Clinical Trial of Dimolegin (DD217) in Prevention of Thrombotic Complications in Patients With COVID-19
Condition: COVID-19; Venous Thromboembolism
MeSH terms: COVID-19; Thromboembolism; Venous Thromboembolism
Study type: Interventional
Phase: Phase 3

Summary: 
      Study purpose was to study the safety and efficacy of Dimolegin - DD217 as a drug for
      prevention of thrombotic complications compared to Clexane (enoxaparin sodium) - the standard
      therapy currently prescribed to patients hospitalized with COVID-19.

      Patients who met all inclusion criteria and no exclusion criteria were randomized into two
      therapy groups:

        -  Group 1 - test drug Dimolegin - DD217 (60 mg orally, 1 time per day);

        -  Group 2 - reference drug Clexane (40 mg subcutaneously, 1 time per day).

      The study drugs were taken once a day until:

        -  the discharge from the hospital due to recovery or positive dynamics;

        -  or up to 30 days of the patient's stay in the hospital;

        -  or until the Investigator decides to discontinue the therapy for other reasons. Planned:
           screening of up to 450 patients, randomization: 430 (215 per group). The required number
           of patients is 200 per group as a result of the entire study.
    

Detailed description: 
      Study purpose:

      To study the safety and efficacy of Dimolegin - DD217 as a drug for prevention of thrombotic
      complications compared to Clexane (enoxaparin sodium) - the standard therapy currently
      prescribed to patients hospitalized with COVID-19.

      Study objectives:

        -  To study the clinical efficacy of Dimolegin - DD217 as a drug for prevention of
           thrombotic complications in patients hospitalized with COVID-19.

        -  To assess the proportion of patients with the development of thrombotic complications:
           deep vein thrombosis (DVT), pulmonary embolism (PE), ischemic stroke, acute mycardial
           infarction (AMI), arterial thrombotic complications of other localizations (thrombosis
           of mesenteric arteries, renal arteries, spleen, upper and lower extremities) during the
           study therapy (maximum - 30 days).

        -  To evaluate the proportion of patients transferred to the ICU due to complications of
           COVID-19 and the all-cause mortality rate during the study therapy (maximum - 30 days)
           and during the study (maximum 90± 2 days); To study the safety of use, the rate of major
           and clinically significant minor bleeding and possible side effects of Dimolegin - DD217
           during the study therapy (maximum - 30 days).

      Methodology:

      Multicenter randomized prospective open-label clinical study.

      Patients who met all inclusion criteria and no exclusion criteria were randomized into two
      therapy groups:

        -  Group 1 - test drug Dimolegin - DD217 (60 mg orally, 1 time per day);

        -  Group 2 - reference drug Clexane (40 mg subcutaneously, 1 time per day). The first
           dosing (or administration) of the drug was performed on day 1 (D1)
           (screening/randomization). Further, patients received drugs according to their
           distribution into groups, preferably in the morning before the end of therapy, i.e.
           every morning patients received either an injection of Clexane 40 mg subcutaneously once
           a day, or test drug Dimolegin - DD217 60 mg (6 tablets of 10 mg).

      The study drugs were taken once a day until:

        -  the discharge from the hospital due to recovery or positive dynamics;

        -  or up to 30 days of the patient's stay in the hospital;

        -  or until the Investigator decides to discontinue the therapy for other reasons. During
           the study therapy, 3 face-to-face follow-up visits were envisaged: Visit 2 (D3±1), Visit
           3 (D5±1), Visit 4/EOT (D7-D30).

      In all groups, specific antithrombotic prophylaxis was carried out only during inpatient
      treatment under the supervision by Investigator. The study drugs were not dispensed to the
      patient.

      End of therapy (EOT) visit V4 was carried out in connection with the end of therapy and
      discontinuation of the study drugs. After the end of therapy, patients were included in the
      follow-up phase. The visit V5 was conducted in the form of a remote survey in 60±2 days after
      the end of therapy.

      Number of subjects:

      Planned: screening of up to 450 patients, randomization: 430 (215 per group). The required
      number of patients is 200 per group as a result of the entire study.

      Actually included: 401 patients were screened, 400 patients were randomized (198 to the
      Dimolegin - DD217 group and 202 to Clexane group), 399 patients received the study drugs (197
      in the Dimolegin - DD217 group and 202 in the Clexane group).

      Test drug, dose and route of administration, batch number:

      Test drug: Amidine hydrochloride (DD217) Dosage form: enteric-coated tablets Active
      substance: N-(5-chloropyridine-2-yl)-2-[(4-
      methylaminophenylcarbonyl)-amino]-5-methylbenzamide hydrochloride Active substance: Amidine
      hydrochloride 10 mg. Dosing regimen: 60 mg (6 x 10 mg tablets) orally, once a day (preferably
      in the morning)

      Duration of treatment and follow-up:

      Duration of treatment: maximum 30 days. Duration of follow-up: 60± 2 days after the end of
      therapy.

      Reference drug, dose and route of administration, batch number:

      Reference drug: Clexane Dosage form: Solution for injection Active substance: Enoxaparin
      sodium

      Composition (for 4000 anti-Xa IU/0.4 mL, equivalent to 40 mg/0.4 mL):

      Active substance: enoxaparin sodium 40 mg Dosing regimen: 40 mg subcutaneously, once a day
      (preferably in the morning)

      Statistical methods:

      Concomitant and past diseases (history), as well as adverse events were encoded using the
      MedDRA classifier in the current version at the time of the analysis (version 24.0). No
      missing data were imputed.

      Analysis of efficacy endpoints:

      For the primary efficacy endpoint, the hypothesis of non-inferiority of Dimolegin - DD217
      compared to Clexane was evaluated.

      This one-sided hypothesis was evaluated with an overall level of statistical significance of
      α=5 %. Two-sided 90 % confidence intervals (CI) were calculated for the tests. The hypothesis
      was evaluated by comparing the lower limit of the two-sided 90 % CI with the limit of
      non-inferiority of Δ = 10 %.

      The analysis was carried out in the per protocol set (PPS). The analysis of secondary
      efficacy endpoints was carried out descriptively, the proportion of patients with the
      corresponding event is presented. Moreover, 90 % CIs were calculated for differences in
      proportions in Dimolegin - DD217 Group 1 compared to Clexane Group 2.

      Analysis of safety endpoints:

      Analysis of the primary safety endpoint (the incidence of cumulative major and clinically
      significant minor bleedings during the study therapy (maximum - 30 days)) was performed
      descriptively by presenting the proportion of patients with the corresponding event.
      Moreover, 90 % CIs were calculated for differences in proportions between the Dimolegin -
      DD217 group and the Clexane group.

      The analysis of secondary safety endpoints was carried out in the same way as described for
      the primary safety endpoint. All other safety endpoints are analyzed descriptively.

      The safety analysis population included all patients who received at least one dose of the
      study drug.
    

Intervention name(s): Dimolegin; Clexane
Intervention type(s): Drug; Drug
Intervention description(s): 60 mg orally, 1 time per day; 40 mg subcutaneously, 1 time per day
Other intervention name(s): DD217; Enoxaparin sodium
Intervention MeSH terms: Enoxaparin; Enoxaparin sodium
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Multicenter, randomized, prospective, open-label clinical trial
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Dimolegin; Dioxaban; DD217; factor Xa Inhibitor; anticoagulant; therapeutic anticoagulation; thromboprophylaxis; anticoagulation; venous thromboembolism; deep venous thrombosis; arterial thromboembolism; pulmonary embolism