Electrocardiographic (ECG) Safety Study of Droxidopa at Clinical and Supratherapeutic Dose
Information source: Chelsea Therapeutics
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: QTc Interval
Intervention: Droxidopa (Drug); Droxidopa (Drug); Moxifloxacin (Drug); Placebo (Drug)
Phase: Phase 1
Status: Completed
Sponsored by: Chelsea Therapeutics Official(s) and/or principal investigator(s): Thomas Hunt, MD, Principal Investigator, Affiliation: PPD Phase I Clinic
Summary
The purpose of this study is define the electrocardiographic (ECG) effects of Droxidopa at
clinical (600 mg) and supratherapeutic (2000 mg) doses compared with placebo and
moxifloxacin in healthy male and female subjects.
Clinical Details
Official title: A Double-Blind Randomized Crossover Trial to Define the Ecg Effects of Droxidopa Using a Clinical and a Supratherapeutic Dose Compared With Placebo and Moxifloxacin (a Positive Control) in Healthy Men and Women: a Thorough ECG Trial
Study design: Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Primary outcome: ECG Effects
Secondary outcome: QTcF and QTcB (for historic reasons only), HR, and PR, QRS, and uncorrected QT intervals, change in ECG morphological patterns, and the correlation between the QTcI change and droxidopa plasma concentrations
Detailed description:
This will be a randomized, double blind, single-site, 4 period crossover study in healthy
male and female subjects to determine if droxidopa administered as a single therapeutic (600
mg) and a single supratherapeutic (2000 mg) dose delays cardiac repolarization as determined
by the measurement of QTc interval. Study drug (droxidopa, placebo, and moxifloxacin) will
be administered in a double blind, double dummy manner. The central ECG laboratory
(eResearch Technology, Inc, Philadelphia, Pennsylvania) will be blinded to treatment.
A total of 52 healthy subjects (approximately 26 women and 26 men) will be enrolled and
randomly assigned to a treatment sequence. Subjects will cross over into 4 treatment periods
where each subject will receive single doses of the following treatments under fasting
conditions separated by a minimum 3 day washout period (from Day 1):
- Droxidopa 600 mg (therapeutic dose), oral capsules
- Droxidopa 2000 mg (supratherapeutic dose), oral capsules
- Placebo (matched to droxidopa), oral capsules
- Moxifloxacin 400 mg (positive control; over encapsulated), oral Subjects will be
screened for study participation from Days - 21 to -2 and admitted to the clinic on Day
- 2 of Period 1 for prestudy assessments. On Day -1 of each period, subjects will
undergo a full day of continuous 12 lead Holter monitoring; 4 ECGs will be extracted
from the H 12+ flash card approximately 1 minute apart at 0. 5, 1, 2, 3, 4, 5, 6, 8, 10,
12, 18, and 23 hours.
On the morning of Day 1 of each period, after at least an 8 hour fast, subjects will receive
a single dose of study drug according to the randomly assigned treatment sequence. After
dosing, subjects will be monitored for 23 hours using a continuous 12 lead ECG Holter
monitor. At the ECG core laboratory, 4 ECGs will be extracted approximately 1 minute apart
at 0. 5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, and 23 hours (Day 2) after dosing. The ECGs will be
extracted from Holter recording flashcards during a 10 minute ECG extraction window that
will end at the onset of each pharmacokinetic (PK) collection nominal time point. Each ECG
extraction window will be preceded by a 10 minute supine rest period.
A single 12 lead ECG will be performed at Screening for inclusion/exclusion in the study,
and a baseline safety 12 lead ECG will be performed at Check in. In addition, a safety 12
lead ECG will be recorded and reviewed by the investigator on Day 1 of each period at 2
hours after dosing.
Pharmacokinetic blood samples will be collected on Day 1 of each period before dosing and
0. 5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, and 23 hours (Day 2) after dosing. Subjects will be
supine for at least 10 minutes before each of the time points for PK samples. The ECG
extractions will be time matched to the PK samples, but will be obtained before the actual
sampling time to avoid changes in autonomic tone associated with the psychological aspects
of blood collection as well as the reduction in blood volume subsequent to blood collection.
Meal timing and components, activity levels, and general conditions in the Phase I unit will
be as similar as possible on Day - 1 and Day 1 of each treatment period. Subjects will be
discharged on Day 2 of Period 4 (ie, 24 hours after the last dose is administered). The
total study duration will be approximately 34 days.
Eligibility
Minimum age: 18 Years.
Maximum age: 45 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria:
1. Male or female subject in good general health and 18 to 45 years of age, inclusive.
2. Female subjects must be nonpregnant, nonlactating, and have a negative serum
pregnancy test before enrollment in the study. Female subjects of childbearing
potential (including perimenopausal women who have had menstrual bleeding within 1
year) must be using appropriate birth control (abstinence and/or barrier methods
and/or oral, injectable, or implantable hormonal contraceptives) during the entire
duration of the study. Women are considered of non-childbearing potential if they are
menopausal (last menstrual period greater than 12 months before Check in and a serum
follicle stimulating hormone level greater than 40 mIU/mL) or have been surgically
sterilized (documented hysterectomy, tubal ligation, or bilateral oophorectomy) at
least 6 weeks before Check in.
3. Subject has a body mass index of 18. 0 to 30. 0 kg/m2, inclusive.
4. Subject provides written informed consent.
5. Subject is willing and able to comply with all study requirements.
6. Subject has no clinically significant abnormal medical history, clinical laboratory
results, vital sign measurements, 12 lead safety ECG results, or physical examination
findings during Screening.
Exclusion Criteria:
1. Subject is currently participating in another clinical study of an investigational
drug (or a medical device), or has participated in a study of this type within 30
days before Check in.
2. Subject has a history or current evidence of clinically significant allergic (except
for untreated, asymptomatic, seasonal allergies at the time of dosing or mild
allergic reactions to drugs other than those listed in exclusion criterion #16),
hematologic, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic,
psychiatric, or neurologic disease. Exceptions to these criteria (eg, stable mild
joint disease, cholecystectomy, or childhood asthma) may be made after discussion
with the medical monitor.
3. Subject has used any prescribed or over the counter medication without the approval
of the investigator or sponsor within 1 week before the first dose of study drug
(including dietary supplements, herbal remedies, and medications known to prolong the
QT/corrected QT [QTc] interval).
4. Subject is receiving any anticoagulant (eg, coumadin, heparin, low molecular weight
heparin) or has received any anticoagulant within 3 months before Check in. Subjects
who are receiving any drugs that affect platelet function (eg, aspirin, including
low-dose aspirin) will also be excluded.
5. Subject has a history of drug or alcohol abuse or dependence within 1 year before
Check in.
6. Subject has donated blood or blood components within 4 weeks before Check in. The
investigator should instruct subjects who participate in this study not to donate
blood or blood components for 4 weeks after completion of the study.
7. Subject has a sustained supine systolic blood pressure > 140 mm Hg or < 90 mm Hg or a
supine diastolic blood pressure > 95 mm Hg or < 50 mm Hg at Screening or Check in.
Blood pressure may be retested once in the supine position. The blood pressure
abnormality is considered sustained if either the systolic or the diastolic pressure
values are outside the stated limits after 2 assessments, and the subject may not be
randomized.
8. Subject has a resting heart rate (HR) of < 45 beats per minute or > 100 beats per
minute when vital signs are measured at Screening or Check in.
9. Subject has an abnormal screening ECG indicating a second or third degree
atrioventricular block, or one or more of the following: QRS interval > 110
milliseconds (ms); QT interval corrected for HR by Fridericia's formula (QTcF) > 450
ms; PR interval > 200 ms; or any rhythm other than sinus rhythm that is interpreted
by the investigator to be clinically significant.
10. Subject has a history of risk factors for torsades de pointes, including unexplained
syncope, known long QT syndrome, heart failure, myocardial infarction, angina, or
clinically significant abnormal laboratory assessments including hypokalemia,
hypercalcemia, or hypomagnesemia. Subjects will also be excluded if there is a family
history of long QT syndrome or Brugada syndrome.
11. Subject uses or has used nicotine-containing products (eg, cigarettes, cigars,
chewing tobacco, snuff) within 2 weeks before Check in, or subject has a positive
cotinine result (indicating active current smoking) at Screening or Check in.
12. Subject has consumed alcohol or xanthine-containing products (eg, tea, coffee,
chocolate, cola) within 72 hours before Check in, or subject has a positive result
for drug(s) of abuse or ethanol at Screening or Check in.
13. Subject consumes ≥ 500 mg per day of caffeine (eg, 5 cups of tea or coffee; 8 cans or
five 20 ounce bottles of cola).
14. Subject has been treated with any investigational agent within 30 days before Check
in (or 5 half-lives of the compound, if longer).
15. Subject who, for any reason, is deemed by the investigator to be inappropriate for
this study, including a subject who is unable to communicate or cooperate with the
investigator.
16. Subject has known allergies to droxidopa, moxifloxacin, any excipient in the study
drug(s), or encapsulation formulations (subject will not be excluded for mild
allergic reactions to drugs other than those listed in this criterion).
17. Subject has received treatment with droxidopa within 30 days before Check in.
Locations and Contacts
PPD Phase I Clinic, Austin, Texas 78744, United States
Additional Information
Starting date: March 2011
Last updated: March 6, 2012
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