Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

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Article Reviewed:

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Effect of an oral Shiga toxin-binding agent on diarrhea-associated hemolytic uremic syndrome in children: a randomized controlled trial.

Trachtman H, Cnaan A, Christen E, et al.

JAMA. 2003;290(10):1337-44. [abstract]

Reviewed by K. Alex Daneshmand DO and Ronald C. Sanders MD, Pediatric Intensive Care, University of Florida, Gainesville, Florida

Review posted September 8, 2004

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I. What is being studied?:

The study objective:

To determine if administration of an oral agent that binds Shiga toxin could diminish the severity of diarrhea-associated HUS in pediatric patients.

The study design:

Multicenter randomized, double-blind, placebo controlled trial

The patients included:

145 children (96 experimental and 49 placebo) aged 6 months to 18 years with diarrhea-associated HUS conducted between July 27, 1997, and April 14, 2001, at 26 tertiary care pediatric nephrology centers in the United States and Canada. The trial included 2 phases, the hospital course for treatment of the acute illness and a 60-day outpatient follow-up period after discharge from the hospital.

Children were diagnosed with HUS if they fulfilled all 4 criteria:

1. Platelet count of less than 140 X 10³/uL
2. Fragmentation of erythrocytes on a peripheral smear (> 5 per high-powered field)
3. Renal injury as indicated by the presence of hematuria (> 1+ by dipstick analysis) and/or proteinuria (> 1+ by dipstick analysis) and/or azotemia (serum creatinine concentration, > 95th percentile for age and sex)
4. A diarrhea illness within 7 days before the identification of HUS

The patients excluded:

Patients not eligible for the study included:

1. An atypical or non-diarrhea prodrome
2. Familial history of hereditary HUS
3. HUS associated with bone marrow transplantation
4. Pneumococcal infection
5. Human immunodeficiency virus infection
6. Preexisting renal disease
7. Preexisting structural or motility disorder of the gastrointestinal tract.

The interventions compared:

Patients were assigned to receive the binding agent SYNSORB Pk (SYNSORB Biotech Inc., Calgary, Alberta) 500 mg/kg daily, or cornmeal placebo orally for 7 days in a 2:1 randomization scheme.

The outcomes evaluated:

There were two end points examined by this study. The primary outcome was to determine whether treatment with the oral binding agents reduces the combined frequency of death or serious extrarenal events and need for dialysis in the experimental vs placebo group. The secondary outcome compared variability between the selected group in transfusion of red blood cells or platelets, time of normalization of platelet count, and the number of patients with hypertension, proteinuria, or a GFR of less than 90 mL/min per 1.73 m2 at the 60-day follow-up visit.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Patient assignment was randomized. This randomization was stratified by site. The assigned group receive binding agent to placebo group in a ratio of 2 to 1 in blocks of 3 patients at each center. Authors' explanation for this was to maximize safety information on the agents while maintaining a blinded randomized design.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete?

Yes. Patients were followed up for the duration of the treatment of the acute illness while hospitalized and 6 days after discharge. All patients entered the trial were properly accounted for and attributed at its conclusion. 44 eligible children were not included because 37 of them declined and 7 others were not offered participation. The authors do not give a specific reason for 7 patients who were not offered participation.

The trial was stopped after 45 months by the data and safety monitoring board because of lack of efficacy on both primary outcome variables.

Were patients analyzed in the groups to which they were randomized?

Yes. A modified intention-to-treat analysis was used. They did not analyze 4 patients in the treatment group and 1 patient in the control group who received ≤ 1 dose of study agent.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

Yes. Both investigators and patients were blinded to study medication.

4. Were the groups similar at the start of the trial?

Yes. There were no significant differences between placebo and binding agent group in patients including laboratory and clinical characteristics. The number of patients enrolled varied between 1 and 13 per site; 13 centers (50%) enrolled no more than 5 patients each. All demographic variables including sex and age along with platelet, white blood cell counts at entry, were comparable at all sites enrolling more than 5 patients.

5. Aside from the experimental intervention, were the groups treated equally?

Authors state that all other aspects of care were left to the discretion of the nephrologists. Specific data was not provided regarding patient management such as fluid therapy, nutrition, antibiotic administration.

III. What were the results?

1. How large was the treatment effect?

During the 7 day treatment period, nearly 75% of all doses were successfully given to the patients. The success rate of medication administration was comparable for the binding agents and placebo.

The prevalence of death or serious extrarenal events was similar in the 2 groups: 18% and 20% in binding agents and placebo-treated groups, respectively (P = 0.82), Relative Risk of 0.87 with 95% CI (0.43, 1.75). There were 3 deaths in the binding agent-treated group and 1 in the placebo-treated group.

The mean duration of dialysis was 5.2 vs 3.6 days in the binding agent and placebo treated groups, respectively (P = 0.59). The overall rate of serious extrarenal events were lower in centers with more than 5 patients enrolled compared with centers with 5 or fewer patients (P = 0.10). However, to truly demonstrate a difference between the different centers according to authors, the study needed 548 children (i.e., 365 randomized to receive the binding agents and 183 assigned to placebo).

Secondary outcome variables did not differ between the two groups. Specifically, 76 (79%) of 96 in the binding agents-treated group vs 39 (80%) of 49 in the placebo-treated group required transfusion of packed red blood cells or platelets. For the outcome variables in the treated group vs. control group therefore the RR is 1.0 (95% CI 0.84, 1.12). The median duration of hospital stay (8 days) was similar in the 2 groups.

The study shows that binding agent was overall ineffective in reduction of primary outcome defined as central nervous system or cardiovascular complication compared with all the other extrarenal complication (P = 0.49).

2. How precise was the estimate of the treatment effect?

The primary outcome of whether treatment with the oral binding agent reduces the combined frequency of death and serious extrarenal events including lowering the need for dialysis required a sample size of 174 patients to show 5% reduction in the primary end point to be statistically significant. This was calculated by the authors based on review of literature that the first primary outcome variables to be predicated at 20%.

Authors enrolled 150 patients into this study. The required sample size set by the authors was not reached because the study was stopped by the data and safety monitoring board due to lack of efficacy. For the primary analysis, The Relative Risk of an adverse outcome in the treated vs. controls was 0.9, with 95% CI (0.4, 1.8). Therefore, there was no statistical difference exist.

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

Yes. This study was a well design multicenter, randomized, double-blind, placebo, controlled clinical trial that examined whether oral therapy with Shiga toxin-binding agent can diminish or eradicate diarrhea associated HUS. The study patients appeared in this study represents a good cross section of hospitalized children with diarrhea-associated HUS. Many patients with HUS require supportive therapy with meticulous attention to fluid and electrolyte management. However, some patients may not respond to the above treatment.

Fresh-frozen plasma administration in previous studies has not reduced the relapse rate of HUS (1). Plasma infusion and exchange results have been mixed to treat this disease (2). Therefore, having a specific oral binding agent that can decrease the course of HUS is another plausible treatment option in this complex disease. This study demonstrates that SYNSORB PK which specifically prevents Shiga toxin from binding to endothelial cell membrane within the gastrointestinal tract does not work in the clinical setting. Therefore, we continue to await the trial of other treatment measures such as monoclonal antibodies that potentially can inhibit the action of circulating Shiga toxin (3).

2. Were all clinically important outcomes considered?

Yes. Authors have looked at two major outcomes in this study. However, other outcomes such as long term renal function or PRISM III score along with duration of hypertension were not considered in this study.

3. Are the likely treatment benefits worth the potential harms and costs?

The study did not show that SYNSORB Pk was effective in treatment of diarrhea-associated HUS. Therefore there is no benefit in administrating a drug that does not affect the clinical course of this disease.

References:

1. Warwicker P, Donne RL, Gooship JA, et al. Familial relapsing haemolytic uraemic syndrome and complement factor H deficiency. Nephrol Dial Transplant 1999; 14:1229-33. [abstract]
2. Misiani R, Appiani AC, Edefonti A, et al. Haemolytic uraemic syndrome: therapeutic effect of plasma infusion. Br. Med J. (Clin Res Ed) 1982; 285:1304-6. [abstract]
3. Kimura T, Co MS, Vasquez M, et al. Development of humanized monoclonal antibody TMA-15 which neutralized Shiga toxin 2. Hybrid Hybridomics. 2002; 21:161-168. [abstract]

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