Staccato Prochlorperazine Thorough QT/QTc

Study Overview
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Brief Summary
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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
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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.

Official Title
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Thorough QT/QTc Study of Staccato® Prochlorperazine for Inhalation in Healthy Volunteers

Conditions
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Cardiotoxicity

Intervention / Treatment
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* Drug: Inhaled placebo
* Drug: Oral placebo
* Drug: Inhaled prochlorperazine 5 mg
* Drug: Inhaled prochlorperazine 10 mg
* Drug: Oral moxifloxacin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects between the ages of 18 to 65 years, inclusive. Body mass index (BMI) ≥21 and ≤30. 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. 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. 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. 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: Subjects who regularly consume large amounts of xanthine-containing substances must be excluded. Subjects who have taken prescription or nonprescription medication within 5 days of Treatment Period 1 must be excluded. Subjects who have had an acute illness within the last 5 days of Treatment Period 1 must be excluded. Subjects who have smoked tobacco within the last year must be excluded. Subjects who have a history of HIV positivity must be excluded. Subjects who have a history of allergy or intolerance to prochlorperazine or phenothiazines must be excluded. Subjects who have a history of contraindication to anticholinergics must be excluded. Subjects who have a history of pheochromocytoma, seizure disorder, Parkinson's disease, or Restless Leg Syndrome must be excluded. Subjects who have an ECG abnormality must be excluded. 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. 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. Subjects who have a history of asthma or chronic obstructive lung disease must be excluded. Subjects who have hypotension (systolic ≤90 mmHg, diastolic ≤50 mmHg), or hypertension (systolic ≥140 mmHg, diastolic blood pressure ≥90 mmHg) must be excluded. Subjects who test positive for alcohol or have a positive urine drug screen must be excluded. Female subjects who have a positive pregnancy test at screening or during randomization visit, or are breastfeeding must be excluded. Subjects who have received an investigational drug within 30 days prior to the Screening Visit must be excluded. 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Female and male subjects in approximately equal numbers were randomly assigned (1:1:1:1) to receive the 4 treatment sequences
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Treatment Sequence ABCD<br>Treatment Sequence ABCD where Treatment: A = Inhaled prochlorperazine (10 mg) + oral placebo, B = Inhaled prochlorperazine (5 mg) + oral placebo, C = Inhaled placebo + oral placebo, D = Inhaled placebo + oral moxifloxacin 400 mg | Drug: Inhaled placebo<br>* Inhaled Staccato placebo (0 mg)<br>Drug: Oral placebo<br>* Oral placebo (identical to 400 mg moxifloxacin)<br>Drug: Inhaled prochlorperazine 5 mg<br>* Staccato prochlorperazine 5 mg, single dose<br>* Other names: ADASUVE;Drug: Inhaled prochlorperazine 10 mg<br>* Inhaled prochlorperazine 10 mg, single dose<br>* Other names: ADASUVE;Drug: Oral moxifloxacin<br>* Oral moxifloxacin 400 mg, si/ngle dose<br>|
| Other: Treatment Sequence BDAC<br>Treatment Sequence BDAC where Treatment: A = Inhaled prochlorperazine (10 mg) + oral placebo, B = Inhaled prochlorperazine (5 mg) + oral placebo, C = Inhaled placebo + oral placebo, D = Inhaled placebo + oral moxifloxacin 400 mg | Drug: Inhaled placebo<br>* Inhaled Staccato placebo (0 mg)<br>Drug: Oral placebo<br>* Oral placebo (identical to 400 mg moxifloxacin)<br>Drug: Inhaled prochlorperazine 5 mg<br>* Staccato prochlorperazine 5 mg, single dose<br>* Other names: ADASUVE;Drug: Inhaled prochlorperazine 10 mg<br>* Inhaled prochlorperazine 10 mg, single dose<br>* Other names: ADASUVE;Drug: Oral moxifloxacin<br>* Oral moxifloxacin 400 mg, si/ngle dose<br>|
| Other: Treatment Sequence CABD<br>Treatment Sequence CABD where Treatment: A = Inhaled prochlorperazine (10 mg) + oral placebo, B = Inhaled prochlorperazine (5 mg) + oral placebo, C = Inhaled placebo + oral placebo, D = Inhaled placebo + oral moxifloxacin 400 mg | Drug: Inhaled placebo<br>* Inhaled Staccato placebo (0 mg)<br>Drug: Oral placebo<br>* Oral placebo (identical to 400 mg moxifloxacin)<br>Drug: Inhaled prochlorperazine 5 mg<br>* Staccato prochlorperazine 5 mg, single dose<br>* Other names: ADASUVE;Drug: Inhaled prochlorperazine 10 mg<br>* Inhaled prochlorperazine 10 mg, single dose<br>* Other names: ADASUVE;Drug: Oral moxifloxacin<br>* Oral moxifloxacin 400 mg, si/ngle dose<br>|
| Other: Treatment Sequence DCBA<br>Treatment Sequence DCBA where Treatment: A = Inhaled prochlorperazine (10 mg) + oral placebo, B = Inhaled prochlorperazine (5 mg) + oral placebo, C = Inhaled placebo + oral placebo, D = Inhaled placebo + oral moxifloxacin 400 mg | Drug: Inhaled placebo<br>* Inhaled Staccato placebo (0 mg)<br>Drug: Oral placebo<br>* Oral placebo (identical to 400 mg moxifloxacin)<br>Drug: Inhaled prochlorperazine 5 mg<br>* Staccato prochlorperazine 5 mg, single dose<br>* Other names: ADASUVE;Drug: Inhaled prochlorperazine 10 mg<br>* Inhaled prochlorperazine 10 mg, single dose<br>* Other names: ADASUVE;Drug: Oral moxifloxacin<br>* Oral moxifloxacin 400 mg, si/ngle dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 22 hr | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 22 hr | 
| Numbers and % of Subjects With QTcI > 450 ms | Numbers and Percents of Subjects with QTcI exceeding 450 ms | 24 hours | 
| 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 | 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 22 hr | 
| 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 | 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 22 hr | 
| 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 | 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 22 hr | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Inhaled prochlorperazine, Thorough Qt/QTc,