will in        |
|                    | particular be designed to be able to detect     |
|                    | intussusception occurring among study           |
|                    | participants..                                  |
+--------------------+-------------------------------------------------+
|                    |                                                 |
+--------------------+-------------------------------------------------+

+-----------+----------------------------------------------------------+
| **Study   | The study will be conducted within the Maternal Child    |
| Desig     | Health-Family Planning intervention area in Matlab over  |
| n/Plan:** | a 2 and half year period. All children born during the   |
|           | first year of the study period will be eligible          |
|           | (approximately 2600 children Participating children will |
|           | receive either rotavirus vaccine or an identically       |
|           | appearing oral placebo. Infants will be vaccinated with  |
|           | 3 doses at 6-8, 10-12, and 14-16 weeks of age, each dose |
|           | separated by 21-48 days from the other dose at the same  |
|           | time as visits for other routine EPI vaccinations. The   |
|           | study will follow strict Good Clinical Practices (GCP).  |
|           |                                                          |
|           | Episodes of severe diarrhea will be recorded when        |
|           | children appear at the Matlab Hospital or at one of the  |
|           | community treatment centers for treatment. Study         |
|           | personnel will record symptoms and clinical history, and |
|           | collect a fecal specimen to screen for rotavirus.        |
|           | Vaccine efficacy will be assessed by comparing rates of  |
|           | hospitalization and clinic visits for rotavirus          |
|           | diarrhea.                                                |
|           |                                                          |
|           | NVPO unmet needs funding will be used to implement       |
|           | surveillance. The main outcome event will be             |
|           | hospitalizations for rotavirus diarrhea detected by      |
|           | passive surveillance among children \<2 years old        |
|           | presenting with diarrhea to Matlab Hospital or Nayergaon |
|           | treatment centre. These children will have a stool       |
|           | specimen collected and be tested for rotavirus by EIA    |
|           | and for Vibrios, *Salmonella*. *Shigella* and            |
|           | Enterotoxigenic *E.coli* in order to detect mixed        |
|           | infections. A Diarrhea Treatment Record will be          |
|           | completed for all patients according to standard         |
|           | hospital format containing information on length of      |
|           | illness, dehydration status, associated symptoms,        |
|           | outcome of illness and lab results\-- these forms will   |
|           | be collected by the study coordinator for data entry.    |
|           | Rotavirus diarrhea will be defined as any episode in     |
|           | which a child 1) receives treatment for diarrhea at a    |
|           | surveillance site and 2) has a stool specimen that tests |
|           | positive for rotavirus by EIA.                           |
|           |                                                          |
|           | In addition, as part of routine surveillance the         |
|           | community health research worker will visit each child   |
|           | monthly. During their visit the CHRW will record if a    |
|           | child has a diarrheal episode on the day of visit and    |
|           | information about treatment. Specimens will be taken and |
|           | sent to Matlab laboratory for testing and preservation.  |
|           |                                                          |
|           | We will continue prospective surveillance (initiated     |
|           | with NVPO support) for intussusception. Field research   |
|           | assistants (FRAs) will visit homes on a monthly basis    |
|           | and ask whether children \<5 years of age have           |
|           | experienced symptoms consistent with IS (based on        |
|           | Brighton criteria). FRAs will encourage parents to bring |
|           | children to Upazilla Health Centres (UHC) or the         |
|           | hospital should their child develop relevant symptoms.   |
|           | Staff at the UHCs are trained to recognize possible      |
|           | intussusception and to refer, to the hospital where we   |
|           | provide and train medical officers on diagnosis and      |
|           | management. Ultrasound equipment is provided to the      |
|           | hospital and hospital staff are trained on               |
|           | ultrasonographic technique, in particular the            |
|           | recognition of intussusception. All cases of             |
|           | intussusception are transferred rapidly to Shishu        |
|           | Hospital in Dhaka where staff are experienced with       |
|           | successful surgical and non-surgical management of IS.   |
|           | Epidemiologic information and diagnostic specimens will  |
|           | be obtained from all suspected cases of IS.              |
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