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A Phase 1 Study to Evaluate Safety, Tolerability, and PK of TBI-223 in Healthy Adults

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03758612
Recruitment Status : Recruiting
First Posted : November 29, 2018
Last Update Posted : January 22, 2020
Sponsor:
Information provided by (Responsible Party):
Global Alliance for TB Drug Development

Brief Summary:
Partially-Blinded, Placebo-Controlled, Randomized, Single Ascending Dose (SAD) with a Food Effect Cohort to Evaluate the Safety, Tolerability, and Pharmacokinetics of TBI-223 in Healthy Adults.

Condition or disease Intervention/treatment Phase
Tuberculosis Tuberculosis, Pulmonary Drug: TBI-223 50mg Drug: Placebo for TBI-223 50mg Drug: TBI-223 100, 300, 600, 1200, 1400 mg Drug: Placebo for TBI-223 100, 300, 600, 1200, 1400 mg Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 1, Partially-Blinded, Placebo-Controlled, Randomized, Single Ascending Dose (SAD) With a Food Effect Cohort Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TBI-223 in Healthy Adult Participants.
Actual Study Start Date : January 16, 2019
Estimated Primary Completion Date : April 2020
Estimated Study Completion Date : May 1, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

Arm Intervention/treatment
Active Comparator: Cohort 1 (sentinel group) - Active
Single dose of TBI-223 50 mg (n=2) dosed at least 24 hours before the Cohort 1 (remainder of cohort)
Drug: TBI-223 50mg
TBI-223 50 mg supplied for oral administration.

Placebo Comparator: Cohort 1 (sentinel group) - Placebo
Single dose of Placebo for TBI-223 50 mg (n=1) dosed at least 24 hours before the Cohort 1 (remainder of cohort)
Drug: Placebo for TBI-223 50mg
Matching placebo for TBI-223 50mg supplied for oral administration.

Active Comparator: Cohort 1 (remainder of cohort) - Active
Single dose of TBI-223 50 mg (n=4)
Drug: TBI-223 50mg
TBI-223 50 mg supplied for oral administration.

Placebo Comparator: Cohort 1 (remainder of cohort) - Placebo
Single dose of Placebo for TBI-223 50 mg (n=1)
Drug: Placebo for TBI-223 50mg
Matching placebo for TBI-223 50mg supplied for oral administration.

Active Comparator: Cohort 2 - Cohort 6 - Active
Single dose of TBI-223 100, 300, 600, 1200, 1400 mg; n=3 per cohort
Drug: TBI-223 100, 300, 600, 1200, 1400 mg
TBI-223 100, 300, 600, 1200, 1400 mg supplied for oral administration.

Placebo Comparator: Cohort 2 - Cohort 6 - Placebo
Single dose of matching Placebo for TBI-223 100, 300, 600, 1200, 1400 mg, n=1 per cohort
Drug: Placebo for TBI-223 100, 300, 600, 1200, 1400 mg
Matching placebo for 100, 300, 600, 1200, 1400 mg TBI-223 supplied for oral administration.




Primary Outcome Measures :
  1. Number of participants with treatment-related and other adverse events as assessed by the Division of Microbiology and Infectious Disease (DMID) Toxicity Table [ Time Frame: Day 1 - Day 4 Post Dose ]
    Safety assessments will include physical and detailed neurological examinations (including assessments of mental status, cranial nerves, motor system, sensory system, reflexes, coordination and gait), vital signs including heart rate and respiratory rate, ECGs, cardiac monitor (Holter monitoring starting 24 hours prior to dose and continuing for 48 hours post dose), collection of all AEs (including treatment- related AEs and SAEs) and clinical laboratory tests (including hematology, serum chemistry, coagulation, and urinalysis prior to dosing and at protocol defined time points up to 72 hours post dose). Subjects will be called 11 days post dose to query for AEs.


Secondary Outcome Measures :
  1. Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using AUClast [ Time Frame: Day 1 - Day 2 ]
    AUClast will be calculated from plasma concentrations of TBI-223 and M2. AUClast is area under the concentration-time curve from time-zero to the time of the last quantifiable concentration; calculated using the linear trapezoidal rule.

  2. Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using AUCinf [ Time Frame: Day 1 - Day 2 ]
    AUCinf will be calculated from plasma concentrations of TBI-223 and M2. AUCinf is area under the concentration-time curve from time-zero extrapolated to infinity.

  3. Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using Cmax [ Time Frame: Day 1 - Day 2 ]
    Cmax will be calculated from plasma concentrations of TBI-223 and M2. Cmax is maximum concentration, determined directly from individual concentration-time data.

  4. Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using Tmax [ Time Frame: Day 1 - Day 2 ]
    Tmax will be calculated from plasma concentrations of TBI-223 and M2. Tmax is time of the maximum concentration.

  5. Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using CL/F [ Time Frame: Day 1 - Day 2 ]
    CL/F will be calculated from plasma concentrations of TBI-223 and M2. CL/F is apparent total clearance after single administration.

  6. Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using Vz/F [ Time Frame: Day 1 - Day 2 ]
    Vz/F will be calculated from plasma concentrations of TBI-223 and M2. Vz/F is apparent volume of distribution in the terminal phase.

  7. Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using λz [ Time Frame: Day 1 - Day 2 ]
    λz will be calculated from plasma concentrations of TBI-223 and M2. λz is the observed terminal rate constant; estimated by linear regression through at least three data points in the terminal phase of the log concentration-time profile.

  8. Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using T1/2 [ Time Frame: Day 1 - Day 2 ]
    T1/2 will be calculated from plasma concentrations of TBI-223 and M2. T½ or t½ is the observed terminal half-life.

  9. Compare the rate and extent of absorption of a single dose of TBI-223 using AUClast, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects [ Time Frame: Day 1 - Day 2 ]
    AUClast will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. AUClast is area under the concentration-time curve from time-zero to the time of the last quantifiable concentration; calculated using the linear trapezoidal rule.

  10. Compare the rate and extent of absorption of a single dose of TBI-223 using AUCinf, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects [ Time Frame: Day 1 - Day 2 ]
    AUCinf will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. AUCinf is area under the concentration-time curve from time-zero extrapolated to infinity.

  11. Compare the rate and extent of absorption of a single dose of TBI-223 using Cmax, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects [ Time Frame: Day 1 - Day 2 ]
    Cmax will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. Cmax is maximum concentration, determined directly from individual concentration-time data.

  12. Compare the rate and extent of absorption of a single dose of TBI-223 using Tmax, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects [ Time Frame: Day 1 - Day 2 ]
    Tmax will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. Tmax is time of the maximum concentration.

  13. Compare the rate and extent of absorption of a single dose of TBI-223 using CL/F, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects [ Time Frame: Day 1 - Day 2 ]
    CL/F will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. CL/F is apparent total clearance after single administration.

  14. Compare the rate and extent of absorption of a single dose of TBI-223 using Vz/F, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects [ Time Frame: Day 1 - Day 2 ]
    Vz/F will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. Vz/F is apparent volume of distribution in the terminal phase.

  15. Compare the rate and extent of absorption of a single dose of TBI-223 using λz, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects [ Time Frame: Day 1 - Day 2 ]
    λz will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. λz is the observed terminal rate constant; estimated by linear regression through at least three data points in the terminal phase of the log concentration-time profile.

  16. Compare the rate and extent of absorption of a single dose of TBI-223 using T1/2, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects [ Time Frame: Day 1 - Day 2 ]
    T1/2 will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. T½ or t½ is the observed terminal half-life.



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:   19 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

All volunteers must satisfy the following criteria to be considered for study participation:

  1. Understands study procedures and voluntarily provides written informed consent prior to the start of any study-specific procedures.
  2. Is a healthy adult male or a healthy adult female of non-childbearing potential, 19 to 50 years of age (inclusive) at the time of screening.
  3. Has a body mass index (BMI) ≥18.5 and ≤32.0 (kg/m2) and a body weight of no less than 50.0 kg.
  4. Is medically healthy with no clinically significant screening results, as determined by the Principal Investigator (e.g., laboratory profiles are normal up to and including Grade 1 per DMID toxicity tables; Appendix 3), medical history, vital signs, ECG, or physical/neurological examination findings. Note: If exclusionary lab criteria are met, values may be confirmed by repeat evaluation.
  5. Has not used tobacco- or nicotine-containing products (including smoking cessation products), for a minimum of 6 months before dosing.
  6. If female, she has undergone one of the following sterilization procedures at least 6 months before dosing:

    • Hysteroscopic sterilization;
    • Bilateral tubal ligation or bilateral salpingectomy;
    • Hysterectomy; or
    • Bilateral oophorectomy;
    • Or is postmenopausal with amenorrhea for at least 1 year before the first dose with serum follicle-stimulating hormone (FSH) levels consistent with postmenopausal status (i.e., greater than 40 mIU/mL) at screening.
  7. If a non-vasectomized male (or male vasectomized less than 120 days prior to study start) he must agree to the following during study participation and for 90 days after the last administration of study drug:

    • Use a condom with spermicide while engaging in sexual activity or be sexually abstinent
    • Not donate sperm during this time. In the event the sexual partner is surgically sterile or postmenopausal, use of a condom with spermicide is not necessary. None of the birth control restrictions listed above are required for vasectomized males whose procedure was performed more than 120 days before study start.
  8. Is willing to answer inclusion and exclusion criteria questionnaire at check-in.
  9. Is able to comply with the protocol and the assessments therein, including all restrictions.
  10. Is willing and able to remain in the study unit for the entire duration of the assigned confinement period(s), return for outpatient visit(s), and receive a phone call for follow-up questioning about AEs.
  11. If enrolled in the food-effect cohort, is willing and able to consume the entire high-calorie, high-fat breakfast meal in the timeframe required.

Exclusion Criteria:

Volunteers will be excluded from study participation for any of the following:

  1. History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological (including epilepsy), oncologic, or psychiatric disease or any other condition that, in the opinion of the Investigator, would jeopardize the safety of the subject or the validity of the study results.
  2. Evidence on physical exam and targeted neurologic exam of specific findings such as resting or intention tremor, dysmetria, nystagmus or ataxia, or abnormal deep tendon reflexes (either zero or hyper-reflexia).
  3. History of any illness that, in the opinion of the Investigator, might confound the results of the study or pose an additional risk to the subject by their participation in the study.
  4. Surgery within the past 90 days prior to dosing as determined by the Investigator to be clinically relevant, or any history of cholecystectomy.
  5. History or presence of alcoholism or drug abuse within the past 2 years as determined by the Investigator to be clinically relevant.
  6. History of sensitivity or contraindication to use of linezolid, sulfa drugs, or any study investigational products.
  7. Participation in another clinical trial within 30 days prior to dosing.
  8. Female subjects who are pregnant or lactating.
  9. Positive result on a urine drug/alcohol/cotinine screen at Baseline or check-in.
  10. Seated blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at screening. Out-of-range vital signs may be repeated once for confirmation.
  11. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening. Out-of-range vital signs may be repeated once for confirmation.
  12. Any clinically significant ECG abnormality at Screening (as deemed by decision of the Investigator and the Sponsor's Medical Monitor). NOTE: The following may be considered not clinically significant without consulting the Sponsor's Medical Monitor:

    • Mild first degree A-V block (P-R interval <0.23 sec)
    • Right or left axis deviation
    • Incomplete right bundle branch block
    • Isolated left anterior fascicular block (left anterior hemiblock) in younger athletic subjects
    • Early repolarization
    • Tall T waves
    • RSR in V1/V2 consistent with right ventricular conduction delay (with acceptable QRS)
    • Sinus rhythm or sinus bradycardia with sinus arrhythmia
    • Minimal or moderate voltage criteria for left ventricular hypertrophy (LVH).
  13. QTcF interval >450 msec for males or >470 msec for females at screening, Day -1, or Day 1 (pre-dose), or history of prolonged QT syndrome. For the triplicate ECGs taken at screening and on Day -1, the average QTcF interval of the three ECG recordings will be used to determine qualification.
  14. Family history of long-QT syndrome or sudden death without a preceding diagnosis of a condition that could be causative of sudden death (such as known coronary artery disease, congestive heart failure, or terminal cancer).
  15. History of one or any combination of, the following:

    • Seizures or seizure disorders, other than childhood febrile seizures
    • Brain surgery
    • History of head injury in the last 5 years
    • Any serious disorder of the central nervous system (CNS) or related neurological system, particularly one that may lower the seizure threshold.
  16. Lactose intolerant.
  17. History or presence of allergic or adverse response to Listerine breath strips or aspartame. Specific Treatments
  18. Use of any prescription medication within 14 days prior to dosing.
  19. Use of any of the following medications within 30 days before the first dose of study drug or during the study drug treatment period: monoamine oxidase (MAO) inhibitors (phenelzine, tranylcypromine), tricyclic antidepressants (amitriptyline, nortriptyline, protriptyline, doxepin, amoxapine, etc.), antipsychotics such as chlorpromazine and buspirone, serotonin re-uptake inhibitors (fluoxetine, paroxetine, sertraline, etc.), bupropion, agents known to prolong the QTc interval (erythromycin, clarithromycin, astemizole, type Ia [quinidine, procainamide, disopyramide] and III [amiodarone, sotalol] anti-arrhythmics, carbamazepine, sulfonylureas, and meperidine).
  20. Use of any over-the-counter (OTC) medication, including herbal products and vitamins, within 7 days prior to dosing, except acetaminophen. Up to 3 grams per day of acetaminophen is allowed at the discretion of the Investigator prior to dosing.
  21. Use of any drugs or substances known to be significant inhibitors of cytochrome P450 (CYP) enzymes and/or significant inhibitors or substrates of P-glycoprotein (P-gp) and/or organic anion transporting polypeptides (OATP) within 14 days prior to the first dose of study drug.
  22. Use of any drugs or substances known to be inducers of CYP enzymes and/or Pgp, including St. John's Wort, within 30 days prior to the first dose of study drug.
  23. Use of any drugs or substance known to lower the seizure threshold. Laboratory Abnormalities
  24. Serum magnesium, potassium, or calcium laboratory values outside of the normal range at screening. If exclusionary lab criteria are met, values may be confirmed by repeat evaluation.
  25. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (HCV).
  26. History or presence of allergic or adverse response to Listerine breath strips or aspartame.

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): NCT03758612


Contacts
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Contact: Fran Pappas 646-616-8664 fran.pappas@tballiance.org

Locations
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United States, Texas
Worldwide Clinical Trials (WCT) Recruiting
San Antonio, Texas, United States, 78217
Contact: Cynthia Zamora, PhD         
Sponsors and Collaborators
Global Alliance for TB Drug Development
Investigators
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Study Chair: Paul Bruinenberg, MD, MBA Global Alliance for TB Drug Development

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Responsible Party: Global Alliance for TB Drug Development
ClinicalTrials.gov Identifier: NCT03758612    
Other Study ID Numbers: TBI-223-CL-001
First Posted: November 29, 2018    Key Record Dates
Last Update Posted: January 22, 2020
Last Verified: January 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 Global Alliance for TB Drug Development:
TB
Tuberculosis
TBI-223
Pulmonary Tuberculosis
Additional relevant MeSH terms:
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Tuberculosis
Tuberculosis, Pulmonary
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections