Clinical trial NCT02707497: The Effect of REcombinant Human Thrombopoietin (rhTPO) on Sepsis Patients With aCUte Severe thrombocytopEnia
Official title: The Effect of Recombinant Human Thrombopoietin(rhTPO) on Sepsis Patients With Acute Severe Thrombocytopenia：a Prospective, Multi-center, Open-label, ,Randomized, Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Sepsis
Thrombocytopenia
Keywords: sepsis
severe thrombocytopenia
recombinant human thrombopoietin
platelets
28-day mortality
Lead sponsor: Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Sponsor class: OTHER
Collaborators: name: Huadong Hospital
name: Shanghai Tongji Hospital, Tongji University School of Medicine
name: Changhai Hospital
name: Second Affiliated Hospital of Nanchang University
name: Shanghai Jiao Tong University School of Medicine
name: Shanghai University of Traditional Chinese Medicine
name: Fudan University
First posted: 2016-03-14
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Confirmed or clinical diagnosed infection
2. The change of Sequential Organ Failure Assessment(ΔSOFA) score ≥ 2
3. PLT\< 50×10\^9/L
4. Informed consent

Exclusion Criteria:

1. History of the treatments with chemotherapeutic drugs or heparin within six months
2. History of bone marrow stem cell disorders, malignancy, or immunologic diseases
3. History of bone marrow, lung, liver, kidney, pancreas, or small bowel transplantation.
4. Confirmed End-stage renal failure(GFR \<10ml/min，Scr\>707μmol/L)
5. Confirmed Disseminated Intravascular Coagulation(DIC)
6. Confirmed Hemorrhagic brain injury or need craniocerebral operation
7. Died anticipated within 24 hours
8. Known pregnancy or at breastfeeding

Primary outcomes:
measure: Mortality
timeFrame: 28 days after enrolled
Secondary outcomes:
measure: The changes of platelets counts (PCs) in the first 7 days
timeFrame: 7 days after enrolled
measure: The clinical recovery time of PCs
timeFrame: 28 days after enrolled
measure: The amount of blood transfusion
timeFrame: 28 days after enrolled
measure: The proportion of blood transfusion
timeFrame: 28 days after enrolled
measure: The changes of procalcitonin
timeFrame: 28 days after enrolled
measure: The changes of C-reactive protein
timeFrame: 28 days after enrolled
measure: The changes of endotoxin
timeFrame: 28 days after enrolled
measure: The changes of D-dimer and Fibrinogen
timeFrame: 28 days after enrolled
measure: The changes of PT and APTT
timeFrame: 28 days after enrolled
measure: The changes of liver function
timeFrame: 28 days after enrolled
measure: The changes of renal function
timeFrame: 28 days after enrolled
measure: The changes of cardiac function
timeFrame: 28 days after enrolled
measure: The days free from advanced organ support
timeFrame: 28 days after enrolled
measure: The incidence of bleeding event
timeFrame: 28 days after enrolled
measure: The incidences of drug-related adverse events
timeFrame: 28 days after enrolled
measure: The length of ICU and hospital stay
timeFrame: 28 days after enrolled
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Shanghai General Hospital, Shanghai Jiaotong University
state: Shanghai
Study officials:
affiliation: The department of ICU, Shanghai General Hospital, Shanghai Jiaotong University
name: Ruilan Wang, MD,PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zhou Z, Feng T, Xie Y, Huang P, Xie H, Tian R, Qian B, Wang R. The effect of recombinant human thrombopoietin (rhTPO) on sepsis patients with acute severe thrombocytopenia: a study protocol for a multicentre randomised controlled trial (RESCUE trial). BMC Infect Dis. 2019 Sep 6;19(1):780. doi: 10.1186/s12879-019-4388-2.