Study to Assess the Absorption and Tolerability of Intranasal Ketorolac Tromethamine and to Assess the Effects of Oxymetazoline Hydrochloride and Fluticasone Propionate on the Absorption and Tolerability of Intranasal Ketorolac Tromethamine in Participants With Allergic Rhinitis

Open Label, Three-Way Study to Assess the Absorption and Tolerability of Intranasal Ketorolac Tromethamine and to Assess the Effects of a Single Dose of Oxymetazoline Hydrochloride and Multiple Doses of Fluticasone Propionate on the Absorption and Tolerability of Intranasal Ketorolac Tromethamine in Participants With Allergic Rhinitis

This was an open label, three way study in participants with symptomatic allergic rhinitis. The following 3 treatments were administered to each subject during dosing periods 1, 2 and 3, respectively:

• Treatment A: Single intranasal dose of 30 mg ketorolac tromethamine (one 15 mg spray into each nostril) on Day 1 of Period 1.
• Treatment B: Single intranasal dose of oxymetazoline hydrochloride followed by a single intranasal dose of 30 mg ketorolac tromethamine (one 15 mg spray into each nostril) 30 minutes later on Day 1 of Period 2.
• Treatment C: Seven days of treatment with intranasal fluticasone propionate (between Periods 2 and 3) followed by a single intranasal dose of 30 mg ketorolac tromethamine (one 15 mg spray into each nostril) on Day 1 of Period 3.

Subjects remained resident in the Clinical Unit from Day 1 until the morning of Day 2 in each period and there was a washout period of 2 to 7 days between periods. A post study medical was performed within 7 days of Period 3.

The objectives of this study were:

• To assess the pharmacokinetics (PK) of intranasal ketorolac in participants with symptomatic allergic rhinitis.
• To assess the effects of a single dose of intranasal oxymetazoline hydrochloride on the pharmacokinetics and tolerability of intranasal ketorolac in participants with symptomatic allergic rhinitis.
• To assess the effects of chronic administration of fluticasone propionate on the bioavailability and tolerability of intranasal ketorolac in participants with symptomatic allergic rhinitis.

Study Overview

• Status: Completed
• Conditions: Allergic Rhinitis
• Intervention / Treatment: Drug: Ketorolac Tromethamine; Drug: Oxymetazoline Hydrochloride; Drug: Fluticasone Propionate

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia
    • Pain and Anaesthesia Research Clinic/Royal Adelaide Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female volunteers, aged between 18 and 65 years inclusive
• Participant had a history of allergic rhinitis for which treatment had been required at least 3 days out of 7 within the last 3 months. Subjects who were symptomatic of allergic rhinitis but were not currently using therapy because they had found it ineffective may have been included
• Participant was otherwise considered to exhibit general good health, in the opinion of the Investigator

• Participants may have had known medical conditions that were considered "stable" and not expected to interfere with the study outcome or to be adversely affected by their involvement in the study. This was determined by the Investigator at the time of screening by the following:

  • A pre-study physical examination with no clinically significant abnormalities
  • Vital signs within normal ranges or outside the normal range but not deemed clinically significant in the opinion of the Investigator
  • An electrocardiogram (ECG) with no clinically significant abnormalities
  • Full medical history
• Participant had bilateral patent nasal airways at screening as assessed by the Investigator
• Participant had a body mass index (BMI) between 19 and 29 kg/m2

• Female participants of child bearing potential:

  • Must have had a negative urine pregnancy test prior to entry into the study
  • Must not have been breast feeding
• All female participants of child bearing potential and all male participants with female partners of child bearing potential must have consented to use a medically acceptable method of contraception (oral or implanted contraceptive hormones with combined use of barrier contraception, condom or diaphragm with spermicidal agent, intrauterine device, menopausal [defined as last menstrual period >12 months ago] or surgical sterilization) throughout the study period and for a minimum of 4 weeks or 1 full menstrual cycle prior to inclusion
• Participant must have been able to provide written informed consent
• Participant's pre-study clinical laboratory findings were within normal range or if outside of the normal range not deemed clinically significant in the opinion of the Investigator
• Glomerular filtration rate >75 mL/minute as calculated using the Cockroft-Gault calculation for creatinine clearance

Exclusion Criteria:

• Any known allergy or sensitivity to ketorolac tromethamine, oxymetazoline hydrochloride, fluticasone propionate or formulation ingredients
• Any history of co-existing nasal polyps, NSAID sensitivity and asthma
• Daily use of an intranasal decongestant medication
• Allergic reaction to aspirin or other NSAIDs
• Current upper respiratory tract infection or other respiratory tract condition that could have interfered with the absorption of the nasal spray or with the assessment of AEs
• Use of any non-prescribed drug in the 72 hours prior to study drug administration and during the study. Paracetamol use was not allowed within the 24 hours prior to Day 1 of each period. NSAIDs were restricted for at least 3 days or 5 half-lives, whichever was longer, prior to dosing on Day 1 of Period 1, and must not have been used throughout the study. Current prescribed medications were not discontinued prior to entry into the study or during study participation, unless known to interact with ketorolac as per the product information (injectable)
• Any suspicion of rhinitis medicamentosa (chronic daily use of topical decongestants)
• Use of a monoamine oxidase inhibitor in the 14 days prior to study entry
• Positive serum test for human immunodeficiency virus (HIV) or hepatitis B or C at screening
• Positive serum alcohol test at screening or on entry into the study
• Positive urine drug screen for any non-prescribed drugs of abuse (DOA) at screening or on entry into the study
• Clinically significant abnormality on screening laboratory tests
• History of cocaine use
• Concurrent use of ritonavir or other potent CYP3A4 inducers or inhibitors.
• Blood donation within 30 days of beginning study participation
• Active peptic ulcer disease, gastrointestinal bleeding or perforation, or a history of peptic ulcer disease or gastrointestinal bleeding
• Anemia due to unexplained or known gastrointestinal bleeding
• Renal impairment or a risk for renal failure due to volume depletion.
• History of asthma or any other chronic pulmonary disorder, with the exception of childhood asthma and asymptomatic asthma, which were assessed individually by the Principal Investigator
• Current tobacco use or a past history of smoking > or = 5 pack-years within the last 5 years
• A history of any other clinically significant, unstable medical problem, which in the opinion of the Investigator would have interfered with study participation
• Participation in another investigational drug study within 30 days of study entry, or 5 times the half-life of the investigational drug, whichever was longer
• Positive test for Helicobacter pylori (H. pylori) at screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ketorolac Tromethamine	Drug: Ketorolac Tromethamine; Single intranasal dose of 30 mg ketorolac tromethamine (one 15 mg spray into each nostril) on Day 1 of Period 1
Experimental: Oxymetazoline Hydrochloride	Drug: Oxymetazoline Hydrochloride; Single intranasal dose of oxymetazoline hydrochloride followed by a single intranasal dose of 30 mg ketorolac tromethamine (one 15 mg spray into each nostril) 30 minutes later on Day 1 of Period 2
Experimental: Fluticasone Propionate	Drug: Fluticasone Propionate; Seven days of treatment with intranasal fluticasone propionate (between Periods 2 and 3) followed by a single intranasal dose of 30 mg ketorolac tromethamine (one 15 mg spray into each nostril) on Day 1 of Period 3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax (the Maximum Observed Plasma Concentration)	PK analysis by standard model was performed by a pharmacokineticist using model-independent analysis methods in WinNonlin Professional. Actual blood sampling times for ketorolac assay were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each time, together with individual plasma concentrations of ketorolac.	Blood samples for PK analyses were obtained at pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 12, 15 and 24 hours post administration of ketorolac tromethamine
Tmax (the Time to Maximum Concentration)	PK analysis by standard model was performed by a pharmacokineticist using model-independent analysis methods in WinNonlin Professional. Actual blood sampling times for ketorolac assay were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each time, together with individual plasma concentrations of ketorolac.	Blood samples for PK analyses were obtained at pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 12, 15 and 24 hours post administration of ketorolac tromethamine
AUC 0-t (the Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to the Last Quantifiable Time Point Post-dose)	PK analysis by standard model was performed by a pharmacokineticist using model-independent analysis methods in WinNonlin Professional. Actual blood sampling times for ketorolac assay were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each time, together with individual plasma concentrations of ketorolac.	Blood samples for PK analyses were obtained at pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 12, 15 and 24 hours post administration of ketorolac tromethamine
AUC 0-∞ (the AUC From Time Zero to Infinity, Where Possible)	PK analysis by standard model was performed by a pharmacokineticist using model-independent analysis methods in WinNonlin Professional. Actual blood sampling times for ketorolac assay were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each time, together with individual plasma concentrations of ketorolac.	Blood samples for PK analyses were obtained at pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 12, 15 and 24 hours post administration of ketorolac tromethamine
t1/2z (the Terminal Half-life, Where Possible)	PK analysis by standard model was performed by a pharmacokineticist using model-independent analysis methods in WinNonlin Professional. Actual blood sampling times for ketorolac assay were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each time, together with individual plasma concentrations of ketorolac.	Blood samples for PK analyses were obtained at pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 12, 15 and 24 hours post administration of ketorolac tromethamine
MRT (the Mean Residence Time)	PK analysis by standard model was performed by a pharmacokineticist using model-independent analysis methods in WinNonlin Professional. Actual blood sampling times for ketorolac assay were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each time, together with individual plasma concentrations of ketorolac.	Blood samples for PK analyses were obtained at pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 12, 15 and 24 hours post administration of ketorolac tromethamine

Collaborators and Investigators

• Sponsor: Egalet Ltd
• Investigators: Study Director: Lincoln Bynum, MD, ICON Developmental Solutions

Study record dates

Study Major Dates

• Study Start: December 1, 2007
• Primary Completion (Actual): February 1, 2008
• Study Completion (Actual): June 1, 2008

Study Registration Dates

• First Submitted: June 1, 2011
• First Submitted That Met QC Criteria: June 1, 2011
• First Posted (Estimate): June 3, 2011

Study Record Updates

• Last Update Posted (Actual): March 6, 2018
• Last Update Submitted That Met QC Criteria: March 2, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Immune System Diseases; Hypersensitivity, Immediate; Otorhinolaryngologic Diseases; Respiratory Hypersensitivity; Hypersensitivity; Nose Diseases; Rhinitis; Rhinitis, Allergic; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Protective Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Cardiotonic Agents; Dermatologic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Anti-Allergic Agents; Sympathomimetics; Vasoconstrictor Agents; Mydriatics; Nasal Decongestants; Adrenergic alpha-1 Receptor Agonists; Ketorolac; Fluticasone; Xhance; Ketorolac Tromethamine; Phenylephrine; Oxymetazoline
• Other Study ID Numbers: ROX 2007-03