Staccato Prochlorperazine Thorough QT/QTc

• ClinicalTrials.gov Identifier: NCT00543062
• Recruitment Status: Completed
• First Posted: October 12, 2007
• Results First Posted: March 11, 2019
• Last Update Posted: March 11, 2019
• Sponsor: Alexza Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Alexza Pharmaceuticals, Inc.

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Cardiotoxicity
• Interventions: Drug: Inhaled placebo; Drug: Oral placebo; Drug: Inhaled prochlorperazine 5 mg; Drug: Inhaled prochlorperazine 10 mg; Drug: Oral moxifloxacin
• Enrollment: 48

Participant Flow

Recruitment Details
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.

Arm/Group Title	Treatment Sequence ABCD	Treatment Sequence BDAC	Treatment Sequence CABD	Treatment Sequence DCBA
Arm/Group Description	All subjects were to receive all 4 treatments in this 4 treatment crossover	All subjects were to receive all 4 treatments in this 4 treatment crossover	All subjects were to receive all 4 treatments in this 4 treatment crossover	All subjects were to receive all 4 treatments in this 4 treatment crossover
Period Title: Overall Study
Started	12	12	12	12
Completed	10	11	9	11
Not Completed	2	1	3	1
Reason Not Completed
Withdrawal by Subject	1	0	2	0
Adverse Event	0	1	1	1
Protocol Violation	1	0	0	0

Baseline Characteristics

Arm/Group Title		Safety Population
Arm/Group Description		All subjects were to receive all 4 treatments in this 4 treatment crossover
Overall Number of Baseline Participants		48
Baseline Analysis Population Description		Safety Population
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	48 participants
	<=18 years	0 0.0%
	Between 18 and 65 years	48 100.0%
	>=65 years	0 0.0%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	48 participants
		35.7 (13.4)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	48 participants
	Female	32 66.7%
	Male	16 33.3%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	48 participants
		48

Outcome Measures

1. Primary Outcome

Title	Maximum Effect of Inhaled Prochlorperazine on Cardiac Repolarization (QTc Interval Duration) at the Maximum Clinical Dose Compared to Placebo
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo+Inhaled Prochlorperazine 5 mg Crossover Subjects	Placebo+Inhaled Prochlorperazine 10 mg Crossover Subjects
Arm/Group Description:	All subjects who completed both treatments B and C: Treatment: B = Inhaled prochlorperazine (5 mg) + oral placebo, C = Inhaled placebo + oral placebo The analyses are based on a within (paired) comparison of the time matched drug - placebo QTc values.	All subjects who completed both treatments A and C: Treatment: A = Inhaled prochlorperazine (10 mg) + oral placebo, C = Inhaled placebo + oral placebo. The analyses are based on a within (paired) comparison of the time matched drug - placebo QTc values.
Overall Number of Participants Analyzed	42	42
Least Squares Mean (90% Confidence Interval); Unit of Measure: milliseconds
	5.493; (2.635 to 8.351)	5.229; (2.405 to 8.052)

2. Secondary Outcome

Title	QTcI Versus Prochlorperazine Concentration
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Inhaled Prochlorperazine
Arm/Group Description:	Serum concentrations following Staccato prochlorperazine 5 and 10 mg, single dose
Overall Number of Participants Analyzed	42
Least Squares Mean (90% Confidence Interval); Unit of Measure: milliseconds
	2.83; (1.11 to 4.56)

3. Secondary Outcome

Title	Numbers and % of Subjects With QTcI > 450 ms
Description	Numbers and Percents of Subjects with QTcI exceeding 450 ms
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

QT Population (placebo and prochlorperazine only)

Arm/Group Title	Placebo	Inhaled Prochlorperazine 5 mg	Inhaled Prochlorperazine 10 mg
Arm/Group Description:	Inhaled placebo Oral placebo Inhaled placebo: Inhaled Staccato placebo (0 mg) Oral placebo: Oral placebo (identical to 400 mg moxifloxacin)	Staccato prochlorperazine 5 mg, single dose Oral placebo Oral placebo: Oral placebo (identical to 400 mg moxifloxacin) Inhaled prochlorperazine 5 mg: Staccato prochlorperazine 5 mg, single dose	Staccato prochlorperazine 10 mg, single dose Oral placebo Oral placebo: Oral placebo (identical to 400 mg moxifloxacin) Inhaled prochlorperazine 10 mg: Inhaled prochlorperazine 10 mg, single dose
Overall Number of Participants Analyzed	44	44	46
Measure Type: Count of Participants; Unit of Measure: Participants
	3 6.8%	4 9.1%	6 13.0%

4. Secondary Outcome

Title	Numbers and % of Subjects With QTcI > 480 ms
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Inhaled Prochlorperazine 5 mg	Inhaled Prochlorperazine 10 mg
Arm/Group Description:	Inhaled placebo + Oral placebo	Staccato prochlorperazine 5 mg, single dose Oral placebo	Inhaled prochlorperazine 10 mg: Inhaled prochlorperazine 10 mg, single dose
Overall Number of Participants Analyzed	45	45	46
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	0 0.0%	1 2.2%

5. Secondary Outcome

Title	Numbers and % of Subjects With QTcI Change > 30 ms
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Inhaled Prochlorperazine 5 mg	Inhaled Prochlorperazine 10 mg
Arm/Group Description:	Inhaled placebo + Oral placebo	Staccato prochlorperazine 5 mg, single dose + Oral placebo	Inhaled prochlorperazine 10 mg: Inhaled prochlorperazine 10 mg, single dose + Oral placebo
Overall Number of Participants Analyzed	43	44	46
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	1 2.3%	0 0.0%

6. Secondary Outcome

Title	Numbers and % of Subjects With QTcI Change > 60 ms
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Inhaled Prochlorperazine 5 mg	Inhaled Prochlorperazine 10 mg
Arm/Group Description:	Inhaled placebo + Oral placebo	Staccato prochlorperazine 5 mg, single dose + Oral placebo	Inhaled prochlorperazine 10 mg: Inhaled prochlorperazine 10 mg, single dose + Oral placebo
Overall Number of Participants Analyzed	43	44	46
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	0 0.0%	0 0.0%

7. Other Pre-specified Outcome

Title	Maximum Effect of Moxifloxacin on Cardiac Repolarization (QTc Interval Duration) Compared to Placebo (Study Assay Sensitivity)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo+Oral Moxifloxacin 400 mg Crossover Subjects
Arm/Group Description:	All subjects who completed both treatments C and D: Treatment: C = Inhaled placebo + oral placebo, D = Inhaled placebo + oral moxifloxacin 400 mg The analyses are based on a within (paired) comparison of the time matched drug - placebo QTc values.
Overall Number of Participants Analyzed	42
Least Squares Mean (95% Confidence Interval); Unit of Measure: milliseconds
	9.595; (6.062 to 13.128)

Adverse Events

Time Frame	Adverse events (AEs) were considered treatment related from the first exposure to study treatment until 30 days after the last treatment
Adverse Event Reporting Description	Adverse events (AEs) were assessed predose and at 14 pre-specified time points as well as whenever spontaneously reported by the subjects or study staff
Arm/Group Title	Placebo		Inhaled Prochlorperazine 5 mg		Inhaled Prochlorperazine 10 mg		Oral Moxifloxacin 400 mg
Arm/Group Description	Inhaled placebo Oral placebo Inhaled placebo: Inhaled Staccato placebo (0 mg) Oral placebo: Oral placebo (identical to 400 mg moxifloxacin)		Staccato prochlorperazine 5 mg, single dose Oral placebo Oral placebo: Oral placebo (identical to 400 mg moxifloxacin) Inhaled prochlorperazine 5 mg: Staccato prochlorperazine 5 mg, single dose		Staccato prochlorperazine 10 mg, single dose Oral placebo Oral placebo: Oral placebo (identical to 400 mg moxifloxacin) Inhaled prochlorperazine 10 mg: Inhaled prochlorperazine 10 mg, single dose		Oral moxifloxacin 400 mg Inhaled placebo Inhaled placebo: Inhaled Staccato placebo (0 mg) Oral moxifloxacin: Oral moxifloxacin 400 mg, si/ngle dose
All-Cause Mortality
	Placebo		Inhaled Prochlorperazine 5 mg		Inhaled Prochlorperazine 10 mg		Oral Moxifloxacin 400 mg
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/45 (0.00%)		0/44 (0.00%)		0/46 (0.00%)		0/43 (0.00%)
Serious Adverse Events
	Placebo		Inhaled Prochlorperazine 5 mg		Inhaled Prochlorperazine 10 mg		Oral Moxifloxacin 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/45 (0.00%)		0/44 (0.00%)		0/46 (0.00%)		0/43 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo		Inhaled Prochlorperazine 5 mg		Inhaled Prochlorperazine 10 mg		Oral Moxifloxacin 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/45 (8.89%)		24/44 (54.55%)		29/46 (63.04%)		4/43 (9.30%)
Gastrointestinal disorders
Dysgeusia † 1	0/45 (0.00%)	0	1/44 (2.27%)	1	5/46 (10.87%)	5	0/43 (0.00%)	0
Nausea † 1	0/45 (0.00%)	0	2/44 (4.55%)	2	2/46 (4.35%)	2	0/43 (0.00%)	0
Nervous system disorders
Headache † 1	2/45 (4.44%)	2	4/44 (9.09%)	4	2/46 (4.35%)	2	2/43 (4.65%)	2
Somnolence † 1	0/45 (0.00%)	0	4/44 (9.09%)	4	6/46 (13.04%)	6	0/43 (0.00%)	0
Psychiatric disorders
Anxiety † 1	0/45 (0.00%)	0	1/44 (2.27%)	1	3/46 (6.52%)	3	0/43 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Cough † 1	1/45 (2.22%)	1	13/44 (29.55%)	13	12/46 (26.09%)	12	1/43 (2.33%)	1
Pharyngolaryngeal Pain † 1	1/45 (2.22%)	1	7/44 (15.91%)	7	9/46 (19.57%)	9	1/43 (2.33%)	1
1 Term from vocabulary, MedDRA (10.0); † Indicates events were collected by systematic assessment

Limitations and Caveats

The use of healthy subjects precludes observation of drug-induced QTc prolongation in a population with additional factors predisposing to TdP. Subjects with respiratory disease were excluded.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Executive VP, Research & Development, Regulatory & Quality
• Organization: Alexza Pharmaceuticals, Inc
• Phone: 650.944.7071
• EMail: ClinicalTrialsInfo@alexza.com

• Responsible Party: Alexza Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT00543062
• Other Study ID Numbers: AMDC-001-102; 20 July 2007
• First Submitted: October 10, 2007
• First Posted: October 12, 2007
• Results First Submitted: March 10, 2017
• Results First Posted: March 11, 2019
• Last Update Posted: March 11, 2019