ADASUVE 2-dose Thorough QT/QTc Study

• ClinicalTrials.gov Identifier: NCT01854710
• Recruitment Status: Completed
• First Posted: May 15, 2013
• Results First Posted: October 18, 2017
• Last Update Posted: October 18, 2017
• Sponsor: Alexza Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Alexza Pharmaceuticals, Inc.

Study Description

Brief Summary:

Assess the potential effects on the QT interval of 2 consecutive doses of ADASUVE administered 2 hours apart, in relation to placebo and an active control in healthy volunteers.

Condition or disease	Intervention/treatment	Phase
Healthy Volunteers	Drug: ADASUVE 10 mg 2 doses 2 hours apart; Drug: Inhaled Placebo; Drug: Oral moxifloxacin 400 mg; Drug: Oral placebo	Phase 4

Detailed Description:

It has been shown in a pre-marketing clinical study that clinically relevant QT prolongation does not appear to be associated with a single dose of ADASUVE. The potential risk of QTc prolongation following repeat dosing is unknown. Therefore the current study will assess the potential effects on the QT interval of 2 consecutive doses of ADASUVE administered 2 hours apart, in relation to placebo and an active control in healthy volunteers.

The study hypothesis H0: Placebo-subtracted max mean dQTc > 10 msec

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: Single-center, randomized, double-blind, double-dummy, 2-dose, 3-period, active- and placebo-controlled, crossover QT/QTc and pharmacokinetic (PK) study of ADASUVE in healthy volunteers. All dosing and treatment-day follow-up in the study was conducted in the clinical research unit (CRU)
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: Thorough QT/QTc Study of 2 Doses of ADASUVE® in Healthy Volunteers
• Study Start Date: May 2013
• Actual Primary Completion Date: July 2013
• Actual Study Completion Date: July 2013

Arms and Interventions

Arm	Intervention/treatment
Treatment sequence ABC; Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo	Drug: ADASUVE 10 mg 2 doses 2 hours apart; Inhaled loxapine 10 mg 2 doses 2 hours apart; Other Name: Staccato Loxapine; Drug: Inhaled Placebo; Staccato placebo via inhalation x 2 at 2 hours apart; Drug: Oral moxifloxacin 400 mg; Oral moxifloxacin 400 mg single dose; Other Name: AVELOX; Drug: Oral placebo; Oral capsule identical in appearance to moxifloxacin
Treatment sequence ACB; Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo	Drug: ADASUVE 10 mg 2 doses 2 hours apart; Inhaled loxapine 10 mg 2 doses 2 hours apart; Other Name: Staccato Loxapine; Drug: Inhaled Placebo; Staccato placebo via inhalation x 2 at 2 hours apart; Drug: Oral moxifloxacin 400 mg; Oral moxifloxacin 400 mg single dose; Other Name: AVELOX; Drug: Oral placebo; Oral capsule identical in appearance to moxifloxacin
Treatment sequence BCA; Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo	Drug: ADASUVE 10 mg 2 doses 2 hours apart; Inhaled loxapine 10 mg 2 doses 2 hours apart; Other Name: Staccato Loxapine; Drug: Inhaled Placebo; Staccato placebo via inhalation x 2 at 2 hours apart; Drug: Oral moxifloxacin 400 mg; Oral moxifloxacin 400 mg single dose; Other Name: AVELOX; Drug: Oral placebo; Oral capsule identical in appearance to moxifloxacin
Treatment sequence BAC; Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo	Drug: ADASUVE 10 mg 2 doses 2 hours apart; Inhaled loxapine 10 mg 2 doses 2 hours apart; Other Name: Staccato Loxapine; Drug: Inhaled Placebo; Staccato placebo via inhalation x 2 at 2 hours apart; Drug: Oral moxifloxacin 400 mg; Oral moxifloxacin 400 mg single dose; Other Name: AVELOX; Drug: Oral placebo; Oral capsule identical in appearance to moxifloxacin
Treatment sequence CAB; Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo	Drug: ADASUVE 10 mg 2 doses 2 hours apart; Inhaled loxapine 10 mg 2 doses 2 hours apart; Other Name: Staccato Loxapine; Drug: Inhaled Placebo; Staccato placebo via inhalation x 2 at 2 hours apart; Drug: Oral moxifloxacin 400 mg; Oral moxifloxacin 400 mg single dose; Other Name: AVELOX; Drug: Oral placebo; Oral capsule identical in appearance to moxifloxacin
Treatment sequence CBA; Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo	Drug: ADASUVE 10 mg 2 doses 2 hours apart; Inhaled loxapine 10 mg 2 doses 2 hours apart; Other Name: Staccato Loxapine; Drug: Inhaled Placebo; Staccato placebo via inhalation x 2 at 2 hours apart; Drug: Oral moxifloxacin 400 mg; Oral moxifloxacin 400 mg single dose; Other Name: AVELOX; Drug: Oral placebo; Oral capsule identical in appearance to moxifloxacin

Outcome Measures

Primary Outcome Measures :

1. Maximum Effect of ADASUVE on Cardiac Repolarization (QTc Interval Duration) at the Maximum Clinical Dose Compared to Placebo [ Time Frame: Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 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 ADASUVE treatment at 12 post-inhalation times.

Secondary Outcome Measures :

1. QTc Versus Loxapine Concentration [ Time Frame: Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr ]
   QTc @ Cmax based on linear and nonlinear regression of QTcI versus time matched serum loxapine concentrations
2. Subjects With QTcI > 450 ms [ Time Frame: Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr ]
   Numbers of Subjects with QTcI > 450 ms at any time point
3. Subjects With QTcI > 480 ms [ Time Frame: Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr ]
   Numbers of Subjects with QTcI > 480 ms (or 500 ms) at any time point
4. Subjects With QTcI Increase > 30 ms From Baseline [ Time Frame: Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr ]
   Numbers of Subjects with QTcI Increase > 30 ms from Baseline at any time point
5. Subjects With QTcI Increase > 60 ms From Baseline [ Time Frame: Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr ]
   Numbers of Subjects with QTcI Increase > 60 ms From Baseline at any time point

Other Outcome Measures:

1. Maximum Effect of Moxifloxacin on Cardiac Repolarization (QTc Interval Duration) Compared to Placebo (Study Assay Sensitivity) [ Time Frame: Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr ]
   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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Male and female subjects between the ages of 18 to 65 years, inclusive.
• Body mass index (BMI) ≥18 and ≤32.
• Subjects who are willing and able to comply with the study schedule and requirements, and stay at the CRU for a 4-day period and 2 consecutive 3-day periods.
• Subjects who speak, read, and understand English and/or Dutch and are willing and able to provide written informed consent on an IEC approved form prior to the initiation of any study procedures.
• Subjects who are in good general health prior to study participation
• Female or male participants who agree to use a medically acceptable and effective birth control method

Exclusion Criteria:

• Subjects who regularly consume large amounts of xanthine-containing substances (≥ 5 cups of coffee/day).
• Subjects who have taken prescription or nonprescription medication within 5 days of Visit 2.
• Subjects who have had an acute illness within the last 5 days of Visit 2.
• Subjects who have smoked tobacco within the last 30 days or who have a positive cotinine test.
• Subjects who have a history of HIV, anti-HCV or HbsAg positivity.
• Subjects who have a history within the past 2 years of drug or alcohol dependence or abuse as defined by DSM-IV.
• Subjects who test positive for alcohol or have a positive urine drug screen.
• Subjects who have a history of allergy or intolerance to loxapine or amoxapine or history of bronchospasm following inhaled loxapine treatment.
• Subjects who have an ECG abnormality.
• Subjects who have hypotension, or hypertension.
• Subjects who have a history of unstable angina, syncope, coronary artery disease, myocardial infarction, congestive heart failure, transient ischemic attack, history of convulsions or other neurological disorder.
• Subjects who have a current history of asthma, chronic obstructive lung disease, or any other lung disease associated with bronchospasm.
• Subjects who use medications to treat airways disease, such as asthma or COPD.
• Subjects who have any acute respiratory signs/symptoms (e.g., wheezing).
• Female subjects who have a positive pregnancy test at screening or at admission to any of the treatment visits, or are breastfeeding.
• Subjects who have received an investigational drug within 60 days prior to the Screening Visit.

Contacts and Locations

Locations

Netherlands

PRA International

Zuidlaren, Netherlands

Sponsors and Collaborators

Alexza Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Teresa Nunes, MD; PRA Health Sciences

More Information

Publications:

Cassella JV, Spyker DA, Yeung PP. A randomized, placebo-controlled repeat-dose thorough QT study of inhaled loxapine in healthy volunteers. Int J Clin Pharmacol Ther. 2015 Nov;53(11):963-71.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Cassella JV, Spyker DA, Yeung PP. A randomized, placebo-controlled repeat-dose thorough QT study of inhaled loxapine in healthy volunteers. Int J Clin Pharmacol Ther. 2015 Oct 7. [Epub ahead of print]

• Responsible Party: Alexza Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT01854710
• Other Study ID Numbers: AMDC-204-407; 204-407 ( Other Identifier: Alexza Pharmaceuticals, Inc )
• First Posted: May 15, 2013
• Results First Posted: October 18, 2017
• Last Update Posted: October 18, 2017
• Last Verified: July 2013

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: IPD submitted to regulatory authorities. Others may contact Alexza Pharmaceuticals, Inc. Please send your request to ClinicalTrialsInfo@alexza.com

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Alexza Pharmaceuticals, Inc.:

ADASUVE; inhaled loxapine; thorough QT/QTc study

Additional relevant MeSH terms:

Moxifloxacin; Loxapine; Anti-Bacterial Agents; Anti-Infective Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Physiological Effects of Drugs; Antipsychotic Agents; Tranquilizing Agents; Central Nervous System Depressants; Psychotropic Drugs; Dopamine Antagonists; Dopamine Agents; Neurotransmitter Agents