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Trial of Safety and Tolerability of Oral Verdinexor (KPT-335) in Healthy Adults

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ClinicalTrials.gov Identifier: NCT02431364
Recruitment Status : Terminated (Administrative reason)
First Posted : May 1, 2015
Results First Posted : April 13, 2021
Last Update Posted : April 13, 2021
Sponsor:
Information provided by (Responsible Party):
Karyopharm Therapeutics Inc

Brief Summary:
This is a randomized, double-blind, sequential, dose-escalation, Phase 1 trial to evaluate the safety and tolerability of verdinexor. Verdinexor or placebo will be given on Days 1 and 3 to healthy adult participants.

Condition or disease Intervention/treatment Phase
Healthy Drug: Verdinexor Other: Placebo Phase 1

Detailed Description:

This is a randomized, double-blind, sequential, dose-escalation, Phase 1 trial to evaluate the safety and tolerability of verdinexor. Verdinexor or placebo will be given on Days 1 and 3 to healthy adult participants.

Cohorts of 8 participants each (6 active, 2 placebo) will be sequentially administered verdinexor or placebo (one dose on Day 1 and one dose on Day 3) using a dose-escalation scheme. A conservative, sequential, dose-escalation strategy employing decreasing escalation increments will be used.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 33 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Official Title: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Sequential, Dose-Escalating Trial to Evaluate the Safety and Tolerability of Oral Verdinexor (KPT-335) in Healthy Adult Subjects
Actual Study Start Date : May 26, 2015
Actual Primary Completion Date : October 1, 2015
Actual Study Completion Date : October 1, 2015

Arm Intervention/treatment
Placebo Comparator: Placebo
Participants received matched placebo tablets to verdinexor tablets orally once daily on Days 1 and 3.
Other: Placebo
Participants received placebo matched to verdinexor; Dosage form: coated, immediate release Tablet; Route of administration: oral

Experimental: Verdinexor 5 mg
Participants received verdinexor 5 milligrams (mg) (2 tablets of 2.5 mg each) orally once daily on Days 1 and 3.
Drug: Verdinexor
Participants received verdinexor; Dosage form: coated, immediate release Tablet; Route of administration: oral
Other Name: KPT-335

Experimental: Verdinexor 10 mg
Participants received verdinexor 10 mg tablet orally once daily on Days 1 and 3.
Drug: Verdinexor
Participants received verdinexor; Dosage form: coated, immediate release Tablet; Route of administration: oral
Other Name: KPT-335

Experimental: Verdinexor 20 mg
Participants received verdinexor 20 mg tablet (2 tablets of 10 mg each) orally once daily on Days 1 and 3.
Drug: Verdinexor
Participants received verdinexor; Dosage form: coated, immediate release Tablet; Route of administration: oral
Other Name: KPT-335

Experimental: Verdinexor 40 mg
Participants received verdinexor 40 mg tablet (4 tablets of 10 mg each) orally once daily on Days 1 and 3.
Drug: Verdinexor
Participants received verdinexor; Dosage form: coated, immediate release Tablet; Route of administration: oral
Other Name: KPT-335




Primary Outcome Measures :
  1. Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) [ Time Frame: From start of study drug administration up to Day 33 ]
    An AE was defined as the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition that occur after participant's signed informed consent obtained. A serious adverse event (SAE) was defined as any AE, occurring at any dose (including after the informed consent form was signed and prior to dosing) that and regardless of causality that: results in death, was life-threatening (participant was at immediate risk of death from event as it occurred), requires in-patient hospitalization (formal admission to a hospital for medical reasons) or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect. TEAE was defined as any AE with onset or worsening of a pre-existing condition on or after the first administration of study treatment through 30 days following last dose or any event considered drug-related by the investigator through the end of the study.


Secondary Outcome Measures :
  1. Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) of Verdinexor [ Time Frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose ]
    AUC0-t was defined as area under the concentration-time curve from time zero to the last non-zero concentration

  2. Area Under the Concentration-time Curve From Time Zero to Extrapolated to Infinity (AUC0-inf) of Verdinexor [ Time Frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose ]
    AUC0-inf was defined as area under the concentration-time curve from time zero to infinity (extrapolated). It was calculated as AUC0-t + Ct/kel, where: Ct = the last observed non-zero concentration, kel = elimination rate constant.

  3. Maximum Observed Concentration (Cmax) of Verdinexor [ Time Frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose ]
    Cmax was defined as maximum observed concentration, taken directly from the plasma concentration data.

  4. Average Plasma Concentration From Time Zero to 24 Hours Post-dose (Cavg0-24h) of Verdinexor [ Time Frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24 hours post-dose ]
    Cavg0-24h was defined as average plasma concentration from time zero to 24 hours post-dose.

  5. Time of First Observation of Maximum Observed Concentration (Tmax) of Verdinexor [ Time Frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose ]
    Tmax was defined as time of first observation of Cmax, taken directly from the plasma concentration data.

  6. Elimination Rate Constant (Kel) of Verdinexor [ Time Frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose ]
    Elimination rate constant was calculated using linear regression on the terminal portion of the log-linear concentration versus time curve.

  7. Elimination Half-life (t1/2) of Verdinexor [ Time Frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose ]
    t1/2 was defined as elimination half-life, it was calculated as ln(2)/kel.

  8. Apparent Total Body Clearance (Cl/F) of Verdinexor [ Time Frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose ]
    Apparent total body clearance was calculated as Dose/AUC0-inf, uncorrected for fraction absorbed; reported normalized by participant body weight (kilogram [kg]).

  9. Apparent Volume of Distribution (Vd/F) of Verdinexor [ Time Frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose ]
    Vd/F was calculated as Dose/ (kel *AUC0-inf), uncorrected for fraction absorbed; reported normalized by participant body weight (kg).

  10. Accumulation Factor (AR) of Cmax [ Time Frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose ]
    An AR was defined as a ratio of mean of Cmax Day 3/ Cmax Day 1 for plasma verdinexor.

  11. Accumulation Factor (AR) of Cavg0-24Hour [ Time Frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24 hours post-dose ]
    An AR was defined as a ratio of mean of Cavg0-24hour Day 3/ Cavg0-24hour Day 1 for plasma verdinexor.

  12. Accumulation Factor (AR) of AUC0-t [ Time Frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose ]
    An AR factor was defined as a ratio of mean of AUC0-t Day 3/ AUC0-t Day 1 for plasma verdinexor.

  13. Accumulation Factor (AR) of AUC0-inf [ Time Frame: Days 1 and 3: pre-dose, 15 minutes, 30 minutes, 1, 2, 3, 4, 8, 12, 24, 48 (only for Day 3) hours post-dose ]
    Accumulation factor was defined as a ratio of mean of AUC0-inf Day 3/ AUC0-inf Day 1 for plasma verdinexor.

  14. Maximum Tolerated Dose (MTD) of Verdinexor [ Time Frame: From start of study drug administration up to Day 8 ]
    MTD was defined as the dose level tested in the cohort immediately preceding a cohort where one or more dose limiting toxicities (DLTs) were observed. A DLT was defined as any AE or abnormal laboratory value that the Investigator suspected was probably related to verdinexor that was severe in intensity or serious or Indicative of an unacceptable risk to additional participants in the study in the opinion of the Investigator or Sponsor.



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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Participants must be in good health as determined by the investigator, based on the medical history, ECG, physical examination, and safety laboratory tests at screening.
  • Participants must be identified as a non-smoker at the screening visit (a non-smoker is defined as an individual who has abstained from smoking for at least 1 year prior to the screening visit and who has a ≤ 15 pack year history of lifetime cigarette use). A urine cotinine test will be performed at screening and at the time of clinic check-in prior to study drug treatment.

Exclusion Criteria:

  • The participant has any surgical or medical condition that potentially may alter the absorption, metabolism, or excretion of the study drug such as gastrectomy, Crohn's disease, or liver disease.
  • The participant has a history of clinically significant allergies. Hay fever is allowed unless it is active or has required treatment within the previous 2 months.
  • Presence of a chronic condition(s) with clinical or historical evidence of recent exacerbation, or other information to suggest non-control of such condition(s).
  • History of alcohol abuse or drug addiction within 12 months of the screening visit.
  • Any participant with active cataracts or medical history of cataracts.

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): NCT02431364


Locations
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Australia, Victoria
Nucleus Network
Melbourne, Victoria, Australia
Sponsors and Collaborators
Karyopharm Therapeutics Inc
Investigators
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Principal Investigator: Michael Kauffman, MD, PhD Karyopharm Therapeutics Inc
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Responsible Party: Karyopharm Therapeutics Inc
ClinicalTrials.gov Identifier: NCT02431364    
Other Study ID Numbers: KCP-335-701
First Posted: May 1, 2015    Key Record Dates
Results First Posted: April 13, 2021
Last Update Posted: April 13, 2021
Last Verified: March 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Karyopharm Therapeutics Inc:
KPT-335
Verdinexor
Karyopharm
First-in-Human
Adult Subjects