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A Safety and Tolerability Study of RJX Drug Product in Healthy Participants

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ClinicalTrials.gov Identifier: NCT03680105
Recruitment Status : Completed
First Posted : September 21, 2018
Last Update Posted : February 11, 2019
Sponsor:
Collaborators:
ICON plc
ERT: Clinical Trial Technology Solutions
Information provided by (Responsible Party):
Reven Pharmaceuticals, Inc.

Brief Summary:
Designed as a single center, two-part, double-blind, placebo-controlled, randomized study to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of RJX in healthy participants.

Condition or disease Intervention/treatment Phase
Critical Limb Ischemia Drug: RJX Drug: Placebo Phase 1

Detailed Description:

Part 1 is designed as a Single Ascending Dose (SAD) escalation study with 6 cohorts. Participants will undertake a screening visit between Day -21 and Day -1 to determine eligibility in the study. Those participants that meet the eligibility criteria will be admitted to the study site on the day prior to dosing (Day -1). Participants will receive a single dose of investigational product via IV infusion on Day 1. The first cohort will include the initial dosing of a sentinel group. The remaining participants in Cohort 1 will be dosed if, in the opinion of the investigator or delegate, there are no significant safety concerns identified in the sentinel participants within the first 24 hours after administration of the dose. Participants will be confined to the study site from Day -1 to Day 2 (24 hours post dose) and then required to return to the study site on Day 5 for a final follow up visit. Safety and PK assessments will be performed at selected time points throughout the study.

Part 2 is designed as a Multiple Ascending Dose (MAD) escalation study with 3 cohorts. The MAD arm of the study will commence in parallel with Cohort 6 of Part 1 following completion and review of safety and PK findings for Cohorts 1, 2, 3, 4, and 5 in Part 1. Participants will undertake a screening visit between Day -21 and Day -1 to determine eligibility in the study. Those participants that meet the eligibility criteria will be admitted to the study site on the day prior to dosing (Day -1). Participants will be randomly assigned to receive 1 of 3 proposed doses of investigational product via IV infusion every day for 7 days.Participants will be confined to the study site from Day -1 to Day 8 (24 hours post the final dose on Day 7) and then return to the study site on Day 12 for a final follow up visit. Safety and PK assessments will be performed at selected time points throughout the study.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 76 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Official Title: A Phase 1, Double-blind, Placebo-controlled, Randomized, Two-Part, Ascending Dose-escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Rejuveinix (RJX) in Healthy Participants
Actual Study Start Date : August 24, 2018
Actual Primary Completion Date : January 15, 2019
Actual Study Completion Date : January 15, 2019

Arm Intervention/treatment
Experimental: Part 1; Cohort 1; RJX or Placebo
Participants in Part 1; Cohort 1 will receive a single 0.024 mL/kg dose of RJX or matching placebo on Day 1.
Drug: RJX
RJX is a formulation of known vitamins and a mineral in a diluent suited for parenteral administration.The appropriate RJX dose is calculated based on mL/kg. The administration dose is prepared by adding the appropriate RJX dose to 0.9% sterile saline such that a constant volume of 100 mL per IV infusion is obtained. Infusion time is 100 mL over 45 minutes (+/- 5 minutes).

Drug: Placebo
Matching placebo will be normal saline. To maintain the blind, a sleeve will cover the infusion bag and line such that the appearance will be identical to RJX administration.

Experimental: Part 1; Cohort 2; RJX or Placebo
Participants in Part 1; Cohort 2 will receive a single 0.076 mL/kg dose of RJX or matching placebo on Day 1.
Drug: RJX
RJX is a formulation of known vitamins and a mineral in a diluent suited for parenteral administration.The appropriate RJX dose is calculated based on mL/kg. The administration dose is prepared by adding the appropriate RJX dose to 0.9% sterile saline such that a constant volume of 100 mL per IV infusion is obtained. Infusion time is 100 mL over 45 minutes (+/- 5 minutes).

Drug: Placebo
Matching placebo will be normal saline. To maintain the blind, a sleeve will cover the infusion bag and line such that the appearance will be identical to RJX administration.

Experimental: Part 1; Cohort 3; RJX or Placebo
Participants in Part 1; Cohort 3 will receive a single 0.240 mL/kg dose of RJX or matching placebo on Day 1.
Drug: RJX
RJX is a formulation of known vitamins and a mineral in a diluent suited for parenteral administration.The appropriate RJX dose is calculated based on mL/kg. The administration dose is prepared by adding the appropriate RJX dose to 0.9% sterile saline such that a constant volume of 100 mL per IV infusion is obtained. Infusion time is 100 mL over 45 minutes (+/- 5 minutes).

Drug: Placebo
Matching placebo will be normal saline. To maintain the blind, a sleeve will cover the infusion bag and line such that the appearance will be identical to RJX administration.

Experimental: Part 1; Cohort 4; RJX or Placebo
Participants in Part 1; Cohort 4 will receive a single 0.5 mL/kg dose of RJX or matching placebo on Day 1.
Drug: RJX
RJX is a formulation of known vitamins and a mineral in a diluent suited for parenteral administration.The appropriate RJX dose is calculated based on mL/kg. The administration dose is prepared by adding the appropriate RJX dose to 0.9% sterile saline such that a constant volume of 100 mL per IV infusion is obtained. Infusion time is 100 mL over 45 minutes (+/- 5 minutes).

Drug: Placebo
Matching placebo will be normal saline. To maintain the blind, a sleeve will cover the infusion bag and line such that the appearance will be identical to RJX administration.

Experimental: Part 1; Cohort 5; RJX or Placebo
Participants in Part 1; Cohort 5 will receive a single 0.759 mL/kg dose of RJX or matching placebo on Day 1.
Drug: RJX
RJX is a formulation of known vitamins and a mineral in a diluent suited for parenteral administration.The appropriate RJX dose is calculated based on mL/kg. The administration dose is prepared by adding the appropriate RJX dose to 0.9% sterile saline such that a constant volume of 100 mL per IV infusion is obtained. Infusion time is 100 mL over 45 minutes (+/- 5 minutes).

Drug: Placebo
Matching placebo will be normal saline. To maintain the blind, a sleeve will cover the infusion bag and line such that the appearance will be identical to RJX administration.

Experimental: Part 1; Cohort 6; RJX or Placebo
Participants in Part 1; Cohort 6 will receive a single dose of RJX or matching placebo, to be determined following review of safety and PK data from Cohorts 1 to 5, on Day 1.
Drug: RJX
RJX is a formulation of known vitamins and a mineral in a diluent suited for parenteral administration.The appropriate RJX dose is calculated based on mL/kg. The administration dose is prepared by adding the appropriate RJX dose to 0.9% sterile saline such that a constant volume of 100 mL per IV infusion is obtained. Infusion time is 100 mL over 45 minutes (+/- 5 minutes).

Drug: Placebo
Matching placebo will be normal saline. To maintain the blind, a sleeve will cover the infusion bag and line such that the appearance will be identical to RJX administration.

Experimental: Part 2; Cohort 1; RJX or Placebo

Participants in Part 2; Cohort 1 will receive a dose of RJX or matching placebo, determined based on the findings of Part 1, every day for 7 days.

The Part 2; Cohort 1 dose will be 1 log down from the maximum tolerated dose determined in Part 1 or at a dose determined to be safe and well tolerated in Part 1 with an acceptable PK profile.

Drug: RJX
RJX is a formulation of known vitamins and a mineral in a diluent suited for parenteral administration.The appropriate RJX dose is calculated based on mL/kg. The administration dose is prepared by adding the appropriate RJX dose to 0.9% sterile saline such that a constant volume of 100 mL per IV infusion is obtained. Infusion time is 100 mL over 45 minutes (+/- 5 minutes).

Drug: Placebo
Matching placebo will be normal saline. To maintain the blind, a sleeve will cover the infusion bag and line such that the appearance will be identical to RJX administration.

Experimental: Part 2; Cohort 2; RJX or Placebo
Participants in Part 2; Cohort 2 will receive an escalated dose of RJX or matching placebo, determined based on the findings of Part 1, every day for 7 days.
Drug: RJX
RJX is a formulation of known vitamins and a mineral in a diluent suited for parenteral administration.The appropriate RJX dose is calculated based on mL/kg. The administration dose is prepared by adding the appropriate RJX dose to 0.9% sterile saline such that a constant volume of 100 mL per IV infusion is obtained. Infusion time is 100 mL over 45 minutes (+/- 5 minutes).

Drug: Placebo
Matching placebo will be normal saline. To maintain the blind, a sleeve will cover the infusion bag and line such that the appearance will be identical to RJX administration.

Experimental: Part 2; Cohort 3; RJX or Placebo
Participants in Part 2; Cohort 3 will receive an escalated dose of RJX or matching placebo, determined based on the findings of Part 1, every day for 7 days.
Drug: RJX
RJX is a formulation of known vitamins and a mineral in a diluent suited for parenteral administration.The appropriate RJX dose is calculated based on mL/kg. The administration dose is prepared by adding the appropriate RJX dose to 0.9% sterile saline such that a constant volume of 100 mL per IV infusion is obtained. Infusion time is 100 mL over 45 minutes (+/- 5 minutes).

Drug: Placebo
Matching placebo will be normal saline. To maintain the blind, a sleeve will cover the infusion bag and line such that the appearance will be identical to RJX administration.




Primary Outcome Measures :
  1. Part 1: Number of participants with treatment-related adverse events (AEs) as assessed by CTCAE v4.03. [ Time Frame: Up to Day 5 ]
    All investigational product and protocol procedure AEs will be listed, and if the frequency of events allows, safety data will be summarized using descriptive methodology.

  2. Part 2: Number of participants with treatment-related adverse events (AEs) as assessed by CTCAE v4.03. [ Time Frame: Up to Day 12 ]
    All investigational product and protocol procedure AEs will be listed, and if the frequency of events allows, safety data will be summarized using descriptive methodology.

  3. Part 1: Safety and tolerability of RJX as assessed by electrocardiograms (ECGs). [ Time Frame: Up to Day 2 ]

    PR, QRS, QT, and ECG QT interval corrected for heart rate using Fridericia's formula (QTcF intervals) will be recorded by measuring single ECGs obtained after the patient has rested comfortably in the supine or semi-supine position for at least 5 minutes.

    The investigator will interpret the ECG using one of the following categories:

    • Within normal limits;
    • Abnormal but not clinically significant;
    • Abnormal and clinically significant.

    Observed values and actual changes from baseline of continuous ECG parameters will be summarized descriptively, by actual treatment/dose level and visit/time point. Categorical outcomes will be summarized by frequency tabulations.


  4. Part 2: Safety and tolerability of RJX as assessed by electrocardiograms (ECGs). [ Time Frame: Up to Day 8 ]

    PR, QRS, QT, and ECG QT interval corrected for heart rate using Fridericia's formula (QTcF intervals) will be recorded by measuring single ECGs obtained after the patient has rested comfortably in the supine or semi-supine position for at least 5 minutes.

    The investigator will interpret the ECG using one of the following categories:

    • Within normal limits;
    • Abnormal but not clinically significant;
    • Abnormal and clinically significant.

    Observed values and actual changes from baseline of continuous ECG parameters will be summarized descriptively, by actual treatment/dose level and visit/time point. Categorical outcomes will be summarized by frequency tabulations.


  5. Part 1: Safety and tolerability of RJX as assessed by neurological examinations. [ Time Frame: Up to Day 5 ]

    Neurological assessments per standard of care will be performed by investigator or sub-investigator at selected time points in the study.

    Observed values and actual changes from baseline of continuous neurological assessments will be summarized descriptively, by actual treatment/dose level and visit/time point. Categorical outcomes will be summarized by frequency tabulations.


  6. Part 2: Safety and tolerability of RJX as assessed by neurological examinations. [ Time Frame: Up to Day 12 ]

    Neurological assessments per standard of care will be performed by investigator or sub-investigator at selected time points in the study.

    Observed values and actual changes from baseline of continuous neurological assessments will be summarized descriptively, by actual treatment/dose level and visit/time point. Categorical outcomes will be summarized by frequency tabulations.


  7. Part 1: Assessment of oral body temperature as a safety measure. [ Time Frame: Up to Day 5 ]

    Wherever possible, body temperature will be measured after the patient has rested comfortably in the supine or semi supine position for at least 3 minutes using the same equipment throughout the study.

    Observed values and actual changes from baseline of continuous vital signs will be summarized descriptively, by actual treatment/dose level and visit/time point. Categorical outcomes will be summarized by frequency tabulations.


  8. Part 2: Assessment of oral body temperature as a safety measure. [ Time Frame: Up to Day 12 ]

    Wherever possible, body temperature will be measured after the patient has rested comfortably in the supine or semi supine position for at least 3 minutes using the same equipment throughout the study.

    Observed values and actual changes from baseline of continuous body temperatures will be summarized descriptively, by actual treatment/dose level and visit/time point. Categorical outcomes will be summarized by frequency tabulations.


  9. Part 1: Assessment of respiratory rate as a safety measure. [ Time Frame: Up to Day 5 ]

    Wherever possible, respiratory rate will be measured after the patient has rested comfortably in the supine or semi supine position for at least 3 minutes using the same equipment throughout the study.

    Observed values and actual changes from baseline of continuous respiratory rates will be summarized descriptively, by actual treatment/dose level and visit/time point. Categorical outcomes will be summarized by frequency tabulations.


  10. Part 2: Assessment of respiratory rate as a safety measure. [ Time Frame: Up to Day 12 ]

    Wherever possible, respiratory rate will be measured after the patient has rested comfortably in the supine or semi supine position for at least 3 minutes using the same equipment throughout the study.

    Observed values and actual changes from baseline of continuous respiratory rates will be summarized descriptively, by actual treatment/dose level and visit/time point. Categorical outcomes will be summarized by frequency tabulations.


  11. Part 1: Assessment of heart rate as a safety measure. [ Time Frame: Up to Day 5 ]

    Wherever possible, heart rate will be measured after the patient has rested comfortably in the supine or semi supine position for at least 3 minutes using the same equipment throughout the study.

    Observed values and actual changes from baseline of continuous heart rates will be summarized descriptively, by actual treatment/dose level and visit/time point. Categorical outcomes will be summarized by frequency tabulations.


  12. Part 2: Assessment of heart rate as a safety measure. [ Time Frame: Up to Day 12 ]

    Wherever possible, heart rate will be measured after the patient has rested comfortably in the supine or semi supine position for at least 3 minutes using the same equipment throughout the study.

    Observed values and actual changes from baseline of continuous heart rates will be summarized descriptively, by actual treatment/dose level and visit/time point. Categorical outcomes will be summarized by frequency tabulations.


  13. Part 1: Assessment of systolic and diastolic blood pressure (BP) as a safety measure. [ Time Frame: Up to Day 5 ]

    Wherever possible, systolic and diastolic BP will be measured after the patient has rested comfortably in the supine or semi supine position for at least 3 minutes using the same equipment throughout the study.

    Observed values and actual changes from baseline of continuous systolic and diastolic BPs will be summarized descriptively, by actual treatment/dose level and visit/time point. Categorical outcomes will be summarized by frequency tabulations.


  14. Part 2: Assessment of systolic and diastolic blood pressure (BP) as a safety measure. [ Time Frame: Up to Day 12 ]

    Wherever possible, systolic and diastolic BP will be measured after the patient has rested comfortably in the supine or semi supine position for at least 3 minutes using the same equipment throughout the study.

    Observed values and actual changes from baseline of continuous systolic and diastolic BPs will be summarized descriptively, by actual treatment/dose level and visit/time point. Categorical outcomes will be summarized by frequency tabulations.


  15. Part 1: Number of participants with clinical chemistry values of potential clinical importance criteria (PCC). [ Time Frame: Up to Day 5 ]

    Clinical chemistry parameters include: albumin, total protein, glucose, sodium, magnesium,potassium, chloride, carbon dioxide, creatinine, aspartate transaminase, alanine aminotransferase, alkaline phosphatase, gamma glutamyl transferase, high density lipoprotein, total bilirubin, triglyceride, total cholesterol, lactate dehydrogenase, calcium, uric acid and blood urea nitrogen.

    Observed values and actual changes from baseline of continuous clinical chemistry parameters will be summarized descriptively, by actual treatment/dose level and visit/time point. Categorical outcomes will be summarized by frequency tabulations.


  16. Part 2: Number of participants with clinical chemistry values of potential clinical importance criteria (PCC). [ Time Frame: Up to Day 12 ]

    Clinical chemistry parameters include: albumin, total protein, glucose, sodium, magnesium,potassium, chloride, carbon dioxide, creatinine, aspartate transaminase, alanine aminotransferase, alkaline phosphatase, gamma glutamyl transferase, high density lipoprotein, total bilirubin, triglyceride, total cholesterol, lactate dehydrogenase, calcium, uric acid and blood urea nitrogen.

    Observed values and actual changes from baseline of continuous clinical chemistry parameters will be summarized descriptively, by actual treatment/dose level and visit/time point. Categorical outcomes will be summarized by frequency tabulations.


  17. Part 1: Number of participants with hematology values of potential clinical importance criteria (PCC). [ Time Frame: Up to Day 5 ]

    Hematology Parameters include: hemoglobin, hematocrit, red blood cell count, white blood cell, platelet count, white blood cell subset count (neutrophils, eosinophils, basophils, lymphocytes, and monocytes), with differential count, mean corpuscular volume, mean corpuscular hemoglobin, mean cell hemoglobin concentration.

    Observed values and actual changes from baseline of continuous clinical chemistry parameters will be summarized descriptively, by actual treatment/dose level and visit/time point. Categorical outcomes will be summarized by frequency tabulations.


  18. Part 2: Number of participants with hematology values of potential clinical importance criteria (PCC). [ Time Frame: Up to Day 12 ]

    Hematology Parameters include: hemoglobin, hematocrit, red blood cell count, white blood cell, platelet count, white blood cell subset count (neutrophils, eosinophils, basophils, lymphocytes, and monocytes), with differential count, mean corpuscular volume, mean corpuscular hemoglobin, mean cell hemoglobin concentration.

    Observed values and actual changes from baseline of continuous clinical chemistry parameters will be summarized descriptively, by actual treatment/dose level and visit/time point. Categorical outcomes will be summarized by frequency tabulations.


  19. Part 1: Number of participants with abnormal urinalysis parameters. [ Time Frame: Up to Day 5 ]

    Urinalysis will include: volume, specific gravity, pH, protein, glucose, ketones, blood, leukocyte esterase, nitrite, bilirubin, urobilinogen, reflex microscopy.

    Urinalysis results will be summarized at each protocol scheduled time point, by actual treatment/dose level at each time point, using frequency tabulations.


  20. Part 2: Number of participants with abnormal urinalysis parameters. [ Time Frame: Up to Day 12 ]

    Urinalysis will include: volume, specific gravity, pH, protein, glucose, ketones, blood, leukocyte esterase, nitrite, bilirubin, urobilinogen, reflex microscopy.

    Urinalysis results will be summarized at each protocol scheduled time point, by actual treatment/dose level at each time point, using frequency tabulations.


  21. Part 1: Summary of concomitant medications taken by study participants. [ Time Frame: Up to Day 5 ]

    Prior and concomitant medications will be grouped by preferred term (PT). The summary tables will show the number and percentage of participants by PT, for all participants overall.

    Prior medications are those medications that were stopped prior to first investigational product. Concomitant medications are medications taken at least once after investigational product. Medications stopped on the same day as investigational product will be considered as prior medication only.

    Only concomitant medications will be summarized. Prior medications will be listed only. For the summaries of concomitant medications, participants who take the same medication (in terms of the PT) more than once will only be counted once for that medication.


  22. Part 2: Summary of concomitant medications taken by study participants. [ Time Frame: Up to Day 12 ]

    Prior and concomitant medications will be grouped by preferred term (PT). The summary tables will show the number and percentage of participants by PT, for all participants overall.

    Prior medications are those medications that were stopped prior to first investigational product. Concomitant medications are medications taken at least once after investigational product. Medications stopped on the same day as investigational product will be considered as prior medication only.

    Only concomitant medications will be summarized. Prior medications will be listed only. For the summaries of concomitant medications, participants who take the same medication (in terms of the PT) more than once will only be counted once for that medication.



Secondary Outcome Measures :
  1. Part 1: Maximum observed plasma drug concentration (Cmax) of RJX. [ Time Frame: Day 1: 90 min, 60 min, and 30 min prior to infusion; 15 min, 30 min, 45 min post start of infusion; 30 min, 1 hr, 1.5 hr, 2 hr, 4 hr, 8 hr, 10 hr, 12 hr, and 24 hr post end of infusion. ]
    Blood samples will be collected for pharmacokinetic analysis of RJX at the specified time points. The maximum observed concentrations of RJX components will be evaluated from plasma and will be listed individually and summarized by dose levels. Cmax will be assessed for proportionality.

  2. Part 2: Maximum observed plasma drug concentration (Cmax) of RJX. [ Time Frame: Day 1 & Day 7: 90 min, 60 min, and 30 min prior to infusion; 15 min, 30 min, 45 min post start of infusion; and 30 min, 1 hr, 1.5 hr, 2 hr, 4 hr, 8 hr, 10 hr, 12 hr, and 24 hr post end of infusion. Day 4 & Day 6: 30 min prior to infusion. ]
    Blood samples will be collected for pharmacokinetic analysis of RJX at the specified time points. The maximum observed concentrations of RJX components will be evaluated from plasma and will be listed individually and summarized by dose levels. Cmax will be assessed for proportionality.

  3. Part 1: Time to maximum observed plasma drug concentration (Tmax). [ Time Frame: Day 1: 90 min, 60 min, and 30 min prior to infusion; 15 min, 30 min, 45 min post start of infusion; 30 min, 1 hr, 1.5 hr, 2 hr, 4 hr, 8 hr, 10 hr, 12 hr, and 24 hr post end of infusion. ]
    Blood samples will be collected for pharmacokinetic analysis of RJX at the specified time points. The time to maximum observed concentrations of RJX components will be evaluated from plasma and will be listed individually and summarized by dose levels.

  4. Part 2: Time to maximum observed plasma drug concentration (Tmax). [ Time Frame: Day 1 & Day 7: 90 min, 60 min, and 30 min prior to infusion; 15 min, 30 min, 45 min post start of infusion; and 30 min, 1 hr, 1.5 hr, 2 hr, 4 hr, 8 hr, 10 hr, 12 hr, and 24 hr post end of infusion. Day 4 & Day 6: 30 min prior to infusion. ]
    Blood samples will be collected for pharmacokinetic analysis of RJX at the specified time points. The time to maximum observed concentrations of RJX components will be evaluated from plasma and will be listed individually and summarized by dose levels.

  5. Part 1: Area under the concentration-time curve from time 0 to last (AUC[0-last]). [ Time Frame: Day 1: 90 min, 60 min, and 30 min prior to infusion; 15 min, 30 min, 45 min post start of infusion; 30 min, 1 hr, 1.5 hr, 2 hr, 4 hr, 8 hr, 10 hr, 12 hr, and 24 hr post end of infusion. ]
    Blood samples will be collected for pharmacokinetic analysis of RJX at the specified time points. The AUC[0-last] of RJX components will be evaluated from plasma and will be listed individually and summarized by dose levels. AUC[0-last] will be assessed for proportionality.

  6. Part 2: Area under the concentration-time curve from time 0 to last (AUC[0-last]). [ Time Frame: Day 1 & Day 7: 90 min, 60 min, and 30 min prior to infusion; 15 min, 30 min, 45 min post start of infusion; and 30 min, 1 hr, 1.5 hr, 2 hr, 4 hr, 8 hr, 10 hr, 12 hr, and 24 hr post end of infusion. Day 4 & Day 6: 30 min prior to infusion. ]
    Blood samples will be collected for pharmacokinetic analysis of RJX at the specified time points. The AUC[0-last] of RJX components will be evaluated from plasma and will be listed individually and summarized by dose levels. AUC[0-last] will be assessed for proportionality.

  7. Part 1: Area under the concentration-time curve from time 0 to infinity (AUC[0-inf]). [ Time Frame: Day 1: 90 min, 60 min, and 30 min prior to infusion; 15 min, 30 min, 45 min post start of infusion; 30 min, 1 hr, 1.5 hr, 2 hr, 4 hr, 8 hr, 10 hr, 12 hr, and 24 hr post end of infusion. ]
    Blood samples will be collected for pharmacokinetic analysis of RJX at the specified time points. The AUC[0-inf] of RJX components will be evaluated from plasma and will be listed individually and summarized by dose levels. AUC[0-inf] will be assessed for proportionality.

  8. Part 2: Area under the concentration-time curve from time 0 to infinity (AUC[0-inf]). [ Time Frame: Day 1 & Day 7: 90 min, 60 min, and 30 min prior to infusion; 15 min, 30 min, 45 min post start of infusion; and 30 min, 1 hr, 1.5 hr, 2 hr, 4 hr, 8 hr, 10 hr, 12 hr, and 24 hr post end of infusion. Day 4 & Day 6: 30 min prior to infusion. ]
    Blood samples will be collected for pharmacokinetic analysis of RJX at the specified time points. The AUC[0-inf] of RJX components will be evaluated from plasma and will be listed individually and summarized by dose levels. AUC[0-inf] will be assessed for proportionality.

  9. Part 1: Terminal elimination half-life (t1/2). [ Time Frame: Day 1: 90 min, 60 min, and 30 min prior to infusion; 15 min, 30 min, 45 min post start of infusion; 30 min, 1 hr, 1.5 hr, 2 hr, 4 hr, 8 hr, 10 hr, 12 hr, and 24 hr post end of infusion. ]
    Blood samples will be collected for pharmacokinetic analysis of RJX at the specified time points. The t1/2 of RJX components will be evaluated from plasma and will be listed individually and summarized by dose levels. T1/2 is defined as the time required for one half of the total amount of a particular substance in a biological system to be degraded by biological processes.

  10. Part 2: Terminal elimination half-life (t1/2). [ Time Frame: Day 1 & Day 7: 90 min, 60 min, and 30 min prior to infusion; 15 min, 30 min, 45 min post start of infusion; and 30 min, 1 hr, 1.5 hr, 2 hr, 4 hr, 8 hr, 10 hr, 12 hr, and 24 hr post end of infusion. Day 4 & Day 6: 30 min prior to infusion. ]
    Blood samples will be collected for pharmacokinetic analysis of RJX at the specified time points. The t1/2 of RJX components will be evaluated from plasma and will be listed individually and summarized by dose levels. T1/2 is defined as the time required for one half of the total amount of a particular substance in a biological system to be degraded by biological processes.

  11. Part 1: Apparent clearance (Cl). [ Time Frame: Day 1: 90 min, 60 min, and 30 min prior to infusion; 15 min, 30 min, 45 min post start of infusion; 30 min, 1 hr, 1.5 hr, 2 hr, 4 hr, 8 hr, 10 hr, 12 hr, and 24 hr post end of infusion. ]
    Blood samples will be collected for pharmacokinetic analysis of RJX at the specified time points. The Cl of RJX components will be evaluated from plasma and will be listed individually and summarized by dose levels. Clearance is a proportionality factor that relates the rate of elimination to the concentration measured in the body.

  12. Part 2: Apparent clearance (Cl). [ Time Frame: Day 1 & Day 7: 90 min, 60 min, and 30 min prior to infusion; 15 min, 30 min, 45 min post start of infusion; and 30 min, 1 hr, 1.5 hr, 2 hr, 4 hr, 8 hr, 10 hr, 12 hr, and 24 hr post end of infusion. Day 4 & Day 6: 30 min prior to infusion. ]
    Blood samples will be collected for pharmacokinetic analysis of RJX at the specified time points. The Cl of RJX components will be evaluated from plasma and will be listed individually and summarized by dose levels. Clearance is a proportionality factor that relates the rate of elimination to the concentration measured in the body.

  13. Part 1: Apparent volume of distribution (V). [ Time Frame: Day 1: 90 min, 60 min, and 30 min prior to infusion; 15 min, 30 min, 45 min post start of infusion; 30 min, 1 hr, 1.5 hr, 2 hr, 4 hr, 8 hr, 10 hr, 12 hr, and 24 hr post end of infusion. ]
    Blood samples will be collected for pharmacokinetic analysis of RJX at the specified time points. The Cl of RJX components will be evaluated from plasma and will be listed individually and summarized by dose levels. The volume of distribution is a proportionality factor that relates the amount of drug in the body to the concentration of drug measured in a biological fluid.

  14. Part 2: Apparent volume of distribution (V). [ Time Frame: Day 1 & Day 7: 90 min, 60 min, and 30 min prior to infusion; 15 min, 30 min, 45 min post start of infusion; and 30 min, 1 hr, 1.5 hr, 2 hr, 4 hr, 8 hr, 10 hr, 12 hr, and 24 hr post end of infusion. Day 4 & Day 6: 30 min prior to infusion. ]
    Blood samples will be collected for pharmacokinetic analysis of RJX at the specified time points. The Cl of RJX components will be evaluated from plasma and will be listed individually and summarized by dose levels. The volume of distribution is a proportionality factor that relates the amount of drug in the body to the concentration of drug measured in a biological fluid.

  15. Part 1: pH from venous blood. [ Time Frame: Day 1: 30 min prior to infusion; 45 min post start of infusion; and 30 min, 1 hr, and 4 hr post end of infusion. ]
    Blood samples will be collected for pharmacodynamic analysis of RJX at the specified time points. Blood pH will be summarized at each protocol scheduled time point, by actual treatment/dose level at each time point, using frequency tabulations.

  16. Part 2: pH from venous blood. [ Time Frame: Day 1 & Day 7: 30 min prior to infusion; 45 min post start of infusion; and 30 min, 1 hr, and 4 hr post end of infusion. ]
    Blood samples will be collected for pharmacodynamic analysis of RJX at the specified time points. Blood pH will be summarized at each protocol scheduled time point, by actual treatment/dose level at each time point, using frequency tabulations.

  17. Part 1: Blood bicarbonate. [ Time Frame: Day 1: 30 min prior to infusion; 45 min post start of infusion; and 30 min, 1 hr, and 4 hr post end of infusion. ]
    Blood samples will be collected for pharmacodynamic analysis of RJX at the specified time points. Blood pH will be summarized at each protocol scheduled time point, by actual treatment/dose level at each time point, using frequency tabulations.

  18. Part 2: Blood bicarbonate. [ Time Frame: Day 1 & Day 7: 30 min prior to infusion; 45 min post start of infusion; and 30 min, 1 hr, and 4 hr post end of infusion. ]
    Blood samples will be collected for pharmacodynamic analysis of RJX at the specified time points. Blood pH will be summarized at each protocol scheduled time point, by actual treatment/dose level at each time point, using frequency tabulations.

  19. Part 1: Urinary pH [ Time Frame: Day 1 ]
    The urine sample will be collected prior to infusion and at the first voluntary void post the end of infusion to evaluate urine pH. Urinary pH will be summarized at each protocol scheduled time point, by actual treatment/dose level at each time point, using frequency tabulations.

  20. Part 2: Urinary pH [ Time Frame: Day 1 & Day 7 ]
    The urine sample will be collected prior to infusion and at the first voluntary void post the end of infusion to evaluate urine pH. Urinary pH will be summarized at each protocol scheduled time point, by actual treatment/dose level at each time point, using frequency tabulations.

  21. Part 1: Analysis of Electrocardiogram Extraction QT/QTc Variables [ Time Frame: Part 1: A 25-hour continuous recording will be performed starting within 1.5 hours prior to infusion on Day 1. ]
    Subjects will be supinely resting for at least 10 minutes before and 5 minutes after each time point for ECG extraction. A cardiac report will be prepared for the extensive evaluation of QT/QTc endpoints.

  22. Part 2: Analysis of Electrocardiogram Extraction QT/QTc Variables [ Time Frame: Part 2: A 25-hour continuous recording will be performed starting within 1.5 hours prior to infusion on Day 1 and Day 7. ]
    Subjects will be supinely resting for at least 10 minutes before and 5 minutes after each time point for ECG extraction. A cardiac report will be prepared for the extensive evaluation of QT/QTc endpoints.


Other Outcome Measures:
  1. Exploratory Biomarkers [ Time Frame: Part 2: Day 1 and Day 7 ]
    A urine sample will be collected prior to infusion and at the first voluntary void post the end of infusion to evaluate exploratory biomarkers. Relevant exploratory biomarkers will be summarized at each protocol scheduled time point, by actual treatment/dose level at each time point, using frequency tabulations.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Healthy male and female participants aged 18 to 50 years inclusive (Cohort 1 to Cohort 5) or 51 to 70 years inclusive (Cohort 6 only),at the time of screening;
  2. Have a body mass index of 18 kg/m2 to 35 kg/m2, inclusive, at screening. In addition, weight cannot exceed 132 kg;
  3. Have negative screening assessment for viral hepatitis (hepatitis B or hepatitis C) and human immunodeficiency virus;
  4. Have negative routine urine drug screen and negative alcohol breath test at screening and Day -1;
  5. A female participant is eligible to participate if she is not pregnant,not breastfeeding, and at least 1 of the following conditions applies:

    1. Not of childbearing potential, defined as surgically sterile (documented hysterectomy, bilateral salpingectomy, tubal ligation or bilateral oophorectomy) or postmenopausal (no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone [FSH] level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy; however, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient);
    2. Of childbearing potential and agrees to use 2 highly effective methods of contraception consistently during the treatment period and for at least 60 days after the last dose of investigational product;
  6. A male participant with a female partner of childbearing potential is eligible to participate if he agrees to use acceptable contraception during the treatment period and for at least 60 days after the last dose of investigational product and refrains from donating sperm during this period;
  7. Clinical laboratory test results within normal reference range for the population or investigator site, or any results that are judged to be not clinically significant by the investigator;
  8. Venous access sufficient to allow for blood sampling per the protocol;
  9. Reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures;
  10. Given written informed consent prior to any study procedures being performed

Exclusion Criteria:

  1. Have a history of clinically relevant cardiovascular disease, cancer, respiratory, hepatic, renal, gastrointestinal, endocrine (diabetes), hematological, or neurological disorders. Cohort 6 only - elderly participants with well controlled hypercholesterolemia on a stable dose of statin therapy or well controlled hypertension on a stable dose of antihypertensive medication(s), excluding diuretics, are allowed in Cohort 6 per the clinical judgment of the investigator.
  2. Have impaired renal function (defined as estimated glomerular filtration rate <90 cc/min/1.73m2 Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) creatinine equation at screening);
  3. Have a hsCRP above 1.25 × upper limit of normal;
  4. Have a clinically significant abnormality in the 12-lead electrocardiogram (ECG) or prolongation of QTcF >440 ms in males and >450 ms in females;
  5. Have a supine systolic blood pressure (BP) greater than 140 mm Hg or a diastolic BP greater than 90 mm Hg. Up to 2 additional measurements may be undertaken after an appropriate resting interval at screening to confirm eligibility;
  6. Are currently enrolled in a clinical trial involving an investigational product, or are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study;
  7. Have received an investigational product within the last 3 months;
  8. Have suspected allergies to RJX, related compounds, or any components of the formulation, or history of significant atopy;
  9. Regularly use known drugs of abuse and/or show positive findings on drug screening or Day -1;
  10. Are women who are pregnant, intend to become pregnant, or are lactating;
  11. Participants will be excluded for using any of the following medication:

    • aspirin, multivitamins/vitamins or mineral preparations within 14 days prior to investigational product administration or 24 hours post the last infusion;
    • prescription, herbal or over the counter medications within 14 days of investigational product administration, with the exception of:

      • simple analgesics such as paracetamol, excluding aspirin
      • oral non-steroidal anti-inflammatory drugs
      • thyroid treatment, estrogen replacement therapy
      • hormonal contraception
      • Statins and anti-hypertensives are permitted for elderly participants in Cohort 6 (Part 1) - see inclusion criteria #1
  12. Have donated blood of more than 500 mL within 4 weeks prior to study enrollment;
  13. Have an average weekly alcohol intake that exceeds 21 units per week (males up to age 65) and 14 units per week (males over 65 and females) or are unwilling to stop alcohol consumption for 24 hours prior to study site admission (1 unit = 12 oz or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits). Participants must have a of negative alcohol breath test at Day -1 and no evidence of alcohol abuse in the previous 12 months, defined as > 21 weekly units for males up to age 65 and > 14 weekly units for males over 65 and females;
  14. Have smoked cigarettes in the last 90 days (including occasional smokers who have smoked more than 5 cigarettes per month within the last 90 days);
  15. In the opinion of the investigator or sponsor, are unsuitable for inclusion in the study;
  16. Are investigator site personnel directly affiliated with this study and their immediate families. Immediate family is defined as a spouse, parent, child or sibling, whether biological or legally adopted;
  17. Are Reven employees or employees of third-party organizations involved with the study who require exclusion of their employees.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03680105


Locations
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United States, Texas
ICON Early Phase Services
San Antonio, Texas, United States, 78209
Sponsors and Collaborators
Reven Pharmaceuticals, Inc.
ICON plc
ERT: Clinical Trial Technology Solutions
Investigators
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Principal Investigator: Dennis A Ruff, MD ICON Early Phase Services

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Responsible Party: Reven Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT03680105     History of Changes
Other Study ID Numbers: RPI003
First Posted: September 21, 2018    Key Record Dates
Last Update Posted: February 11, 2019
Last Verified: February 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Ischemia
Pathologic Processes