Clinical trial NCT01986894: A Phase 1 QT Study in Healthy Male Subjects
Official title: A Phase 1, Double-blind, Four Period Crossover Study to Investigate the Effects of Pomalidomide (CC 4047) on the QT Interval in Healthy Male Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Clinical Pharmacology, Healthy Volunteer Study
Keywords: TQT
Pharmacokinetic
Healthy
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2013-11-19
Enrollment: 72
Sex: MALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

Brief summary: This is a single-center, randomized, double-blind crossover study with four treatments, four periods and four sequences to investigate the effects of orally administered pomalidomide on QT interval. The study will be conducted in healthy male subjects. Pomalidomide (clinically indicated dose for multiple myeloma \[MM\] as per the United States Package Insert \[USPI\] of 4 mg and supratherapeutic dose of 20 mg) and placebo treatments will be double-blinded. Moxifloxacin (positive control) will be administered in an open-label fashion to determine the sensitivity of the assay. The core electrocardiogram (ECG) laboratory and ECG readers will be blinded to all study treatments and sequences.

Detailed description: A total of 72 male subjects will be randomized and enrolled, with 18 subjects assigned to each treatment sequence. For each treatment sequence, each subject will participate in a screening phase, four baseline phases, four treatment periods and a follow up visit. Within 28 days prior to Period 1 dosing, subjects will sign an informed consent document (ICD) and undergo screening procedures to confirm eligibility. Qualifying subjects will return to the clinical site on Day -2 of Period 1 to begin baseline assessments, and will be domiciled at the clinical site from Day -2 to Day 2 of Period 1. For all remaining study periods, subjects will return to the clinical site on Day -1 to begin baseline assessments, and will be domiciled at the clinical site from Day -1 to Day 2. Subjects will be assigned randomly to one of four treatment sequences and will receive a single dose of the assigned treatment on Day 1 of each study period. There will be a minimum of 7 days and no more than 14 days between each dose.

Subjects will begin an overnight fast of at least 8 hours prior to the start of continuous Holter monitoring on Day 1 (and Day 1 in Period 1). On the morning of Day 1 (and Day -1 in Period 1), continuous Holter monitoring for approximately 24 hours will be performed. Triplicate ECGs will be extracted for analysis at specific predose and postdose timepoints (or equivalent times on Day -1 of Period 1). Blood samples will be collected at pre specified timepoints for pharmacokinetic (PK) and clinical laboratory assessments. Safety will be monitored throughout the study.

During each study period, subjects will be discharged from the clinical site on Day 2 upon satisfactory safety review and completion of the required study procedures. A safety follow up will be conducted by telephone 5 to 7 days following discharge in Period 4. In the event that a subject discontinues from the study, an early termination visit will be performed.

Eligibility criteria: Inclusion Criteria:

* 1. Must understand and voluntarily sign a written informed consent (ICD) prior to any study related procedures being performed.

  2. Must be able to communicate with the Investigator, understand and comply with the requirements of the study, and agree to adhere to restrictions and examination schedules 3. Healthy male of any race between 18 to 50 years of age (inclusive) at the time of signing the ICD, and in good health as determined by a physical exam (P)E.

  4. Must practice true abstinence\* or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential (FCBP) while participating in the study, during dose interruptions and for at least 28 days following study drug discontinuation, even if he has undergone a successful vasectomy.
* True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Period abstinence (e.g., calendar, ovulation, symptothermal, post ovulation methods) and withdrawal are not acceptable methods of contraception.

  5. Must have a body-mass index (BMI) between 18 and 30 kg/m2 (inclusive). 6. Clinical laboratory tests must be within normal limits or acceptable to the Investigator.

  7. Subject must be afebrile, with supine systolic blood pressure (BP): 90 to 140 mmHg, supine diastolic BP: 60 to 90 mmHg, and pulse rate (PR): 40 to 110 bpm.

At screening: After the supine measurements, when BP and pulse rate are measured again after 5 minutes of standing, there shall be no more than a 20 mmHg drop in systolic BP or no more than a 10 mmHg drop in diastolic BP and/or no more than a 20 bpm increase in pulse rate associated with clinical manifestation of postural hypotension.

8. Must have a normal or clinically acceptable 12-lead electrocardiogram (ECG) at screening; must have a QTcF value ≤ 430 msec.

9. Must agree to refrain from donating sperm or semen while participating in this study and for at least 28 days following the last dose of study drug.

10. Must agree to refrain from donating blood or plasma (other than for this study) while participating in this study and for at least 28 days following the last dose of study drug.

Exclusion Criteria:

* 1. History of any clinically significant and relevant neurological, gastrointestinal, renal, hepatic, cardiovascular (including hypertension, atherosclerosis, heart failure, supraventricular or ventricular arrhythmias and stroke \[Cerebral Vascular Accident (CVA)\] or transient ischemic attack \[TIA\]), psychological, pulmonary (including asthma and chronic obstructive pulmonary disease \[COPD\], treated or not treated), metabolic, endocrine, hematological, allergic disease, drug allergies, known hypersensitivity to a member of the class of IMiDs®, known hypersensitivity to moxifloxacin or other major disorders.

  2. Any condition which places the subject at unacceptable risk if he was to participate in the study, or confounds the ability to interpret data from the study.

  3. Have a first degree relative (parent, sibling, child) with Long QT Syndrome. 4. A hemoglobin level of less than 12.0 g/dL. 5. Abnormal Electrocardiogram (ECG) findings as follows:
  * Heart rate \< 40 or \> 110 bpm, after resting in the supine position for 5 minutes;
  * Pulse rate (PR) interval \> 220 msec;
  * QRS interval \> 120 including any degree of bundle branch block;
  * QTcF \< 300 or \> 430 msec;
  * Evidence of pre-excitation (e.g., Wolfe-Parkinson-White syndrome);
  * Cardiac pacemaker;
  * Atrial fibrillation / flutter. 6. QRS and/or T wave that the Investigator judges to be unfavorable for consistently accurate QT measurements (e.g., indistinct QRS onset, low amplitude T wave, inverted or terminally inverted T wave, merged T/U waves, indistinct T wave offset, or prominent U wave that affects QT measurement).

    7. Neuromuscular artifact that cannot readily be eliminated. 8. Subjects with hypokalemia and/or hypomagnesemia condition. 9. Used any prescribed systemic or topical medication (including but not limited to analgesics, anesthetics, etc) within 30 days of the first dose administration, unless sponsor agreement is obtained.

    10. Used any non-prescribed systemic or topical medication (including vitamin/mineral supplements, and herbal medicines) within 14 days of the first dose administration, unless sponsor agreement is obtained.

    11. Has any surgical or medical conditions possibly affecting drug absorption, distribution, metabolism and excretion (ADME), e.g., bariatric procedure. Appendectomy and cholecystectomy are acceptable.

    12. Donated blood or plasma within 8 weeks before the first dose administration to a blood bank or blood donation center.

    13. History of drug abuse (as defined by the current version of the Diagnostic and Statistical Manual \[DSM\]) within 2 years before dosing, or positive drug test reflecting consumption of illicit drugs.

    14. History of alcohol abuse (as defined by the current version of the DSM) within 2 years before dosing, or positive alcohol screen.

    15. Known to have serum hepatitis or known to be a carrier of hepatitis B surface antigen (HbsAg) or hepatitis C virus antibody (HCV Ab), or have a positive result to the test for human immunodeficiency virus (HIV) antibodies at screening.

    16. Exposed to an investigational drug (new chemical entity) within 30 days preceding the first dose administration, or 5 half-lives of that investigational drug, if known (whichever is longer).

    17. Cotinine level at screening or on Day 2 of Period 1 indicates subject is a moderate or heavy smoker.

    18. History of autonomic dysfunction (e.g., history of fainting or orthostatic hypotension).

    19. Subjects who are part of the clinical staff personnel or family members of the clinical site staff.

Primary outcomes:
measure: Time matched, baseline corrected change from placebo of QTcF
timeFrame: From before dosing until 23 hours after dosing
measure: Categorical analyses on ECG intervals and changes in ECG morphology
timeFrame: From before dosing until 23 hours after dosing
Secondary outcomes:
measure: Time matched, baseline corrected changes from placebo of other ECG intervals (RR, PR, QRS) and categorical analyses on ECG intervals and changes in ECG morphology
timeFrame: From before dosing until 23 hours after dosing
measure: Safety
timeFrame: 2 months (from screening visit until end of study
measure: Pharmacokinetics - Cmax
timeFrame: From before dosing until 32 hours after dosing
measure: Pharmacokinetics - Tmax
timeFrame: From before dosing until 32 hours after dosing
measure: Pharmacokinetics - AUCinf
timeFrame: From before dosing until 32 hours after dosing
measure: Pharmacokinetics - AUCt
timeFrame: From before dosing until 32 hours after dosing
measure: Pharmacokinetics - t1/2
timeFrame: From before dosing until 32 hours after dosing
measure: Pharmacokinetics - CL/F
timeFrame: From before dosing until 32 hours after dosing
measure: Pharmacokinetics - Vz/F
timeFrame: From before dosing until 32 hours after dosing
Other outcomes:
Locations:
city: Austin
country: United States
facility: PPD Phase I Clinic
state: Texas
Study officials:
affiliation: Celgene Corporation
name: Edward O'Mara, MD
role: STUDY_DIRECTOR
References: