Cardiotoxicity
Conditions
Keywords
Inhaled prochlorperazine, Thorough Qt/QTc,
Brief summary
To assess the safety of Staccato Prochlorperazine on cardiac repolarization (QTc interval duration) at 2 dose levels compared to placebo in healthy volunteers.
Detailed description
The planned study is a single dose, double-blind, double-dummy, active and placebo controlled, randomized, 4-period cross-over study investigating investigating 2 doses levels of Staccato Prochlorperazine, a positive control with known QT/QTc prolongation (oral moxifloxacin), and placebo.
Interventions
DRUGInhaled placebo
Inhaled Staccato placebo (0 mg)
DRUGOral placebo
Oral placebo (identical to 400 mg moxifloxacin)
Staccato prochlorperazine 5 mg, single dose
Inhaled prochlorperazine 10 mg, single dose
Oral moxifloxacin 400 mg, si/ngle dose
Sponsors
Alexza Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
This was a double-blind, double dummy, placebo controlled, randomized 4-period crossover study to assess the effects of single doses of 5 and 10 mg of Staccato Prochlorperazine on QT intervals.
Intervention model description
Female and male subjects in approximately equal numbers were randomly assigned (1:1:1:1) to receive the 4 treatment sequences
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. Male and female subjects between the ages of 18 to 65 years, inclusive. 2. Body mass index (BMI) ≥21 and ≤30. 3. Subjects who are willing and able to comply with the study schedule and requirements, and stay at the CRU for a 3-day period and 3 consecutive 2-day periods. 4. Subjects who speak, read, and understand English and are willing and able to provide written informed consent on an IRB approved form prior to the initiation of any study procedures. 5. Subjects who are in good general health prior to study participation as determined by a detailed medical history, physical examination, 12-lead ECG, blood chemistry profile, hematology, urinalysis, and in the opinion of the Principal Investigator. 6. Female participants (if of child-bearing potential and sexually active) and male participants (if sexually active with a partner of child-bearing potential) who agree to use a medically acceptable and effective birth control method throughout the study and for one week following the end of the study.
Exclusion criteria
1. Subjects who regularly consume large amounts of xanthine-containing substances must be excluded. 2. Subjects who have taken prescription or nonprescription medication within 5 days of Treatment Period 1 must be excluded. 3. Subjects who have had an acute illness within the last 5 days of Treatment Period 1 must be excluded. 4. Subjects who have smoked tobacco within the last year must be excluded. 5. Subjects who have a history of HIV positivity must be excluded. 6. Subjects who have a history of allergy or intolerance to prochlorperazine or phenothiazines must be excluded. 7. Subjects who have a history of contraindication to anticholinergics must be excluded. 8. Subjects who have a history of pheochromocytoma, seizure disorder, Parkinson's disease, or Restless Leg Syndrome must be excluded. 9. Subjects who have an ECG abnormality must be excluded. 10. Subjects who have a history within the past 2 years of drug or alcohol dependence or abuse as defined by DSM-4 must be excluded. 11. Subjects who have a history of syncope, unstable angina, myocardial infarction (within 6 months), congestive heart failure, transient ischemic attack, or pheochromocytoma must be excluded. 12. Subjects who have a history of asthma or chronic obstructive lung disease must be excluded. 13. Subjects who have hypotension (systolic ≤90 mmHg, diastolic ≤50 mmHg), or hypertension (systolic ≥140 mmHg, diastolic blood pressure ≥90 mmHg) must be excluded. 14. Subjects who test positive for alcohol or have a positive urine drug screen must be excluded. 15. Female subjects who have a positive pregnancy test at screening or during randomization visit, or are breastfeeding must be excluded. 16. Subjects who have received an investigational drug within 30 days prior to the Screening Visit must be excluded. 17. Subjects who are considered by the investigator, for any reason, to be an unsuitable candidate for receiving prochlorperazine, or unable to use the inhalation device, must be excluded. 18. Subjects who have any other disease(s), by history, physical examination, or laboratory abnormalities (ALT or AST \> 2-fold the upper limit of normal, bilirubin \> 1.5 mg/dL, or creatinine \> 1.8 mg/dL) or that in the investigator's opinion present undue risk to the subject or may confound the interpretation of study results must be excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Effect of Inhaled Prochlorperazine on Cardiac Repolarization (QTc Interval Duration) at the Maximum Clinical Dose Compared to Placebo | 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 22 hr | Time-matched differences in QTcI values between the maximum of the mean difference from baseline of the QTcI interval after time-matched placebo subtraction for treatment at 11 post-inhalation times. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| QTcI Versus Prochlorperazine Concentration | 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 22 hr | QTcI @ median prochlorperazine concentration (3.75 mcg/mL) based on linear and nonlinear regression of QTcI versus time matched serum prochlorperazine concentrations |
| Numbers and % of Subjects With QTcI > 450 ms | 24 hours | Numbers and Percents of Subjects with QTcI exceeding 450 ms |
| Numbers and % of Subjects With QTcI Change > 30 ms | 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 22 hr | Numbers and Percents of Subjects with QTcI increase from baseline exceeding 30 ms at any of the outcome measure time points |
| Numbers and % of Subjects With QTcI Change > 60 ms | 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 22 hr | Numbers and Percents of Subjects with QTcI increase from baseline exceeding 60 ms at any of the outcome measure time points |
| Numbers and % of Subjects With QTcI > 480 ms | 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 22 hr | Numbers and Percents of Subjects with QTcI exceeding 480 ms at any of the outcome measure time points |
Other
| Measure | Time frame | Description |
|---|---|---|
| Maximum Effect of Moxifloxacin on Cardiac Repolarization (QTc Interval Duration) Compared to Placebo (Study Assay Sensitivity) | 1, 1.5, 2, 2.5, 3, 5 hours | A thorough QT/QTc study may be considered to have demonstrated assay sensitivity if 1 or more of the lower 95% CI values exceeds 5 msec |
Countries
United States
Participant flow
Pre-assignment details
Eligible subjects reported to the CRU for baseline assessments (Day 1). The subjects were confined to the Clinical Research Unit under continuous medical or paramedical observation until at least 24 hours after each dose of Staccato Prochlorperazine or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Safety Population All subjects were to receive all 4 treatments in this 4 treatment crossover | 48 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 1 | 1 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | Safety Population |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 48 Participants |
| Age, Continuous | 35.7 years STANDARD_DEVIATION 13.4 |
| Region of Enrollment United States | 48 participants |
| Sex: Female, Male Female | 32 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 45 | 0 / 44 | 0 / 46 | 0 / 43 |
| other Total, other adverse events | 4 / 45 | 24 / 44 | 29 / 46 | 4 / 43 |
| serious Total, serious adverse events | 0 / 45 | 0 / 44 | 0 / 46 | 0 / 43 |
Outcome results
Primary
Maximum Effect of Inhaled Prochlorperazine on Cardiac Repolarization (QTc Interval Duration) at the Maximum Clinical Dose Compared to Placebo
Time-matched differences in QTcI values between the maximum of the mean difference from baseline of the QTcI interval after time-matched placebo subtraction for treatment at 11 post-inhalation times.
Time frame: 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 22 hr
Population: QT population -- LSM and CI statistics were based on the individual (within subject) corrected differences between prochlorperazine and placebo exposures per ICH Guideline E14 for a thorough QT/QTc study.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo+Inhaled Prochlorperazine 5 mg Crossover Subjects | Maximum Effect of Inhaled Prochlorperazine on Cardiac Repolarization (QTc Interval Duration) at the Maximum Clinical Dose Compared to Placebo | 5.493 milliseconds |
| Placebo+Inhaled Prochlorperazine 10 mg Crossover Subjects | Maximum Effect of Inhaled Prochlorperazine on Cardiac Repolarization (QTc Interval Duration) at the Maximum Clinical Dose Compared to Placebo | 5.229 milliseconds |
Secondary
Numbers and % of Subjects With QTcI > 450 ms
Numbers and Percents of Subjects with QTcI exceeding 450 ms
Time frame: 24 hours
Population: QT Population (placebo and prochlorperazine only)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo+Inhaled Prochlorperazine 5 mg Crossover Subjects | Numbers and % of Subjects With QTcI > 450 ms | 3 Participants |
| Placebo+Inhaled Prochlorperazine 10 mg Crossover Subjects | Numbers and % of Subjects With QTcI > 450 ms | 4 Participants |
| Inhaled Prochlorperazine 10 mg | Numbers and % of Subjects With QTcI > 450 ms | 6 Participants |
Secondary
Numbers and % of Subjects With QTcI > 480 ms
Numbers and Percents of Subjects with QTcI exceeding 480 ms at any of the outcome measure time points
Time frame: 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 22 hr
Population: QT population -- LSM and CI statistics were based on the individual (within subject) corrected differences between active and placebo exposures per ICH Guideline E14 for a thorough
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo+Inhaled Prochlorperazine 5 mg Crossover Subjects | Numbers and % of Subjects With QTcI > 480 ms | 0 Participants |
| Placebo+Inhaled Prochlorperazine 10 mg Crossover Subjects | Numbers and % of Subjects With QTcI > 480 ms | 0 Participants |
| Inhaled Prochlorperazine 10 mg | Numbers and % of Subjects With QTcI > 480 ms | 1 Participants |
Secondary
Numbers and % of Subjects With QTcI Change > 30 ms
Numbers and Percents of Subjects with QTcI increase from baseline exceeding 30 ms at any of the outcome measure time points
Time frame: 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 22 hr
Population: QT population -- LSM and CI statistics were based on the individual (within subject) corrected differences between active and placebo exposures per ICH Guideline E14 for a thorough QT/QTc study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo+Inhaled Prochlorperazine 5 mg Crossover Subjects | Numbers and % of Subjects With QTcI Change > 30 ms | 0 Participants |
| Placebo+Inhaled Prochlorperazine 10 mg Crossover Subjects | Numbers and % of Subjects With QTcI Change > 30 ms | 1 Participants |
| Inhaled Prochlorperazine 10 mg | Numbers and % of Subjects With QTcI Change > 30 ms | 0 Participants |
Secondary
Numbers and % of Subjects With QTcI Change > 60 ms
Numbers and Percents of Subjects with QTcI increase from baseline exceeding 60 ms at any of the outcome measure time points
Time frame: 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 22 hr
Population: QT population -- LSM and CI statistics were based on the individual (within subject) corrected differences between active and placebo exposures per ICH Guideline E14 for a thorough QT/QTc study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo+Inhaled Prochlorperazine 5 mg Crossover Subjects | Numbers and % of Subjects With QTcI Change > 60 ms | 0 Participants |
| Placebo+Inhaled Prochlorperazine 10 mg Crossover Subjects | Numbers and % of Subjects With QTcI Change > 60 ms | 0 Participants |
| Inhaled Prochlorperazine 10 mg | Numbers and % of Subjects With QTcI Change > 60 ms | 0 Participants |
Secondary
QTcI Versus Prochlorperazine Concentration
QTcI @ median prochlorperazine concentration (3.75 mcg/mL) based on linear and nonlinear regression of QTcI versus time matched serum prochlorperazine concentrations
Time frame: 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 22 hr
Population: 846 paired QTcI and prochlorperazine concentration pairs from 42 subjects receiving prochlorperazine (5 or 10 mg)~Each measure was based on the individual (within subject) corrected differences between prochlorperazine and placebo exposures per ICH Guideline E14 for a thorough QT study.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo+Inhaled Prochlorperazine 5 mg Crossover Subjects | QTcI Versus Prochlorperazine Concentration | 2.83 milliseconds |
Other Pre-specified
Maximum Effect of Moxifloxacin on Cardiac Repolarization (QTc Interval Duration) Compared to Placebo (Study Assay Sensitivity)
A thorough QT/QTc study may be considered to have demonstrated assay sensitivity if 1 or more of the lower 95% CI values exceeds 5 msec
Time frame: 1, 1.5, 2, 2.5, 3, 5 hours
Population: QT population -- LSM and CI statistics were based on the individual (within subject) corrected differences between moxifloxacin and placebo exposures per ICH Guideline E14 for a thorough QT study.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo+Inhaled Prochlorperazine 5 mg Crossover Subjects | Maximum Effect of Moxifloxacin on Cardiac Repolarization (QTc Interval Duration) Compared to Placebo (Study Assay Sensitivity) | 9.595 milliseconds |