A Phase II Study to Assess Safety, Efficacy, and Pharmacokinetics of INM004 (Anti-Shiga Toxin) in Pediatric Patients With Hemolytic Uremic Syndrome Associated With Shiga Toxin-producing Escherichia Coli Infection
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 57
- 试验地点
- 16
- 主要终点
- Days of dialysis
研究概览
简要总结
Hemolytic Uremic Syndrome (HUS) is a foodborne disease which mainly affects children. It is caused by Escherichia coli bacteria, which release a toxin called Shiga toxin within the body. This infectious form of HUS, defined as STEC-HUS, can cause sporadic cases or outbreaks, as observed in different countries. Argentina has the highest incidence of STEC-HUS worldwide. The disease is endemic, representing approximately 95% of all HUS cases nationwide.
STEC-HUS generally begins with diarrhea (with or without blood), and can also cause fever, abdominal pain, and cramps. Then the child may have pallor, altered consciousness, decreased urine output, seizures, and other symptoms. Although death is uncommon (it occurs in 2-4% of cases), it is a very serious disease that mainly affects the kidneys, and also other organs such as the brain. About half of children need to undergo a risky procedure such as dialysis (due to malfunctioning kidneys); and most of them also receive blood transfusions.
Around 30% of the patients are left with lifelong consequences that can range from permanent kidney damage to the need for a transplant.
So far there is no drug, antibiotic or vaccine to prevent or treat HUS. Current treatment protocols include hospitalization for all patients with HUS, and supportive therapy such as hydration and salt intake. Support therapy is not a specific treatment, but rather helps the body better defend itself against the disease.
The purpose of this study is to establish whether it is safe and effective to treat patients who are diagnosed with STEC-HUS, with INM004 (study drug). INM004 is an investigational product "Fraction F(ab')2 of Equine Shiga Antitoxin Immunoglobulin". It is a concentrated and sterile serum obtained from healthy horses immunized against Shiga toxin that contains antibodies capable of neutralizing it.
The initial hypothesis is that INM004 would neutralize the entry of Shiga toxin into the body's cells thus preventing the consequent toxic damage. With the proposed treatment, INM004 would eliminate the Shiga toxin, preventing the progression of HUS symptoms and its serious complications (such as the need for and duration of dialysis, duration of hospital stays, as well as neurological, cardiovascular, intestinal complications, among others) which are associated with high morbidity and mortality. This treatment could then have an impact in health costs of STEC-HUS as well as the social costs.
详细描述
Hemolytic uremic syndrome (HUS) is a form of thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. HUS of infectious origin, associated with infection by Shiga toxin (Stx)-producing Escherichia coli.
This disease can cause sporadic cases or outbreaks. Argentina is the country with the highest incidence of STEC-HUS worldwide. The disease is endemic, representing approximately 95% of all HUS cases.
There is no specific treatment capable of preventing or controlling renal and extrarenal damage caused by Stx. The treatment is mainly symptomatic. Therapy for patients with acute kidney injury is supportive and includes hydric and electrolyte management; thus, most cases require red blood cell transfusions and approximately half of cases require dialysis.
INM004 is a neutralizing serum consisting of the F(ab')2 fragment of equine immunoglobulins with specificity against the B subunits of Stx1 and Stx2. The F(ab')2 fragments are obtained through the processing of serum from horses immunized with Stx1B and Stx2B immunogens, obtained through genetic engineering techniques. A polyclonal therapy based on INM004 offers the advantage that the different subtypes of Stx could be recognized by multiple antibodies simultaneously, even when the toxin circulates bound to neutrophils or microvesicles derived from them.
The objective of this study is to evaluate the efficacy, safety, and pharmacokinetics of INM004 administered in patients between 1 and 12 years of age who are in the early stage of the disease.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 12 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age: ≥1 and <12 years.
- •With hospitalization criterion in the participating facility.
- •Clinical event with a diagnosis compatible with STEC-HUS defined as:
- •Presence of signs of kidney injury defined as:
- •Serum creatinine value above the UNL for age and sex, and/or
- •Hematuria (≥5 red blood cells per field or ≥27 red blood cells/μL in urine sediment),
- •And at least 1 of the following 2 criteria:
- •Presence of hemolysis documented by: LDH levels above the UNL for age, and/or presence of schistocytes in peripheral blood smears.
- •Platelet consumption according to any of the following laboratory criteria: Platelet count <150 × 103/μl, in peripheral blood, and/or ≥50% decrease in peripheral blood platelet count compared to the baseline sample or within the previous 24 h.
- •Onset of diarrhea no more than 13 days at the time of diagnosis of a condition compatible with STEC-HUS at the participating facility.
- •For the treatment group, informed consent form signed and dated by the parent(s) or legal guardian with the assent of the subject as appropriate based on age and regulatory guidelines.
- •For the treatment group, female girls/adolescents who are already fertile must have a negative pregnancy test. Note: They will be considered fertile when they have already had menarche.
排除标准
- •With dialysis for more than 48 h at the time of diagnosis of a condition compatible with STEC-HUS in the participating facility.
- •History of chronic/recurrent hemolytic anemia, thrombocytopenia, or chronic renal failure.
- •Personal and/or family history of atypical HUS.
- •Suspected HUS secondary to other infectious processes not from gastrointestinal origin.
- •Evidence of clinically significant chronic active disease that is not medically controlled whose symptoms/signs may interfere with the treatment/diagnosis of this study, in the opinion of the investigator.
- •For the interventional group, history of: a) anaphylaxis of any type; b) previous administration of equine serum (for example, anti-venom serum, anti-spider toxin serum, anti-SARS-CoV-2 serum, etc.) or an allergic reaction from contact or exposure to horses.
- •Pregnant or lactating women.
- •For the interventional group, the impossibility of hospitalization in the participating institution.
研究组 & 干预措施
INM004
2 doses of 4 mg/kg separated by 24 h
干预措施: INM004 (Drug)
INM004
2 doses of 4 mg/kg separated by 24 h
干预措施: SoC (Other)
结局指标
主要结局
Days of dialysis
时间窗: 28 days
Days of dialysis recorded as a continuous variable from 0 to 28 days
Adverse events (AEs)
时间窗: 28 days
Incidence of AEs classified according to affected organ systems and according to severity Incidence of AEs of special interest: incidence of injection site reactions and hypersensitivity reactions (ie, allergic reaction, anaphylaxis, and serum sickness).
Pharmacokinetics (PK) Evaluation of INM004
时间窗: 0, 1, 24, 26, 48 and 120 hours post-dose
Serum concentration of INM004 at different time intervals in subjects participating in this substudy
次要结局
- Mortality(28 days)
- Change in extrarenal involvement (gastrointestinal)(28 days)
- Change in extrarenal involvement (hematological Interventions)(28 days)
- Change in thrombotic microangiopathy involvement (Hematuria)(28 days)
- Change in thrombotic microangiopathy involvement (Hemoglobin %)(28 days)
- Change in renal involvement (anuria)(28 days)
- Change in thrombotic microangiopathy involvement (GFR %)(28 days)
- Change in thrombotic microangiopathy involvement (Proteinuria)(28 days)
- Change in thrombotic microangiopathy involvement (Hemoglobin)(28 days)
- Change in secondary complications (infectious involvement)(28 days)
- Change in laboratory parameters associated with worse prognosis(28 days)
- Change in thrombotic microangiopathy involvement (GFR)(28 days)
- Change in thrombotic microangiopathy involvement (Creatinine %)(28 days)
- Change in thrombotic microangiopathy involvement (Creatinine)(28 days)
- Change in thrombotic microangiopathy involvement (Hematuria %)(28 days)
- Change in thrombotic microangiopathy involvement (LDH %)(28 days)
- Change in thrombotic microangiopathy involvement (LDH)(28 days)
- Change in extrarenal involvement (cardiovascular)(28 days)
- Change in thrombotic microangiopathy involvement (Proteinuria %)(28 days)
- Change in thrombotic microangiopathy involvement (Platelet)(28 days)
- Change in thrombotic microangiopathy involvement (Platelet %)(28 days)
- Change in renal involvement (dialysis)(28 days)
- Change in renal involvement (dialysis subgroups)(28 days)
- Change in renal involvement (hypertension)(28 days)
- Change in extrarenal involvement (hematological Clinical)(28 days)
- Change in extrarenal involvement (neurological)(28 days)
- Change in extrarenal involvement (endocrine)(28 days)
- Change in secondary complications (pulmonary)(28 days)
- Change in the length of hospital stay(28 days)