A Study of Pharmacokinetics, Safety and Tolerability of Dimolegin (DD217)
Condition: Healthy Volunteers
Study type: Interventional
Phase: Phase 1

Summary: 
      In the course of the clinical study, the pharmacokinetics, pharmacodynamics, safety and
      tolerability of Dimolegin (DD217) 10 mg enteric-coated tablets after single administration to
      healthy volunteers at increasing doses were studied.

      24 volunteers participated in the study. The randomization procedure was carried out for 24
      volunteers selected at screening. In Group 1 6 volunteers were randomized , in Group 2 6
      volunteers were randomized, and in Group 3 12 volunteers were enrolled. Group 1 volunteers
      took the study drug at a dose of 20 mg once, group 2 volunteers took the study drug at a dose
      of 40 mg once, and group 3 volunteers took the study drug at a dose of 60 mg once.
    

Detailed description: 
      Study objectives were:

        1. to evaluate the safety of different single doses of Dimolegin (DD217) in healthy
           volunteers;

        2. to evaluate the tolerance of different single doses of Dimolegin (DD217) in healthy
           volunteers;

        3. to evaluate pharmacokinetic parameters with a single dose of Dimolegin (DD217) in
           increasing doses;

        4. to evaluate the effect of Dimolegin (DD217) on coagulation profile parameters
           (prothrombin time, activated partial thromboplastin time (aPTT), anti-Xa activity) with
           a single dose in healthy volunteers (pharmacodynamic study).

      Study design was an open study of the pharmacokinetics, safety and tolerability of Dimolegin
      (DD217) after single administration to healthy volunteers in fasting conditions (phase 1).

      Study population was: screened - 40, randomized - 24, per protocol population - 24.

      The study was open, prospective, non-randomized with sequential enrollment of volunteers with
      dose escalation Group No. 1 (n=6) consisted of 2 cohorts with 3 volunteers per each.
      Volunteers of Cohorts 1 and 2 received Dimolegin (DD217) once at a dose of 20 mg.

      Group No. 2 (n=6) consisted of 2 cohorts with 3 volunteers per each. Volunteers of Cohorts 3
      and 4 received Dimolegin (DD217) once at a dose of 40 mg.

      Group No. 3 (n=12) consisted of 3 cohorts. Cohorts 5 and 6 included 3 volunteers per each,
      and Cohort 7 included 6 volunteers. All Group 3 volunteers received Dimolegin (DD217) once at
      a dose of 60 mg.

      Initially, the first cohort (n=3) of volunteers was included in the study, in which
      volunteers received the study drug once at a dose of 20 mg. After evaluation of the interim
      safety results (complete blood count and blood chemistry, urinalysis, clinical health
      assessment, electrocardiogram (ECG)) 3 days after dosing in the absence of SAEs, the
      Investigator decided to include the second cohort (n=3), in which volunteers continued to
      receive the drug at a single dose of 20 mg.

      28 days after dosing in Cohort 2 of Group 1, the Investigator compiled a report on the safety
      of the study drug dose based on the results of all safety tests (complete blood count and
      blood chemistry, urinalysis), ECG and clinical health assessment, based on the submitted IDMC
      report, a decision was made to enroll volunteers to Group 2, also consisting of 2 cohorts:
      the third and the fourth.

      Volunteers of Group 2, Cohort 3 (n=3) received a single study drug dose of 40 mg. After
      evaluation of the interim safety results (complete blood count and blood chemistry,
      urinalysis, clinical health assessment, ECG) 3 days after dosing in the absence of SAEs, the
      Investigator decided to include the forth cohort (n=3), in which volunteers continued to take
      the drug at a single dose of 40 mg. 28 days after dosing in Cohort 4 of Group 2, the
      Investigator compiled a report on the safety of the study drug dose based on the results of
      all safety tests (complete blood count and blood chemistry, urinalysis), ECG and clinical
      health assessment, based on the submitted IDMC report, a decision was made to enroll
      volunteers to Group 3, also consisting of 3 cohorts: the fifth, the sixth and the seventh.

      The volunteers of Group 3, Cohort 5 (n=3), took a single study drug dose of 60 mg. After
      evaluation of the interim safety results (complete blood count and blood chemistry,
      urinalysis, clinical health assessment, ECG) 3 days after dosing in the absence of SAEs, the
      Investigator decided to include the sixth cohort (n=3), in which volunteers continued to take
      the drug at a single dose of 60 mg. 28 days after dosing in Cohort 6 of Group 3, the
      Investigator compiled a report on the safety of the study drug dose based on the results of
      all safety tests (complete blood count and blood chemistry, urinalysis), ECG and clinical
      health assessment, based on the submitted IDMC report, a decision was made to enroll
      volunteers to Cohort 7 (n=6) of Group 3. Cohort 7 volunteers continued to take 60 mg of the
      study drug orally once and completed the study.

      In chronic toxicity studies, adverse effects were achieved on Day 42 in rats at a dose of 90
      mg/kg of DD217 substance and on Day 46 in rabbits at a dose of 100 mg/kg of DD217 substance,
      which, after conversion to maximum recommended starting dose (MRSD) for human, gave 0.60
      mg/kg and 1.56 mg/kg, respectively. These doses were considered as an estimate of the upper
      limit of dose, that is, the MRSD should have been less than 0.60 mg/kg. Thus, 0.28 mg/kg was
      taken as MRSD, i.e. in terms of a person weighing 70 kg, MRSD = 0.28*70 = 20 mg as a single
      dose. To ensure the safety of volunteers, the study was performed with a phased dose
      escalation. Given Cmax and T1/2 values, in the absence of any SAEs, dosing in the next cohort
      should be no earlier than 3 days after the drug is given to the previous cohort. In the case
      of SAE dosing in the next cohort could be performed only after approval by an Independent
      Data Monitoring Committee (IDMC - created before the start of the study, the composition of 3
      experts is approved by the Local Ethics Committee). Dose escalation (switch to the next
      group) was possible no earlier than 28 days after the last dosing in the study group and with
      the approval of the IDMC.

      The study drug was used once in the morning in fasting state. Clinical assessment of health
      state (physical examination and measurement of vital signs (blood pressure, heart rate,
      respiratory rate, body temperature), laboratory parameters (complete blood count, blood cell
      morphology differentials, blood chemistry, urinalysis) were determined in accordance with the
      set goal and objectives.

      Blood coagulation profile parameters (prothrombin time, APTT and anti-Xa activity) were
      determined for construction of pharmacodynamic curves in discrete time intervals in
      accordance with the set goal and objectives.

      Dioxaban (DD217) concentration was determined in discrete time intervals in accordance with
      the set goal for the construction of pharmacokinetic curves based on which, in turn, the
      pharmacokinetic parameters of the active substances were calculated.

      Pharmacokinetic parameters were calculated by a model-independent method. The following
      parameters were calculated for all the subjects:

      AUCo-t- area under concentration-time curve from 0 to the last blood sampling; AUCo-inf-area
      under concentration-time curve (from 0 to infinity); Cmax- maximum concentration value; Tmax-
      time to maximum concentration; T1/2-half-life; Cl - clearance. Study duration Maximum
      duration for each volunteer did not exceed 42 days. Descriptive statistics was provided for
      all demographic and other baseline characteristics, safety parameters and their changes (if
      applicable) in course of the study by time points of evaluation and by groups. Descriptive
      statistics for quantitative variables included mean, median, standard deviation, minimum and
      maximum values, and the number of observations. Qualitative data are presented as frequencies
      and proportions in percentage terms. The baseline values for laboratory, instrumental and
      vital safety parameters were the values obtained at Visit 0 (Screening) or at Visit 1 before
      dosing.

      Per Protocol (PP) population included all volunteers for the assessment of pharmacodynamics
      and pharmacokinetics who met the inclusion/exclusion criteria and received the prescribed
      dose of the study drug. There were no volunteers who withdrew from this study.

      When planning the sample size for an experimental study, the number of 24 healthy volunteers
      was recognized as acceptable. Due to the descriptive nature of this study, the sample size
      determination was not based on any formal statistical assumptions.
    

Intervention name(s): Dimolegin
Intervention type(s): Drug
Intervention description(s): Dimolegin (DD217) - enteric coated tablets 10 mg developed by PharmaDiall Ltd (Moscow), manufactured by Federal State Unitary Enterprise Research and Practical Center "Pharmaceutical Protection" at The Federal Medical Biological Agency (FMBA) of Russia
Other intervention name(s): DD217
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: The study is single center, open-label, prospective, non-randomized with sequential enrollment of volunteers with dose escalation
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Dimolegin; Dioxaban; DD217; Factor Xa Inhibitor; anticoagulant; therapeutic anticoagulation; thromboprophylaxis; anticoagulation; healthy