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A Single-Center, Double-Blind, Randomized, Placebo- and Positive-Controlled, Parallel Group, Thorough QT/QTc Study to Evaluate the Effect of Custirsen (640 mg) on Cardiac Repolarization in Healthy Men

Phase 1
18 Years
45 Years
Open (Enrolling)
Cardiac Conduction and Repolarization

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Trial Information

A Single-Center, Double-Blind, Randomized, Placebo- and Positive-Controlled, Parallel Group, Thorough QT/QTc Study to Evaluate the Effect of Custirsen (640 mg) on Cardiac Repolarization in Healthy Men

The effects of custirsen will be evaluated following administration of a single dose
following dose-titration period combined with dexamethasone pretreatment. On days −1 and 7,
subjects will undergo a full ECG assessment for 24 hours. On day 1, randomization and
assignment to the treatment groups will be performed prior to drug administration. Subjects
will remain in the study center throughout the treatment period. All subjects will be
discharged at the end of day 8 procedures, 24 hours after the last dose of custirsen has
been administered. Subjects in groups 1 and 2 will return for an additional visit on day 9,
10 and 14 (±2 days) (approximately 7 days after the last study drug administration).
Subjects in group 3 will not return for a follow-up visits.

Inclusion Criteria:

1. The subject is a man aged 18 through 45 years of age with a body mass index (BMI) of
18 through 30 kg/m2 at screening.

2. The subject is in good health as determined by medical history, ECG, vital signs
measurements, physical examination, and clinical laboratory tests.

3. The subject must be able to understand and comply with the requirements of the study
(eg, all medication, dietary, exercise, tobacco, and alcohol restrictions).

4. The subject must provide written informed consent to participate in the study after
reading the information and consent form, and after having an opportunity to discuss
the study with the investigator or delegate.

5. Other inclusion criteria apply.

Exclusion Criteria:

1. Exclusion criteria related to ECG findings include the following:

- The subject has an ECG abnormality that may interfere with the accurate
assessment of the QT interval, including intraventricular conduction delays
(QRS >120 msec or PR >200 as measured at the screening and check-in visits) and
complete or incomplete bundle branch blocks.

- The subject has a resting QTcF interval of ≤360 msec and/or ≥450 msec
measured at screening or day -2.

2. Exclusion criteria related to cardiac function include the following:

- The subject has a known clinically significant (in the opinion of the
investigator) cardiovascular disorder, including coronary artery disease,
valvular heart disease, cardiomyopathies, or an ECG abnormality suggestive of
prior myocardial infarction, angina pectoris, chamber enlargement, or
hypertrophy. Notwithstanding, subjects with known significant disorders will be

- The subject has a known clinically significant arrhythmia or rhythm disturbance
observed on the screening and/or day -2 12-lead ECG.

- The subject has a supine pulse rate outside of the range of 40 to 100 bpm
(following at least a 10-minute rest) measured at screening or day -2.

- The subject has a supine blood pressure outside of the range of 90 to 139 mm Hg
systolic or 50 to 89 mm Hg diastolic (following at least a 10-minute rest)
measured at screening and on day -2. Note: The blood pressure measurement may
be repeated up to 3 times to meet eligibility requirements. In this case, the
average of these 3 measurements must meet eligibility criteria.

- The subject reports a history of, or risk factors for, Torsades de Pointes (eg,
congestive heart failure, serum electrolyte abnormalities) including a family
history of arrhythmia, sudden unexplained death at a young age (before 40 years)
in a first-degree relative, or long QT syndrome, or a personal history of

3. The subject has low serum potassium and/or magnesium and/or corrected calcium blood
levels (less than 3.5 milliequivalent/liter (mEq/L), 1.8 mEq/L, and 8.9 mg/dL,
respectively) at screening and/or day-2.

4. The subject has any condition that may possibly interfere with drug absorption,
distribution, metabolism, or excretion (eg, previous surgery on the gastrointestinal
tract [including removal of parts of stomach, bowel, liver, gall bladder, or
pancreas] or stomach banding).

5. The subject has an abnormality in medical history, physical examination,
biochemistry, hematology, coagulation, serology, or urinalysis at the screening or
admission visit that is considered clinically significant by the investigator or
meets grades 2-4 Common Terminology Criteria for Adverse Events (CTCAE) v.4 criteria,
or in the opinion of the investigator, could interfere with the objective of the
study or the safety of the subject. Notwithstanding, the following values must remain
within the normal range values (as determined by the Physician Reference Laboratory
[PRL]) in order for a subject to be eligible for the study: calcium, magnesium,
potassium, creatinine, ALT, AST, GGT, hemoglobin, absolute lymphocyte count, absolute
50 mg/dL in asymptomatic subjects and absolute leukocyte count values as low as
3.1x109/L in African American subjects will be considered for enrollment at the
investigator's discretion. Lastly, the upper limit value for exclusion is modified
for the following values and is as follows: INR>1.2, total bilirubin>1.2 mg/dL, serum
amylase >143 U/L, LDH>261 U/L, and CPK>367 U/L, which do not normalize upon repeat
testing, will be exclusionary.

6. The subject has used one of the prohibited drugs, substances or foods as follows:

- any investigational product within 60 days (or 5 half-lives, whichever is
longer) preceding the study

- any prescription or nonprescription medication (including herbal remedies,
vitamins, or dietary supplements) or vaccine within 14 days of the first day of
study drug administration (day 1) or within 5 half-lives before the first day of
study drug administration, whichever is longer. Exceptions are locally acting
medications (eg, topical creams), which are not allowed within 5 days of study
drug administration, and the occasional use of acetaminophen (up to 3 g/day) and
ibuprofen (up to 1200 mg/day).

- consumption of grapefruit, grapefruit juice, Seville oranges, pomelo-containing
products, within the 14 days prior to day -1 and then throughout the entire

- consumption of excessive amounts of alcoholic beverages, defined as more than 3
drinks per day (beer, wine, or distilled spirits), or unwillingness to comply
with the restricted use of alcohol during the study (96 hours prior to admission
and until 48 hours after the last study drug administration), history of
alcoholism, or evidence of drug/chemical abuse

- positive urine drug (cocaine, amphetamines, barbiturates, opiates,
phencyclidine, benzodiazepines, tetrahydrocannabinol), cotinine, or alcohol
screen at the screening visit or admission

- consumption of quinine (eg, tonic water) within 7 days prior to admission

7. The subject has any other condition, which, in the opinion of the investigator, makes
the subject inappropriate for the study.

8. Other exclusion criteria apply.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Outcome Measure:

Individually-corrected QT interval (QTcI)

Outcome Description:

The primary ECG variable and endpoint for this study is the time-matched change from baseline in QTcI method on day 7 at each time point. Holter ECGs will be performed at baseline (day -1) and prior to the start of infusion on day 7 and 1, 2 (end of infusion), 2.5, 3, 4, 5, 6, 8, 12, 16, 20, and 23.5 hours after the start of infusion.

Outcome Time Frame:

Up to 23.5 hours after the start of study drug infusion on Day 7

Safety Issue:



United States: Food and Drug Administration

Study ID:




Start Date:

May 2013

Completion Date:

December 2013

Related Keywords:

  • Cardiac Conduction and Repolarization
  • Custirsen sodium
  • TV1011
  • OGX-011
  • Thorough QT study
  • cancer



Teva Investigational Site 10565Lenexa, Kansas