Oral Rehydration Solution With Zinc and Prebiotics in Acute Diarrhea
Condition: Diarrhea
MeSH terms: Diarrhea
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Hypotonic oral rehydration solutions (ORS) containing zinc and/or prebiotics have been
      proposed for the treatment of pediatric acute diarrhea but conclusive clinical data about
      their effect are scanty, especially for children living in developed countries. The
      investigators aim to evaluate the efficacy of a new hypotonic ORS containing zinc and
      prebiotics in children with acute diarrhea.
    

Detailed description: 
      Study Design and Funding Prospective, randomized controlled trial in collaboration with
      family pediatricians, who care for children up to 14 years of age in the Italian Public
      Health System. The study protocol was illustrated and discussed during 3 meetings. The
      research is not funded by any pharmaceutical company and all the authors declared no conflict
      of interest. The study protocol was reviewed and approved by the Ethics Committee of the
      University Federico II of Naples.

      Participants Children 3-36 months old seen in the pediatrician offices from November 2007 to
      March 2008 presenting acute diarrhea lasting less than 48 h are considered eligible for the
      study. Exclusion criteria are: diarrhea lasting more than 48 h, malnutrition as judged by a
      body weight/height ratio below the 5th percentile, clinical signs of severe dehydration,
      clinical signs of a coexisting severe acute systemic illness (meningitis, sepsis, pneumonia),
      immunodeficiency, underlying severe chronic disease, malnutrition, cystic fibrosis, food
      allergy or other chronic gastrointestinal diseases, use of pre/probiotics in the previous 3
      weeks, use of antibiotics or any antidiarrheal medication in the previous 3 weeks.

      Acute diarrhea is defined as a decrease in the consistency of stools (loose or liquid) and/or
      an increase of frequency of evacuations (3 or >3 in 24 h), with or without fever or vomiting.
      Informed consent is obtained from the parents of all enrolled children. Microbiologic and
      other laboratory investigations performed only if required for specific clinical reasons.

      Intervention Enrolled patients are randomly allocated to standard hypotonic ORS (group 1) or
      to super-hypotonic ORS containing zinc and prebiotics (group 2). We used two commercial ORS
      ORS preparations available on the market as sachets with similar cost and packaging. The
      composition of the two ORSs is reported in Table 1.

      Randomization and Blinding Patients are allocated to each group according to a
      computer-generated randomization list. The researchers responsible for enrolling patients
      allocate the next available number upon entry into the trial. The parents are instructed to
      rehydrate orally their children with 30-50 ml/kg of ORS in 3-4 h for mild dehydration and
      with 50-100 ml/kg of ORS in 3-4 h for moderate dehydration, and to administer 10 ml/kg/die of
      ORS in a graduated glass or bottle for dehydration prevention until cessation of symptoms.
      Three to four hours after, children are fed with a normal appropriate-for-age diet including
      full strength lactose-containing formula or cow's milk.Treatment allocation is concealed to
      maintain the single-blind status. Upon enrolment, the patient's parent receive the envelope
      containing a written prescription of the name of the ORS product and instructions about how
      it should be administered. To circumvent the problems in performing a double-blind study on
      commercially available products in a large population, we use the third-part blind observer
      method to assess the efficacy of the ORS preparations. To ensure unbiased efficacy
      assessment, the investigators collecting the reporting forms completed by the parent are
      blind to the patient's treatment assignment, whereas the family pediatricians in charge of
      treatment allocation are excluded from efficacy assessment. The reporting forms are sent to
      the coordinating centre at the Department of Pediatrics for analysis. We previously used this
      procedure in a study of 5 probiotic preparations in children affected by acute diarrhea
      (Berni Canani R et al. BMJ 2007;335-340). Upon enrollment, patients undergo a physical
      examination and clinical history taking to identify the patient, to determine the duration
      and severity of diarrhea, to assess associated clinical features (fever, vomiting and
      dehydration) and to establish nutritional status and previous therapy. The parents of
      enrolled children are instructed to record daily on a specific form: i) the number of fecal
      outputs and their consistency; ii) the amount of daily ORS assumed by the child; and iii)
      possible adverse events. We also record the number of the parent's missed work days, the
      number of hospital admissions in each group, the use of other medications.

      Outcome measures The primary outcome of the study is the rate of resolution of diarrhea 72 h
      after starting oral rehydration therapy. We selected this time point because of a study
      indicated that the risk of dehydration was highest during this period and that zinc is able
      to reduce diarrhea after 72 h of treatment. The latter finding was recently confirmed in a
      Cochrane meta-analysis.

      Diarrhea is considered stopped after a patient had passed the last abnormal (loose or liquid)
      stools preceding a normal stool output, as applied in a previous study. Secondary outcome
      measures are the total amount of ORS intake in the first 24 h, the number of missed work days
      of the parent, the number of hospital admissions in each group, and the use of other
      medications. Safety was also investigated.

      Sample size Fifty-seven patients in each group are required to obtain a power of the study =
      80%, type 1 error = 0.05, 2-tailed test considering a difference of 25% (75% vs 50%) in the
      rate of resolution of diarrhea at 72 h between the study groups. This estimation is based on
      our preliminary data and on previous results obtained in children with acute diarrhea treated
      with zinc. We decide to enroll 65 patients per group considering a possible drop out up to
      15%.

      Statistical analysis Statistical analysis is performed by a statistician blind to individual
      ORS preparations received by children in the two groups. Continuous variables are expressed
      as means ± standard deviation (SD). For categorical variables, the Pearson chi-square test is
      performed. The two groups are compared for continuous variables by t-test for equality of
      means. After checking for assumptions, linear regression analysis with stepwise method is
      used to study the effect of different variables (age, sex, body weight, duration of symptoms
      before enrollment) on the presence of diarrhea after 72 h of treatment. Analyses are
      conducted on an intention-to-treat and per-protocol basis. All tests of significance are
      two-sided. A p value of less than 0.05 is considered significant. The statistical analysis is
      performed using the SPSS software package for Windows (release 16.0.0; SPSS Inc., Chicago,
      IL, USA) and Starts Direct (release 2.6.6).

      Table 1. Composition of the two ORSs compared in the study

      Standard ORS Super ORS Commercial brand name Reidrax® Prereid® Assigned group Group 1 Group 2
      Osmolarity (mOsm/L) 225 200 Na+ (mmol/L) 60 50 K+ (mmol/L) 20 20 Cl- (mmol/L) 60 40 Glucose
      (mmol/L) 75 77 Citrate (mmol/L) 10 10 Zn2+ (mmol/L) 0 1 Fructooligosaccharides (g/L) 0 0.35
      xylooligosaccharides (g/L) 0 0.35
    

Intervention name(s): hypotonic oral rehydration solution; Hypotonic oral rehydration solution with Zn and prebiotics
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): 30-50 ml/kg of ORS in 3-4 h for mild dehydration and with 50-100 ml/kg of ORS in 3-4 h for moderate dehydration, and to administer 10 ml/kg/die of ORS in a graduated glass or bottle for dehydration prevention until cessation of symptoms.; 30-50 ml/kg of ORS in 3-4 h for mild dehydration and with 50-100 ml/kg of ORS in 3-4 h for moderate dehydration, and to administer 10 ml/kg/die of ORS in a graduated glass or bottle for dehydration prevention until cessation of symptoms.
Other intervention name(s): REIDRAX; PREREID
Intervention MeSH terms: Pharmaceutical Solutions
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: acute gastroenteritis; intestinal infection; intestinal fluid secretion; intestinal microflora; treatment of childhood acute diarrhea