Subjects will receive a 1st intravenous dose of 4 mg/kg INM004 (Anti-Stx hyperimmune equine immunoglobulin F[ab']2 fragments) and a 2nd intravenous dose of 4 mg/kg of INM004. Each dose will be separated by 24 h (± 2 h).

Subjects will receive a 1st intravenous dose of 4 mg/kg INM004 (Anti-Stx hyperimmune equine immunoglobulin F[ab']2 fragments) and a 2nd intravenous dose of Placebo. Each dose will be separated by 24 h (± 2 h).

Subjects will receive a 1st intravenous dose of Placebo and a 2nd intravenous dose of Placebo. Each dose will be separated by 24 h (± 2 h).

In the case, the high treatment regime is selected, subjects will receive a 1st intravenous dose of 4 mg/kg INM004 and a 2nd intravenous dose of 4 mg/kg of INM004. Each dose will be separated by 24 h (± 2 h).
In the case, the low treatment regime is selected subjects will receive an intravenous dose of 4 mg/kg INM004

In the case, the high treatment regime is selected, subjects will receive a 1st intravenous dose of Placebo and a 2nd intravenous dose of Placebo, each dose separated by 24 h (± 2 h)
In the case, low treatment regime is selected subjects will receive a single intravenous dose of Placebo

Bloody Diarrhea

STEC, Unspecified

Hemolytic-Uremic Syndrome

Pediatric Kidney Disease

The IMP dose to be studied will be 4 mg of protein/kg of subject's weight. Each vial contains 25 mg protein/mL. Therefore, each subject must receive 0.16 mL/kg.
The IMP will be added to the 100 mL infusion bag of saline solution. Doses will be administered as an infusion at 2.0 mL/min over 50 min with an interval of 24 h between doses.

INM004

Placebo

Hospital Penna

Hospital Sor Maria Ludovica

Hospital Lucio Molas

Hospital Castro Rendon

Hospital Elizalde

Hospital Italiano de Buenos Aires

Hospital Orlando Alassia

Phase 2/3 Study to Evaluate PK, Safety & Efficacy of INM004 in STEC Positive Pediatric Patients for Prevention of HUS

A Double-blind, Placebo-controlled, Adaptive, Phase 2/3 Study to Evaluate the Pharmacokinetics, Safety, and Efficacy of INM004 in Pediatric Patients With Shiga Toxin-positive Bloody Diarrhea for Prevention of Hemolytic Uremic Syndrome

The primary endpoint is a binary (Y/N) endpoint defined as having confirmed HUS by week 4. This endpoint will be centrally adjudicated by a Clinical Endpoint Committee. This committee will classify all potential events into one of the following categories:
Confirmed HUS
Probable HUS
No HUS
The proportion of children with HUS by week 4 confirmed by central adjudication will be reported for each treatment arm (optimal dose of INM004 vs placebo).

Frequency of subjects with TEAEs will be summarized by treatment group providing the number of subjects with event, the proportion subjects with event and the number of events
The statistics above will also be provided for the following events:
Serious TEAEs
TEAEs leading to study withdrawal
Treatment related TEAEs
Serious and treatment related TEAEs
Severe TEAEs
TEAEs leading to death
treatment emergent adverse events of special interest (TEAESI)
treatment-emergent adverse events related to background disease (TEAEBD) The frequency of TEAEs will also be reported by System Organ Class (SOC), and will also be reported by severity and relationship to study drug.
AEs will be coded by Preferred Term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA) classification

the time to death will be calculated in order to assess overall survival,
The time to the first serious extrarenal events will be calculated (in days) for the following events:
Major neurological involvement
Cardiovascular involvement
Gastrointestinal involvement
Pancreatic involvement
Hepatic involvement

The time to long-term sequelae will be calculated for the following events:
Long-term renal sequelae
Neurological sequelae
Cardiovascular sequelae
Pancreatic sequelae
Gastrointestinal sequelae
Overall survival

Pharmacokinetic profile will be assessed by measuring serum INM004 concentration at different timepoints. Serum INM004 concentration will be followed by a specific ELISA. Concentration of INM004 will be plotted as a function of time and pharmacokinetic profile will be defined.

Length of the hospital stay will be calculated as the discharge date minus the admission date + 1 as collected in the HUS admission/ discharge forms .

The following resources, measured in duration of days, utilized during the entire hospitalization for HUS will be collected: peritoneal dialysis, hemodialysis, transfusions, antibiotics, erythropoietin, plasmapheresis, diuretics, frozen plasma, hypotensors, mechanical ventilation, insulin duration in the intensive care unit, duration in the general ward and abdominal surgery

For each subject hospitalized for HUS, the following binary (Y/N) variables will be created:
White blood cell (WBC) value > 20,000/mL
Hemoglobin (Hb) value > 10.8 g/dL
Sodium (Na) < 128 mEq/L
Neurological involvement

All E. coli strains isolated from patients will be Serotyped and genotyped. A correlation between a certain type of strain and the development of HUS will be investigated. Strains will be aggregated by serotype and/or genotype and a correlation between a specific combination and development of HUS will be explored.

Descriptive statistics will be produced for the values and the changes from baseline at each assessment time point by treatment arm.
The absolute frequency (n) and percentage (%) of subjects with clinically significant abnormalities by visit and at any post-baseline moment during the study will be reported by treatment arm.

Assessment of the immunogenicity of INM004 determined by the presence of anti-drug antibodies (ADA) in serum samples by a specific ELISA test. This will be evaluated at baseline and at day 30 post drug administration

A secondary binary endpoint defined as having either probable or confirmed HUS by week 4 will be defined using the CEC assessment.
A secondary qualitative endpoint defined as having either mild, moderate or severe HUS (probable or confirmed) by week 4 will be defined using the CEC assessment.

Inmunova S.A.

Exeltis

This study will be an adaptive seamless design (ASD) phase 2/3 investigation using an "inferentially seamless" platform.
Stage 1 In Stage 1, subjects will be randomly assigned to receive 1 of the 3 treatment regimens (high treatment regimen, low treatment regimen, or placebo) in a 1:1:1 ratio.
Review for Dose Selection The Data Monitoring Committee will conduct a blinded safety review at the end of Stage 1 to determine the best active dose based on safety.
Stage 2 Stage 2 is considered the efficacy portion of the study. The randomization ratio for subjects in Stage 2 will be 1:1 (active treatment regimen of INM004: placebo).
Interim Analysis The intent of the unblinded interim analysis is to demonstrate superiority of INM004 versus the placebo, based on 80% reduction in the incidence of HUS in the treated cohort to stop study due to overwhelming efficacy, or declare futility, or re-estimate sample.

A Double-blind, Placebo-controlled, IWRS based. access to unblinded interim results will be limited to the DMC and unblinded statistician

Patients in remifentanil group received an intravenous bolus injection of 2 mg/kg lidocaine followed by a continuous remifentanil infusion of 0,1 mcg/kg/min.

Patients in lidocaine group received an intravenous bolus injection of 2 mg/kg lidocaine followed by a continuous lidocaine infusion of 3 mg/kg/hr.

Patients in lidocaine group received an intravenous bolus injection of 50 mg/kg magnesium sulphate followed by a continuous magnesium sulphate infusion of 15 mg/kg/hr.

Patients received an intravenous bolus injection of 2 mg/kg lidocaine plus 50 mg/kg magnesium sulphate followed by a continuous lidocaine infusion of 3 mg/kg/hr plus 15 mg/kg/hr magnesium sulphate

Postoperative Pain

Patients in Remifentanil group received an intravenous bolus injection of 2 mg/kg lidocaine followed by a continuous remifentanil infusion of 0,1 mcg/kg/min.

Remifentanil infusion

Patients in Lidocaine group received an intravenous bolus injection of 2 mg/kg lidocaine followed by a continuous lidocaine infusion of 3 mg/kg/hr.

Lidocaine infusion

Patients in Magnesium group received an intravenous bolus injection of 50 mg/kg magnesium sulphate plus an intravenous bolus injection of 2 mg/kg lidocaine followed by a continuous magnesium sulphate infusion of 15 mg/kg/hr.

Magnesium sulphate infusion

Patients in Magnesium and Lidocaine group received an intravenous bolus injection of 2 mg/kg lidocaine plus 50 mg/kg magnesium sulphate followed by a continuous lidocaine infusion of 3 mg/kg/hr plus 15 mg/kg/hr magnesium sulphate

Magnesium sulphate and Lidocaine infusion

Hospital de Base do Distrito Federal

Effect of Infusion of Lidocaine, Magnesium and Remifentanil Perioperatively in Patients Undergoing Mastectomy

Effect of Intravenous Infusion of Lidocaine, Magnesium Sulphate and Remifentanil Perioperatively in Patients Undergoing Mastectomy: a Prospective, Randomized and Double-blind Study

Qualification of pain assessed by the amount of analgesics required postoperatively and the time to request them

Quantify pain by Visual Analogue Scale (VAS, ranging from 0 to 10 cm, zero being found when the patient is no pain and ten, with maximum or unbearable pain)

Verbal Rating Scale (VRS), consisting of a list of phrases (no pain, mild pain, moderate pain, intense pain, maximum pain)

amount of intravenous and inhalational anesthetics consumed during surgery

Intraoperative hemodynamic stability analysis through the incidence of tachycardia, hypertension, bradycardia, hypotension and consumed vasopressors

Incidence of adverse effects such as time of awakening, nausea, vomiting, pruritus, urinary retention, drowsiness

Fabricio Tavares Mendonca

MD, TSA

Hospital de Base

The investigators will evaluated the primary endpoint and secondary endpoints comparing with historical control, that is used tacrolimus/methotrexate as a GVHD prophylaxis after HLA-matched, related PBSCT.

Acute Leukemia in Remission

Myelodysplastic Syndromes

Leukemia, Myeloid, Chronic-Phase

Leukemia, Myeloid, Accelerated-Phase

Sirolimus will be administered as a 6-mg oral loading dose beginning on day -1, followed by 3 mg per day orally in a single morning dose with a target trough level of 5-12 ng/mL. Trough levels will be measured once a week. Sirolimus will be gradually tapered beginning at day +100, and eliminated by day +180, unless the patient required continued treatment for GVHD or experienced toxicity related to drugs.

Sirolimus

Tacrolimus will be administered beginning on day -1 at 0.05 mg/kg intravenously by continuous infusion every 24 hours, with a target serum level of 5 to 10 ng/mL. Tacrolimus dosing is converted to oral capsules prior to discharge. Trough levels will be measured once a week. Tacrolimus will be gradually tapered beginning at day +100, and eliminated by day +180, unless the patient required continued treatment for GVHD or experienced toxicity related to drugs.

Tacrolimus

Soonchunhyang University Bucheon Hospital

Sirolimus/Tacrolimus Combination After HLA Matched Related Peripheral Blood Stem Cell Transplants

Multicenter Trials to Evaluate the Efficacy and Toxicity of Sirolimus/Tacrolimus Combination as a GVHD Prophylaxis After HLA Matched Related PBSCT

Patients will be followed for 100 days post transplantation for evaluation of the primary endpoint (the incidence and severity of acute GVHD) and clinical data will be collected at 100 day after HSCT using case report form. Acute GVHD will be graded according to the consensus grading scale.

The time of engraftment is defined as the first of three consecutive days on which the absolute neutrophil counts exceed 0.5 X 10(9)/L and platelet count to 20 X 10(9)/L, respectively.

Acute GVHD will be graded according to the consensus grading scale.

All deaths without relapse or progression of underlying disease

It will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE v3.0).

The incidence and type of infectious complications

The incidence of venoocclusive disease of liver and syndrome of thrombotic microangiopathy.

thrombotic microangiopathies/nelabums

Phase 2/3 Study to Evaluate PK, Safety & Efficacy of INM004 in STEC Positive Pediatric Patients for Prevention of HUS

Effect of Infusion of Lidocaine, Magnesium and Remifentanil Perioperatively in Patients Undergoing Mastectomy

Sirolimus/Tacrolimus Combination After HLA Matched Related Peripheral Blood Stem Cell Transplants

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