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Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of ST-2427

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ClinicalTrials.gov Identifier: NCT04475198
Recruitment Status : Not yet recruiting
First Posted : July 17, 2020
Last Update Posted : July 17, 2020
Sponsor:
Collaborator:
National Institute on Drug Abuse (NIDA)
Information provided by (Responsible Party):
SiteOne Therapeutics, Inc.

Brief Summary:

This randomized, double-blind, placebo controlled, study will be conducted to evaluate the safety, tolerability, and pharmacokinetics of ST-2427. The study will be conducted in 2 parts. In Part A of this study, subjects will be randomized to receive a single dose of ST-2427 or placebo in a Single Ascending Dose (SAD) design. In Part B of this study, subjects will be randomized to receive up to 6 repeat doses of ST-2427 or placebo, administered twice-daily (BID) every 12 hours, in a Multiple Ascending Dose (MAD) design. In Part A and Part B, study drug (ST-2427 or placebo) will be administered intravenously (IV) over 1 hour.

A total of 48 subjects will be enrolled. Subjects will be randomized in a 4:2 ratio of ST-2427 to placebo. Study drug will be blinded to all subjects and investigators.


Condition or disease Intervention/treatment Phase
Acute, Post-operative Pain Drug: ST-2427 Drug: Placebo Phase 1

Detailed Description:

This is a Phase 1, randomized, double-blind, placebo-controlled study in healthy adult males and females of non-child-bearing potential to evaluate the safety, tolerability, and pharmacokinetics (PK) of ST-2427. This trial will include careful assessments of treatment effects on vital signs including cardiac and respiratory function and body temperature over a range of doses of ST-2427, administered as single or repeat doses for up to 3 days. SiteOne Therapeutics, Inc. plans to use the safety, tolerability, and PK findings from this study to inform the doses and study design for Phase 2 clinical studies in subjects with acute post-operative pain.

Approximately 48 subjects, 6 subjects into each of 8 cohorts, will be enrolled in this study at a single clinical site.

This study will be conducted in 2 parts. In Part A of this study, subjects will be randomized 4:2 to receive a single dose of ST-2427 or placebo in a Single Ascending Dose (SAD) design. Part A will evaluate 5 dose strengths of ST-2427, infused intravenously (IV) over 1 hour; one dose level in each of 5 cohorts of subjects. In Part B of this study, subjects will be randomized 4:2 to receive up to 6 repeat doses of ST-2427 or placebo, administered twice-daily (BID) every 12 hours, in a Multiple Ascending Dose (MAD) design. Part B will evaluate 3 dose strengths of ST-2427, infused IV over 1 hour, twice daily for 3 days [a total of 6 repeat doses] in 3 cohorts.

Enrollment into Part B will commence after the safety, tolerability and PK of the SAD have been examined.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking Description: Double-blind
Primary Purpose: Treatment
Official Title: A Phase 1, Randomized, Double-Blind, Placebo-Controlled Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of ST-2427 IV Infusion in Healthy Subjects
Estimated Study Start Date : September 2020
Estimated Primary Completion Date : February 2021
Estimated Study Completion Date : May 2021

Arm Intervention/treatment
Experimental: Part A Single Ascending Dose: Cohort 1
7 mg ST-2427 (n=4) or placebo (n=2) administered once over a 60-minute intravenous (IV) infusion. 2 sentinel subjects will receive dosing for review of safety data (ST-2427 n=1, placebo n=1) before remainder of cohort.
Drug: ST-2427
Investigational drug

Drug: Placebo
5% Dextrose Injection

Experimental: Part A Single Ascending Dose: Cohort 2
20 mg ST-2427 (n=4) or placebo (n=2) administered once over a 60-minute intravenous (IV) infusion. 2 sentinel subjects will receive dosing for review of safety data (ST-2427 n=1, placebo n=1) before remainder of cohort.
Drug: ST-2427
Investigational drug

Drug: Placebo
5% Dextrose Injection

Experimental: Part A Single Ascending Dose: Cohort 3
50 mg ST-2427 (n=4) or placebo (n=2) administered once over a 60-minute intravenous (IV) infusion. 2 sentinel subjects will receive dosing for review of safety data (ST-2427 n=1, placebo n=1) before remainder of cohort.
Drug: ST-2427
Investigational drug

Drug: Placebo
5% Dextrose Injection

Experimental: Part A Single Ascending Dose: Cohort 4
100 mg ST-2427 (n=4) or placebo (n=2) administered once over a 60-minute intravenous (IV) infusion. 2 sentinel subjects will receive dosing for review of safety data (ST-2427 n=1, placebo n=1) before remainder of cohort.
Drug: ST-2427
Investigational drug

Drug: Placebo
5% Dextrose Injection

Experimental: Part A Single Ascending Dose: Cohort 5
200 mg ST-2427 (n=4) or placebo (n=2) administered once over a 60-minute intravenous (IV) infusion. 2 sentinel subjects will receive dosing for review of safety data (ST-2427 n=1, placebo n=1) before remainder of cohort.
Drug: ST-2427
Investigational drug

Drug: Placebo
5% Dextrose Injection

Experimental: Part B Multiple Ascending Dose: Cohort 6
ST-2427 (n=4) or placebo (n=2) administered over a 60-minute intravenous (IV) infusion, twice daily for 3 days. Dose of ST-2427 will be determined after review of safety, tolerability and pharmacokinetic data from Cohorts 1-5.
Drug: ST-2427
Investigational drug

Drug: Placebo
5% Dextrose Injection

Experimental: Part B Multiple Ascending Dose: Cohort 7
ST-2427 (n=4) or placebo (n=2) administered over a 60-minute intravenous (IV) infusion, twice daily for 3 days. Dose of ST-2427 will be determined after review of safety, tolerability and pharmacokinetic data from Cohorts 1-5.
Drug: ST-2427
Investigational drug

Drug: Placebo
5% Dextrose Injection

Experimental: Part B Multiple Ascending Dose: Cohort 8
ST-2427 (n=4) or placebo (n=2) administered over a 60-minute intravenous (IV) infusion, twice daily for 3 days. Dose of ST-2427 will be determined after review of safety, tolerability and pharmacokinetic data from Cohorts 1-5.
Drug: ST-2427
Investigational drug

Drug: Placebo
5% Dextrose Injection




Primary Outcome Measures :
  1. Incidence and severity of treatment-emergent adverse events [ Time Frame: Day 1 through Day 8 ]
    For purposes of monitoring safety, treatment-emergent adverse events (AEs) will be graded using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers (FDA 2007) which is appropriate for healthy subjects.

  2. Incidence and severity of adverse events assessed by blood pressure [ Time Frame: Day 1 through Day 8 ]
    Blood pressure, including orthostatic blood pressure (BP; diastolic blood pressure [DBP], systolic blood pressure [SBP], will be used to analyze for change from baseline.

  3. Incidence and severity of adverse events assessed by ECG [ Time Frame: Day 1 through Day 8 ]
    Cardiodynamic evaluation will be performed to evaluate the treatment effects on heart rate-corrected QT interval using the Fridericia (QTcF) corrections, using concentration-QTc analysis, and on other ECG parameters (heart rate, PR and QRS interval and treatment emergent T and U-wave abnormalities).

  4. Incidence and severity of adverse events assessed by Continous Holter Monitoring [ Time Frame: Day 1 through Day 8 ]
    The Holter recordings will also be analyzed for the presence of arrhythmias and for derivation of heart rate variability (HRV).

  5. Incidence and severity of treatment-emergent events assessed by clinical laboratory assessments [ Time Frame: Day 1 through Day 8 ]
    Descriptive statistics will be used to evaluate the treatment effects on clinical laboratory assessments including clinical chemistry, hematology, and urinalysis.

  6. Incidence and severity of adverse events assessed by body weight [ Time Frame: Day 1 through Day 8 ]
    Body weight (kg) will be assessed for changes relative to baseline.


Secondary Outcome Measures :
  1. Pharmacokinetics of ST-2427 concentration in whole blood: Cmax [ Time Frame: Day 1 through Day 5 ]
    PK modeling will be performed using compartmental methods. The maximum concentration of ST-2427 in whole blood after the ST-2427 infusion in the SAD, and after the first and fifth infusions of ST-2427 in the MAD will be measured.

  2. Pharmacokinetics of ST-2427 concentration in whole blood: Elimination half-life [ Time Frame: Day 1 through Day 5 ]
    PK modeling will be performed using compartmental methods. The elimination half-life of ST-2427 in whole blood after the ST-2427 infusion in the SAD, and after the first and fifth infusions of ST-2427 in the MAD will be measured.

  3. Pharmacokinetics of ST-2427 concentration in whole blood: Area under the curve [ Time Frame: Day 1 through Day 5 ]
    PK modeling will be performed using compartmental methods. The AUC (area under the curve) of ST-2427 in whole blood after the ST-2427 infusion in the SAD, and after the first and fifth infusions of ST-2427 in the MAD will be measured.

  4. Pharmacokinetics of ST-2427 concentration in urine [ Time Frame: Day 1 through Day 5 ]
    The ST-2427 concentrations in the urine will be measured in 4 hour increments by cohort for the SAD.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Only subjects who meet the following criteria will be eligible for inclusion:

    1. Healthy adult males and/or females (of non-childbearing potential), 18 to 55 years of age (inclusive) at the time of screening;
    2. Body mass index (BMI) within 18.0 to 35.0 kg/m2, inclusive (minimum weight of at least 50.0 kg at Screening);
    3. Medically healthy without clinically significant abnormalities at the screening visit, including physical examination and vital signs within the following ranges: heart rate 50 to 100 bpm, systolic blood pressure 100 to 149 mmHg; diastolic 70 to 94 mmHg;
    4. The mean QTcF interval duration ≤450 msec for males and ≤470 msec for females measured from the triplicate ECGs taken at least 1 minute apart with QT wave corrected for heart rate (HR) using Fredericia's method
    5. Hemoglobin/hematocrit, white blood cell (WBC) count, and platelet count equal to or greater than the lower limit of normal range of the reference laboratory (may be confirmed upon repeat testing without Sponsor approval);
    6. Creatinine, blood urea nitrogen (BUN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) equal to or less than the upper limit of normal for the reference laboratory (may be confirmed upon repeat testing); results of all other clinical chemistry and urine analytes without any clinically significant abnormality;
    7. Non-smokers (including tobacco, e-cigarettes or marijuana), and no use of any tobacco product for at least 1 month prior to admission in the study;
    8. Willing and able to provide written informed consent;
    9. Willing and able to comply with all study assessments and adhere to the protocol schedule;
    10. Have suitable venous access for blood sampling, as determined by an Investigator at screening;
    11. If female, be of non-childbearing potential (e.g. post-menopausal as demonstrated by follicle stimulating hormone (>40 mIU/mL), or surgically sterilized by tubal ligation or hysterectomy). Site personnel's review of the subject's medical records, medical examination, or medical history interview is acceptable evidence of female sterilization, verbal confirmation is adequate;
    12. If male, willing not to donate sperm from the time of first study drug administration until 90 days after the final administration of study drug. If male and not intending to engage in sexual intercourse over the duration of the study, willing to agree to abstinence at screening. If male and engaging in sexual intercourse, willing to use a double barrier method of contraception (condom and spermicide). The latter criterion applies to all males (and/or female partners) including males who are surgically sterile and must be followed from the time of first study drug administration until 90 days after the final administration of study drug.

Exclusion Criteria:

  • Subjects will be excluded from the study if they meet any of the following criteria:

    1. History or presence of significant cardiovascular (including arrhythmia and ventricular tachyphylaxis), pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic or neurological disease, including any acute illness or surgery within the past 3 months determined by an Investigator to be clinically relevant;
    2. Creatinine, blood urea nitrogen (BUN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) equal to 1.5 x upper limit of normal for the reference laboratory (may be confirmed upon repeat testing);
    3. History of orthostatic reactions
    4. Orthostatic reaction at screening defined as drop in systolic blood pressure by ≥20 mmHg or drop in systolic blood pressure to <90 mmHg on standing for 3 minutes from the supine position.
    5. History of seizure disorders, except for non-complex febrile seizures in childhood with absence of non-febrile seizures in parents and siblings.;
    6. Positive urine drug/alcohol testing at Screening or Day -2;
    7. Positive test results for HIV-1/HIV-2 Antibodies, Hepatitis B surface Antigen (HBsAg) or Hepatitis C Antibody (HCVAb);
    8. Positive test results for COVID-19 (PCR or Antibodies)
    9. History of substance abuse or alcohol abuse (defined as greater than 2 standard drinks per day) within the previous 2 years;
    10. Use of any prescription medication or any over-the-counter medication, including herbal products and vitamins within 14 days or 5 half-lives (whichever is longer) prior to randomization;
    11. Documented hypersensitivity reaction or anaphylaxis to any medication;
    12. Blood donation (excluding plasma donation) of approximately 500 mL within 56 days prior to screening, or receipt of a blood transfusion within 1 year of screening;
    13. Dosed in another investigational clinical trial within 30 days prior to Screening;
    14. Any condition or prior therapy, e.g. seizures, or head trauma, that may lead to CNS effects during the study;
    15. Documented or self-reported history of orthostatic hypotension or symptoms of hypotension such as dizziness, syncope or blurred vision upon standing;
    16. Any condition which is associated with increased brain permeability, e.g. cerebral ischemia, brain trauma, multiple sclerosis, brain tumors, brain infection.

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): NCT04475198


Contacts
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Contact: Debra Odink, Ph.D. +1 (406) 602-4558 debra.odink@site1therapeutics.com

Sponsors and Collaborators
SiteOne Therapeutics, Inc.
National Institute on Drug Abuse (NIDA)
Investigators
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Study Director: Markus Jerling, MD, PhD Unaffliated
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Responsible Party: SiteOne Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT04475198    
Other Study ID Numbers: ST-2427-CS-001
1UG3DA049599 ( U.S. NIH Grant/Contract )
First Posted: July 17, 2020    Key Record Dates
Last Update Posted: July 17, 2020
Last Verified: July 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by SiteOne Therapeutics, Inc.:
Pain
Additional relevant MeSH terms:
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Pain, Postoperative
Postoperative Complications
Pathologic Processes
Pain
Neurologic Manifestations