The Effect of REcombinant Human Thrombopoietin (rhTPO) on Sepsis Patients With aCUte Severe thrombocytopEnia

Study Overview
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Brief Summary
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The purpose of this study is to determine whether recombinant human thrombopoietin(rhTPO) can rapidly increase the platelets counts, shorten the time of the platelet returned to normal, reduce platelet transfusion and bleeding events, prompt recovery of organ function, decrease the length of ICU stay, and eventually reduce the 28-day mortality in sepsis patients with severe thrombocytopenia.

Detailed Description
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Sepsis is a high morbidity and mortality in critical care unit. Clinically, we found that secondary thrombocytopenia was common in the patients with sepsis, and the incidence can be as high as 55%. Moreover, many studies have shown that thrombocytopenia is an early prognostic marker in sepsis and an independent risk factor for the mortality of sepsis. Furthermore, sepsis patients with severe thrombocytopenia(PLT< 50×10^9/L) have the higher mortality of 50%-90%. And then, it has been reported that early recovery from thrombocytopenia helps to prevent the coagulopathy and decreases the mortality. Until now, the treatment of thrombocytopenia are mainly platelet transfusion and platelet-increased drugs. Because of source scarcity, transfusion-related infectious and immunological complications, platelet transfusion is limited in the clinical treatment. So, the use of platelet-increased drugs for replacement therapy becomes an inevitable trend. The primary purpose of this study is to explore the effect of platelet-increased drugs (rhTPO) on sepsis patients with severe thrombocytopenia. The study is designed as a prospective, multi-center, open-label, randomized, controlled trial in 7 tertiary academic medical centers which are medical, surgical or general ICUs. Patient enrollment is expected to last up to 30 months. Eligible patients will be randomly assigned to the control and rhTPO add-on treatment in a dynamic random and competitive design in clinical trial sites. Sequential organ failure assessment (SOFA), Acute Physiology and Chronic Health Evaluation II (APACHE II) scores are as the dynamic equilibrium factors. Randomization will be done after the first assessment, ensuring that the assessing occupational therapist will not be biased at this time by knowing the group assignment. Both groups receive appropriate medical support and treatment based on guidelines issued by the surviving sepsis campaign. The intervention group will receive rhTPO at a dose of 15000u/d, subcutaneous injection, for 7 consecutive days. It will be terminated when platelet counts (PCs) reach the standard of clinical recovery of platelets: increased by 50×10^9/L for 3 consecutive days compared with PCs at baseline, or PCs are more than 100×10^9/L, or the duration of rhTPO is more than 7 days. The time from randomization to administration of rhTPO will be within 24 hours. The control group will not use any platelet-increased drugs. Platelet transfusion is advised to be administered when PCs are below 10×10^9/L in the absence of apparent bleeding; or below 20 ×10^9/L if the patient has a significant risk of bleeding in both two groups; or below 50 ×10^9/L if the patient has active bleeding or need invasive operation. Patients will be followed for 28 days. PCs will be monitored every day until the first 7 days, followed by tests once a week. Liver and renal function, coagulation function, inflammatory biomarkers (CRP, PCT), and the severity of the disease (SOFA, APACHEǁ) will be monitored before treatment, followed by tests once a week. And then, the number of blood transfusion (including platelets), the length of ICU stay, days free from advanced cardiovascular/respiratory/renal support, bleeding events, and any adverse effects will be recorded after treatment.

Official Title
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The Effect of Recombinant Human Thrombopoietin(rhTPO) on Sepsis Patients With Acute Severe Thrombocytopenia：a Prospective, Multi-center, Open-label, ,Randomized, Controlled Trial

Conditions
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Sepsis, Thrombocytopenia

Intervention / Treatment
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* Drug: rhTPO
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed or clinical diagnosed infection The change of Sequential Organ Failure Assessment(ΔSOFA) score ≥ 2 PLT< 50×10^9/L Informed consent Exclusion Criteria: History of the treatments with chemotherapeutic drugs or heparin within six months History of bone marrow stem cell disorders, malignancy, or immunologic diseases History of bone marrow, lung, liver, kidney, pancreas, or small bowel transplantation. Confirmed End-stage renal failure(GFR <10ml/min，Scr>707μmol/L) Confirmed Disseminated Intravascular Coagulation(DIC) Confirmed Hemorrhagic brain injury or need craniocerebral operation Died anticipated within 24 hours Known pregnancy or at breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rhTPO<br>Recombinant Human Thrombopoietin，TPIAO®, Shenyang Sunshine Pharmaceutical Company Limited [SUNSHINE], Shenyang, China）， 15000u/d, qd, subcutaneous injection, daily for no more than 7 consecutive days | Drug: rhTPO<br>* Recombinant Human Thrombopoietin，TPIAO®, Shenyang Sunshine Pharmaceutical Company Limited [SUNSHINE], Shenyang, China）， 15000u/d, qd, subcutaneous injection, daily for no more than 7 consecutive days<br>* Other names: Recombinant Human TPO;|
| Placebo Comparator: placebo<br>The control group will not use any platelet-increased drugs. | Drug: Placebo<br>* The control group will not use any platelet-increased drugs.<br>* Other names: No platelet-increased drug;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | The 28-day mortality of the patients | 28 days after enrolled | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The changes of platelets counts (PCs) in the first 7 days | The changes of PCs in the first 7 days | 7 days after enrolled | 
| The clinical recovery time of PCs | The time of PCs that reach the standard of clinical recovery | 28 days after enrolled | 
| The amount of blood transfusion | The amount of blood transfusion (including platelets, RBC, FP) | 28 days after enrolled | 
| The proportion of blood transfusion | The proportion of patients who need blood transfusion(including platelets, RBC, FP) | 28 days after enrolled | 
| The changes of procalcitonin | The data of procalcitonin (PCT) in different time points | 28 days after enrolled | 
| The changes of C-reactive protein | The data of C-reactive protein (CRP) in different time points | 28 days after enrolled | 
| The changes of endotoxin | The data of endotoxin in different time points | 28 days after enrolled | 
| The changes of D-dimer and Fibrinogen | The data of D-dimer and Fibrinogen in different time points | 28 days after enrolled | 
| The changes of PT and APTT | The data of PT and APTT in different time points | 28 days after enrolled | 
| The changes of liver function | The data of the markers of liver function (including ALT, AST, TBIL, DBIL) in different time points | 28 days after enrolled | 
| The changes of renal function | The data of the markers of renal function (including serum Cr and BUN) in different time points | 28 days after enrolled | 
| The changes of cardiac function | The data of the markers of cardiac function (including Troponin I and BNP) in different time points | 28 days after enrolled | 
| The days free from advanced organ support | The days without advanced cardiovascular/respiratory/ renal support within 28 days | 28 days after enrolled | 
| The incidence of bleeding event | The incidence of bleeding event, according to Bleeding Academic Research Consortium Definition for Bleeding | 28 days after enrolled | 
| The incidences of drug-related adverse events | The incidences of drug-related adverse events as assessed by CTCAE v4.0 | 28 days after enrolled | 
| The length of ICU and hospital stay | The days from enrolled to discharge from ICU or hospital | 28 days after enrolled | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sepsis, severe thrombocytopenia, recombinant human thrombopoietin, platelets, 28-day mortality