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

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01365650

Enrollment

Registered

2011-06-03

Start date

2007-12-31

Completion date

2008-06-30

Last updated

2018-03-06

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Allergic Rhinitis

Brief summary

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.

Interventions

DRUGFluticasone 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

DRUGKetorolac Tromethamine

Single intranasal dose of 30 mg ketorolac tromethamine (one 15 mg spray into each nostril) on Day 1 of Period 1

DRUGOxymetazoline 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

Study design

Allocation

NON_RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Cmax (the Maximum Observed Plasma Concentration)	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	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.
Tmax (the Time to Maximum Concentration)	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	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.
AUC 0-t (the Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to the Last Quantifiable Time Point Post-dose)	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	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.
AUC 0-∞ (the AUC From Time Zero to Infinity, Where Possible)	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	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.
t1/2z (the Terminal Half-life, Where Possible)	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	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.
MRT (the Mean Residence Time)	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	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.

Countries

Australia

Participant flow

Recruitment details

December 18, 2007 through February 15, 2008; Medical Clinic

Pre-assignment details

After subjects had given their informed consent, subjects were required to pass a screening visit within 3 weeks prior to study drug administration.

Participants by arm

Arm	Count
All Study Participants Treatment A: Single intranasal (i.n.) dose of Ketorolac tromethamine (KT) 30 mg (one 15 mg spray into each nostril) on day 1 of Period 1 followed by a 2-7 day washout interval Treatment B: Single i.n. dose of oxymetazoline hydrochloride (OH) followed 30 minutes later by a single i.n. dose of KT 30 mg (one 15 mg spray into each nostril) of Period 2 followed by a 2-7 day washout interval Treatment C: Seven days of treatment with i.n. fluticasone propionate (between Periods 2 and 3) followed by a single i.n. dose of KT 30 mg (one 15 mg spray into each nostril) on day 1 of Period 3	24
Total	24

Arm

Count

All Study Participants

Treatment A: Single intranasal (i.n.) dose of Ketorolac tromethamine (KT) 30 mg (one 15 mg spray into each nostril) on day 1 of Period 1 followed by a 2-7 day washout interval Treatment B: Single i.n. dose of oxymetazoline hydrochloride (OH) followed 30 minutes later by a single i.n. dose of KT 30 mg (one 15 mg spray into each nostril) of Period 2 followed by a 2-7 day washout interval Treatment C: Seven days of treatment with i.n. fluticasone propionate (between Periods 2 and 3) followed by a single i.n. dose of KT 30 mg (one 15 mg spray into each nostril) on day 1 of Period 3

Total

Baseline characteristics

Characteristic	All Study Participants
Age, Categorical <=18 years	0 Participants
Age, Categorical >=65 years	2 Participants
Age, Categorical Between 18 and 65 years	22 Participants
Age, Continuous	42.6 years STANDARD_DEVIATION 16.3
Region of Enrollment Australia	24 participants
Sex: Female, Male Female	9 Participants
Sex: Female, Male Male	15 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	17 / 24	22 / 24	17 / 24
serious Total, serious adverse events	0 / 24	0 / 24	0 / 24

Outcome results

Primary

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.