A Multicenter Randomized Double-blind Placebo-controlled Prospective Study to Evaluate the Safety and Efficacy of the Direct Factor Xa Inhibitor Dimolegin (DD217) in Prevention of Venous Thromboembolic Complications During Knee Replacement
试验速览
- 阶段
- 2 期
- 发起方
- 入组人数
- 240
- 试验地点
- 15
- 主要终点
- The total venosus thromboembolism (VTE) index
研究概览
简要总结
This study is a multicenter, double-blind, randomized, prospective phase 2 dose ranging study to evaluate the safety and efficacy of Dimolegin - DD217 in prevention of venous thromboembolic complications in patients underwent knee replacement.
The study model is at each stage in parallel groups. Dimolegin - DD217 efficacy and safety in prevention of venous thromboembolic complications during knee replacement in groups of 80 patients will be investigated.
Patients who meet all inclusion criteria and none of the exclusion criteria will be randomized into three therapy groups: two therapy groups of the test drug Dimolegin - DD217 (40 mg (group 1a) and 60 mg (group 1b)) and one reference group (Fragmin).
Bilateral phlebography (preferably) or ultrasound duplex scanning (USDS) will be performed on the Day of the V13 visit.
It is planned to randomize 240 patients (160 patients in two different groups of Dimolegin - DD217 therapy and 80 patients in the reference group of Fragmin (INN: dalteparin).
The number of patients included in the study and randomized to receive Dimolegin - DD217, at the first stage, can be increased in the case of starting recruitment to additional group 1b.
The maximum number of patients who can be included in the study at the first stage is 320.
In total, no more than 480 patients can take part in the screening. Pharmacokinetic (PK) and pharmacodynamic (PD) parameters will be determined in patients who voluntarily give their consent to participate in the pharmacokinetic study (PKS) and pharmacodynamic study (PDS) and sign a Patient Information Leaflet with an informed consent form for participation in the PKS and PDS.
PK parameters are planned to be determined in 18-20 patients (50 % of each sex) in each patient group. Participation in the voluntary part of PK study will be offered to all patients.
The analysis of the composite endpoint frequency will be carried out using a generalized linear model for binary response.
A formal conclusion about superiority will be made if the lower limit of the specified confidence intervals exceeds the value of 0.0.
A formal conclusion on non-inferiority will be made if the lower limit of the specified confidence intervals exceeds the value of -0.05 (-5.0 %).
详细描述
This study is a multicenter, double-blind, randomized, prospective phase 2 dose ranging study to evaluate the safety and efficacy of Dimolegin - DD217 in prevention of venous thromboembolic complications in patients underwent knee replacement.
The study model is at each stage in parallel groups. Dimolegin - DD217 efficacy and safety in prevention of venous thromboembolic complications during knee replacement in groups of 80 patients will be investigated.
If the power of statistical tests (at α = 0.05) after the evaluation of intermediate data is at least 80 %, and the hypothesis of non-inferiority or superiority of Dimolegin - DD217 in comparison with Fragmin is proved, the study will be completed.
If the power of statistical tests (at α = 0.05) is less than 80 %, the recruitment of patients will continue. The required number of patients will be calculated taking into account the results obtained earlier, but no more than 120 patients per group.
Patients who meet all inclusion criteria and none of the exclusion criteria will be randomized into three therapy groups: two therapy groups of the test drug Dimolegin - DD217 (40 mg (group 1a) and 60 mg (group 1b)) and one reference group (Fragmin).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
Dose Dimolegin - DD217 in each group was blinded for a patient and investigator (double-blind method) using six tablets for each administration, some of them contained Dimolegin - DD217, and others were masked as Placebo of the study product
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Men and women aged 18 years and older who need elective primary total knee replacement (cement or cementless arthroplasty)
- •Signed informed consent
- •Ability to comply with all protocol requirements
- •Patients' consent to use adequate methods of contraception throughout the study
排除标准
- •Surgery for an acute fracture 4 weeks before screening; septic inflammation of the joint, revision of the prosthesis or the absence of one leg
- •Venous thrombosis of any localization or a confirmed PE episode at the present time or in the medical history
- •Heparin-induced thrombocytopenia or other thrombocytopathies currently or in the history, hemorrhagic diathesis
- •Obvious coagulopathy ongoing or in the history of the patient or a blood relative
- •Congenital thrombophilia according to the medical history (deficiency of antithrombin III, protein C, protein S, Leiden mutation of coagulation factor V, increased level of coagulation factor VIII, mutation of prothrombin G20210A)
- •Active bleeding (intracranial, intraocular, nasal, digestive or other localization) at present or within 6 months prior to screening, high risk of bleeding
- •Collection of at least one volume unit of donated blood (> 500 mL) or blood transfusion during the previous 12 weeks
- •Surgery on the brain or spinal cord, spine, ophthalmic or major surgery or injury in the last 90 days
- •Gastrointestinal tract disorders that can disrupt the absorption of the study drug (Crohn's disease, ulcerative colitis, irritable bowel syndrome)
- •Acute gastric or duodenal ulcer, erosive gastritis with increased risk of bleeding
- •Significant cardiovascular diseases ongoing or within 6 months prior to screening, including: chronic heart failure of class III or IV (according to the classification of the New York Heart Association), myocardial infarction, unstable angina, surgery on the heart and coronary vessels (including percutaneous coronary intervention with or without coronary artery stenting), significant diseases of the heart valves, hemodynamically significant cardiac arrhythmias, transient ischemic attack, ischemic or hemorrhagic stroke, uncontrolled hypertension
- •Active liver disease (viral hepatitis B or C, cirrhosis of the liver) and biliary tract disease, with the exception of non-alcoholic steatohepatitis with normal levels of hepatic transaminases (ALT and AST)
- •Nephrotic syndrome, significant kidney diseases with the events of nephrotic syndrome (decreased filtration renal function with decreased estimated glomerular filtration rate (eGFR) < 60 according to the MDRD formula (MDRD)
- •Malignant neoplasms during the last 5 years (with the exception of basal cell carcinoma for which radical treatment was carried out).
- •Positive test for HIV, syphilis, hepatitis B or C markers (HBsAg and Anti-HCV)
- •Significant drug or alcohol abuse according to the Investigator in the history or currently
- •The development of trophic disorders of the lower extremities that do not respond to medical treatment
- •Any condition, in which, according to the Investigator, surgical intervention or anticoagulants are contraindicated
- •Body mass index (BMI) less than 18.5 or more than 40 kg/m
- •Body weight above 130 kg
- •Systolic BP > 180 mmHg and/or diastolic BP >110 mmHg, reported with two consecutive measurements for 15-30 minutes
- •Hemoglobin < 105 g/L in women or < 115 g/L in men
- •Abnormal laboratory parameters of the coagulation system (platelets, activated partial thromboplastin time (APTT), international normalized ratio (INR) and D-dimer), which, according to the Investigator and Medical Expert of the study, cause suspicion of blood clotting or problems in the hemostasis system in the patient
- •eGFR < 60 mL/min/1.73 m2 (by MDRD formula)
- •ALT or AST > 2 x upper limit of normal (ULN) or total bilirubin > 1.5 x ULN
- •Hypersensitivity or contraindications to Dimolegin - DD217, dalteparin sodium, unfractionated heparin or warfarin; pig tissue preparations, radiopaque preparations (for multislice spiral computed tomography (MSCT) with intravenous enhancing)
- •The need for constant use of parenteral or oral anticoagulants (for example, patients with artificial heart valves, patients with atrial fibrillation who are indicated for warfarin therapy)
- •Systemic therapy with azole group drugs (ketoconazole, fluconazole, etc.), as well as other CYP3A4 inhibitors 7 days before and during screening.
- •Previous and concomitant therapy: taking antiplatelet drugs, therapy with vitamin K antagonists, therapy with unfractionated heparin, low molecular weight heparin (LMWH), direct oral anticoagulants, the use of NSAIDs should be stopped at least 7 days before the start of the study therapy, systemic therapy with strong CYP3A4 and P-glycoprotein inhibitors, systemic therapy with strong inducers of CYP3A4 and P-glycoprotein
- •Women who are pregnant or breastfeeding
- •Women planning pregnancy during a clinical trial (including women who received a positive pregnancy test result during screening or before taking the study drug)
- •Women of childbearing potential (including non-sterilized surgically and in the postmenopausal period less than 2 years) who do not want or cannot use adequate methods of contraception throughout the study. Adequate methods of contraception include the use of a condom or diaphragm (barrier method) with spermicide
- •Participation in another clinical trial currently or within 30 days prior to screening, use of any investigational drug for 30 days or 5 half-lives (which is longer) prior to screening
- •Affiliation to the investigational site: close relatives of the Investigator, dependent persons (for example, an employee or a person studying at the investigational site)
- •Inability to read or write; unwillingness to understand and follow the study protocol procedures; non-compliance with the regimen of treatment or procedures which, according to Investigator, may affect the study results or patient's safety and prevent the patient from further participating in the study; any other concomitant medical or serious mental conditions, which make the patient ineligible for the clinical study, restrict validity of the consent or may affect the patient's ability to participate in the study
研究组 & 干预措施
Group 1a
Patients from groups 1a took the study product once a day in doses 40 mg per os and saline solution subcutaneously. Dose was blinded for a patient and investigator (double-blind method) using six tablets for each administration, some of them contained Dimolegin - DD217, and others were masked as Placebo of the study product.
干预措施: Dimolegin 40 mg (Drug)
Group 1b
Patients from groups 1b took the study product once a day in doses 60 mg per os and saline solution subcutaneously. Dose was blinded for a patient and investigator (double-blind method) using six tablets for each administration, some of them contained Dimolegin - DD217, and others were masked as Placebo of the study product.
干预措施: Dimolegin 60 mg (Drug)
Group 2
Patients from the control group (group 2) were received Fragmin in accordance with the instruction for medical use (5000 IU s/c once a day with 24-hour interval) and six Placebo tablets masked as study product Dimolegin - DD217 once a day.
干预措施: Fragmin (Drug)
结局指标
主要结局
The total venosus thromboembolism (VTE) index
时间窗: 14 Days
The frequency of composite endpoint, which includes: * Asymptomatic deep vein thrombosis (DVT) detected by bilateral phlebography (preferably) or USDS at Visit V13 (Day D14±1); * Objectively confirmed by phlebography, USDS, computed tomography or other method symptomatic or asymptomatic DVT before Visit V13 (Day D14±1) inclusive; * Non-fatal PE before Visit V13 (Day D14±1) inclusive; * Fatal PE before Visit V13 (Day D14±1) inclusive; * Unexplained death, in which pulmonary embolism (PE) cannot be excluded before the Visit V13 (Day D14 ± 1) inclusive.
次要结局
- The total venosus thromboembolism (VTE) index (W6)(6 Weeks)