ADASUVE 2-dose Thorough QT/QTc Study

NCT01854710 | Completed Phase 4 Results FDA Drug

• 2 other identifiers: AMDC-204-407204-407
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

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.

Conditions

Healthy Volunteers

Keywords

ADASUVE; inhaled loxapine; thorough QT/QTc study

Outcome Measures

Primary Outcomes (1)

• Maximum Effect of ADASUVE 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 ADASUVE treatment at 12 post-inhalation times.

  Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr

Secondary Outcomes (5)

• QTc Versus Loxapine Concentration

  Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr

• Subjects With QTcI > 450 ms

  Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr

• Subjects With QTcI > 480 ms

  Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr

• Subjects With QTcI Increase > 30 ms From Baseline

  Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr

• Subjects With QTcI Increase > 60 ms From Baseline

  Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr

Other Outcomes (1)

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

  Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr

Study Arms (6)

Treatment sequence ABC

OTHER

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; Drug: Inhaled Placebo; Drug: Oral moxifloxacin 400 mg; Drug: Oral placebo

Treatment sequence ACB

OTHER

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; Drug: Inhaled Placebo; Drug: Oral moxifloxacin 400 mg; Drug: Oral placebo

Treatment sequence BCA

OTHER

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; Drug: Inhaled Placebo; Drug: Oral moxifloxacin 400 mg; Drug: Oral placebo

Treatment sequence BAC

OTHER

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; Drug: Inhaled Placebo; Drug: Oral moxifloxacin 400 mg; Drug: Oral placebo

Treatment sequence CAB

OTHER

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; Drug: Inhaled Placebo; Drug: Oral moxifloxacin 400 mg; Drug: Oral placebo

Treatment sequence CBA

OTHER

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; Drug: Inhaled Placebo; Drug: Oral moxifloxacin 400 mg; Drug: Oral placebo

Interventions

ADASUVE 10 mg 2 doses 2 hours apart DRUG

Inhaled loxapine 10 mg 2 doses 2 hours apart

Also known as: Staccato Loxapine

Treatment sequence ABC; Treatment sequence ACB; Treatment sequence BAC; Treatment sequence BCA; Treatment sequence CAB; Treatment sequence CBA

Inhaled Placebo DRUG

Staccato placebo via inhalation x 2 at 2 hours apart

Treatment sequence ABC; Treatment sequence ACB; Treatment sequence BAC; Treatment sequence BCA; Treatment sequence CAB; Treatment sequence CBA

Oral moxifloxacin 400 mg DRUG

Oral moxifloxacin 400 mg single dose

Also known as: AVELOX

Treatment sequence ABC; Treatment sequence ACB; Treatment sequence BAC; Treatment sequence BCA; Treatment sequence CAB; Treatment sequence CBA

Oral placebo DRUG

Oral capsule identical in appearance to moxifloxacin

Treatment sequence ABC; Treatment sequence ACB; Treatment sequence BAC; Treatment sequence BCA; Treatment sequence CAB; Treatment sequence CBA

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Alexza Pharmaceuticals, Inc.: lead

Study Sites (1)

PRA International

Zuidlaren, Netherlands

Location

Related Publications (2)

• 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. doi: 10.5414/CP202457.

  PMID: 26501204 BACKGROUND

• 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. doi: 10.5414/CP202457. Online ahead of print.

  PMID: 26445139 DERIVED

MeSH Terms

Interventions

Loxapine; Moxifloxacin

Intervention Hierarchy (Ancestors)

Dibenzoxazepines; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring

Limitations and Caveats

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

Results Point of Contact

• Title: Chief Scientific Officer
• Organization: Alexza Pharmaceuticals, Inc

jcassella@alexza.com

650.944.7777

Study Officials

• Teresa Nunes, MD

  PRA Health Sciences

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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)

Study Record Dates

• First Submitted: May 8, 2013
• First Posted: May 15, 2013
• Study Start: May 1, 2013
• Primary Completion: July 1, 2013
• Study Completion: July 1, 2013
• Last Updated: October 18, 2017
• Results First Posted: October 18, 2017

Record last verified: 2013-07

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)