Study to Determine the Tolerability, Safety and Pharmacokinetics of Ketorolac Tromethamine by Intranasal Administration in Healthy Volunteers

• Sponsor: Egalet Ltd (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01363050
• Collaborator: (none)
• Enrollment: 15
• Location: 1
• Arm: 1
• Duration (Months): 8
• Patients Per Site Per Month: 1.9

Study Details

Study Description

Brief Summary

This was a phase 1, open label, multiple dose study in healthy male and female volunteers. Subjects received intranasal ketorolac tromethamine (30 mg) three times daily (t.i.d.) for three days (seven doses in total). Doses were administered every eight hours.

The objective of this study in healthy volunteers was to determine the safety, tolerability, and pharmacokinetics of multiple doses of intranasal ketorolac tromethamine.

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers	Drug: Ketorolac tromethamine	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1, Open Label, Multiple Dose Study to Determine the Tolerability, Safety and Pharmacokinetics of Ketorolac Tromethamine by Intranasal Administration in Healthy Volunteers
• Study Start Date: Jan 1, 2006
• Actual Primary Completion Date: Feb 1, 2006
• Actual Study Completion Date: Sep 1, 2006

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ketorolac tromethamine	Drug: Ketorolac tromethamine; Subjects received intranasal ketorolac tromethamine (30 mg) three times daily (t.i.d.) for three days (seven doses in total). Doses were administered every eight hours.

Outcome Measures

Primary Outcome Measures

1. Cmax (the Maximum Observed Plasma Concentration) [Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 1 (morning doses)]

   PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.

2. Tmax (the Time to Maximum Concentration) [Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 1 (morning doses)]

   PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.

3. AUC 0-8h (the Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose) [Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 1 (morning doses)]

   PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.

4. Cmax,ss (the Maximum Observed Plasma Concentration at Steady State) [Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 3 (morning doses)]

   PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.

5. Tmax,ss (the Time to Maximum Concentration at Steady State) [Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 3 (morning doses)]

   PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.

6. Cmin,ss (the Minimum Observed Plasma Concentration at Steady State) [Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 3 (morning doses)]

   PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.

7. Tmin,ss (the Time to Minimum Concentration at Steady State) [Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 3 (morning doses)]

   PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.

8. AUCτ (the Area Under the Plasma Concentration-time Curve Over the Dosing Interval at Steady-state) [Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 3 (morning doses)]

   PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.

9. MRT (the Mean Residence Time [Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 3 (morning doses)]

   PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Male or female volunteers, aged 18 to 60 years inclusive

• Female subjects of child bearing potential were to have a negative urine pregnancy test prior to entry into the study and must not have been breast feeding

• All female subjects of child bearing potential and all male subjects with female partners of child bearing potential must have consented to using a medically acceptable method of contraception (oral or implanted contraceptive hormones, condom or diaphragm with spermicidal agent, intrauterine device or surgical sterilisation) throughout the study period

• Subject had given signed informed consent

• Subject was within 20% of normal weight for his/her height and body build according to the table of "Desirable Weights for Men and Women" (Metropolitan Life Insurance Co.

• Subject's medical history was considered normal, with no clinically significant abnormalities

• Subject was considered to be in good health in the opinion of the Investigator, as determined by a pre-study physical examination with no clinically significant abnormalities, vital signs within normal ranges and an ECG with no clinically significant abnormalities

• Subject'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

• Subject had bilateral patent nasal airways at screening as assessed by the Investigator

• Body weight of at least 60 kg

Exclusion Criteria:

• Subject had a clinically significant illness in the four weeks prior to screening

• Use of prescribed medications in the three weeks prior to dosing or over-the-counter preparations for seven days prior to dosing, except paracetamol which was allowed up to 48 hours prior to dosing. Use of multivitamins and oral contraceptives were permitted

• Subject had a significant history of drug/solvent abuse, or a positive drugs of abuse test at screening

• Subjects with a history of alcohol abuse or those currently drinking more than 28 units per week (males) or 21 units per week (females)

• Current tobacco use or a history of smoking within the past five years

• Subject was, in the opinion of the Investigator, not suitable to participate in the study

• Subjects who had participated in any clinical study with an investigational drug/device within three months prior to the first day of dosing

• Subjects who had a positive result of HIV screen, Hepatitis B screen or Hepatitis C screen

• Subjects who had a serious adverse reaction or significant hypersensitivity to any drug

• Subjects having donated 500 mL or more of blood within the three months prior to screening

• Any history of co-existing nasal polyps, NSAID sensitivity and asthma

• Allergic reaction to aspirin or other NSAIDs

• Current upper respiratory tract infection or other respiratory tract condition that may have interfered with the absorption of the nasal spray or with the assessment of adverse events (AEs)

• Any suspicion of rhinitis medicamentosa (chronic daily use of topical decongestants)

• Use of a monoamine oxidase inhibitor (MAOI) in the 14 days prior to study entry

• 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

• History of asthma or any other chronic pulmonary disorder

• Renal impairment or a risk of renal failure due to volume depletion

• Known sensitivity to lidocaine hydrochloride

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Medeval Limited	Manchester		United Kingdom

Sponsors and Collaborators

• Egalet Ltd

Investigators

• Principal Investigator: Cyril Clarke, BSc MB BS MFPM, Medeval Limited

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Egalet Ltd
• ClinicalTrials.gov Identifier: NCT01363050
• Other Study ID Numbers: ROX 2005-03
• First Posted: Jun 1, 2011
• Last Update Posted: Mar 16, 2017
• Last Verified: Feb 1, 2017

• Additional relevant MeSH terms: Ketorolac; Ketorolac Tromethamine

Study Results

Participant Flow

Recruitment Details	January 9, 2006 - February 27, 2006; Clinical Unit
Pre-assignment Detail	After subjects had given their informed consent, subjects were required to pass a screening visit within 3 weeks prior to study drug administration.

Arm/Group Title	Ketorolac Tromethamine
Arm/Group Description	Ketorolac tromethamine : Subjects received intranasal ketorolac tromethamine (30 mg) three times daily (t.i.d.) for three days (seven doses in total). Doses were administered every eight hours.
Period Title: Overall Study
STARTED	15
COMPLETED	15
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Ketorolac Tromethamine
Arm/Group Description	Ketorolac tromethamine : Subjects received intranasal ketorolac tromethamine (30 mg) three times daily (t.i.d.) for three days (seven doses in total). Doses were administered every eight hours.
Overall Participants	15
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	15 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	31.7 (10.4)
Sex: Female, Male (Count of Participants)
Female	5 33.3%
Male	10 66.7%
Region of Enrollment (participants) [Number]
United Kingdom	15 100%

Outcome Measures

1. Primary Outcome

Title	Cmax (the Maximum Observed Plasma Concentration)
Description	PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.
Time Frame	Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 1 (morning doses)

Outcome Measure Data

Analysis Population Description

Two subjects were considered pharmacokinetic outliers and were excluded from the PK population.

Arm/Group Title	Ketorolac Tromethamine
Arm/Group Description	Ketorolac tromethamine (Day 1) : Subjects received intranasal ketorolac tromethamine (30 mg) three times daily (t.i.d.) for three days (seven doses in total). Doses were administered every eight hours.
Measure Participants	13
Mean (Standard Deviation) [ng/mL]	1147.9 (186.0)

2. Primary Outcome

Title	Tmax (the Time to Maximum Concentration)
Description	PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.
Time Frame	Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 1 (morning doses)

Outcome Measure Data

Analysis Population Description

Two subjects were considered pharmacokinetic outliers and were excluded from the PK population.

Arm/Group Title	Ketorolac Tromethamine
Arm/Group Description	Ketorolac tromethamine (Day 1) : Subjects received intranasal ketorolac tromethamine (30 mg) three times daily (t.i.d.) for three days (seven doses in total). Doses were administered every eight hours.
Measure Participants	13
Median (Full Range) [hours]	1.000

3. Primary Outcome

Title	AUC 0-8h (the Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose)
Description	PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.
Time Frame	Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 1 (morning doses)

Outcome Measure Data

Analysis Population Description

Two subjects were considered pharmacokinetic outliers and were excluded from the PK population.

Arm/Group Title	Ketorolac Tromethamine
Arm/Group Description	Ketorolac tromethamine (Day 1): Subjects received intranasal ketorolac tromethamine (30 mg) three times daily (t.i.d.) for three days (seven doses in total). Doses were administered every eight hours.
Measure Participants	13
Mean (Standard Deviation) [ng*hours/mL]	4713.8 (744.8)

4. Primary Outcome

Title	Cmax,ss (the Maximum Observed Plasma Concentration at Steady State)
Description	PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.
Time Frame	Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 3 (morning doses)

Outcome Measure Data

Analysis Population Description

Two subjects were considered pharmacokinetic outliers and were excluded from the PK population.

Arm/Group Title	Ketorolac Tromethamine
Arm/Group Description	Ketorolac tromethamine (Day 3): Subjects received intranasal ketorolac tromethamine (30 mg) three times daily (t.i.d.) for three days (seven doses in total). Doses were administered every eight hours.
Measure Participants	13
Mean (Standard Deviation) [ng/mL]	1382.6 (224.3)

5. Primary Outcome

Title	Tmax,ss (the Time to Maximum Concentration at Steady State)
Description	PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.
Time Frame	Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 3 (morning doses)

Outcome Measure Data

Analysis Population Description

Two subjects were considered pharmacokinetic outliers and were excluded from the PK population.

Arm/Group Title	Ketorolac Tromethamine
Arm/Group Description	Ketorolac tromethamine (Day 3): Subjects received intranasal ketorolac tromethamine (30 mg) three times daily (t.i.d.) for three days (seven doses in total). Doses were administered every eight hours.
Measure Participants	13
Median (Full Range) [hours]	1.000

6. Primary Outcome

Title	Cmin,ss (the Minimum Observed Plasma Concentration at Steady State)
Description	PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.
Time Frame	Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 3 (morning doses)

Outcome Measure Data

Analysis Population Description

Two subjects were considered pharmacokinetic outliers and were excluded from the PK population.

Arm/Group Title	Ketorolac Tromethamine
Arm/Group Description	Ketorolac tromethamine (Day 3): Subjects received intranasal ketorolac tromethamine (30 mg) three times daily (t.i.d.) for three days (seven doses in total). Doses were administered every eight hours.
Measure Participants	13
Mean (Standard Deviation) [ng/mL]	367.7 (67.7)

7. Primary Outcome

Title	Tmin,ss (the Time to Minimum Concentration at Steady State)
Description	PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.
Time Frame	Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 3 (morning doses)

Outcome Measure Data

Analysis Population Description

Two subjects were considered pharmacokinetic outliers and were excluded from the PK population.

Arm/Group Title	Ketorolac Tromethamine
Arm/Group Description	Ketorolac tromethamine (Day 3): Subjects received intranasal ketorolac tromethamine (30 mg) three times daily (t.i.d.) for three days (seven doses in total). Doses were administered every eight hours.
Measure Participants	13
Median (Full Range) [hours]	0.000

8. Primary Outcome

Title	AUCτ (the Area Under the Plasma Concentration-time Curve Over the Dosing Interval at Steady-state)
Description	PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.
Time Frame	Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 3 (morning doses)

Outcome Measure Data

Analysis Population Description

Two subjects were considered pharmacokinetic outliers and were excluded from the PK population.

Arm/Group Title	Ketorolac Tromethamine
Arm/Group Description	Ketorolac tromethamine (Day 3): Subjects received intranasal ketorolac tromethamine (30 mg) three times daily (t.i.d.) for three days (seven doses in total). Doses were administered every eight hours.
Measure Participants	13
Mean (Standard Deviation) [ng*hours/mL]	6379.2 (1031.0)

9. Primary Outcome

Title	MRT (the Mean Residence Time
Description	PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.
Time Frame	Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 3 (morning doses)

Outcome Measure Data

Analysis Population Description

Two subjects were considered pharmacokinetic outliers and were excluded from the PK population.

Arm/Group Title	Ketorolac Tromethamine
Arm/Group Description	Ketorolac tromethamine (Day 3): Subjects received intranasal ketorolac tromethamine (30 mg) three times daily (t.i.d.) for three days (seven doses in total). Doses were administered every eight hours.
Measure Participants	13
Mean (Standard Deviation) [hours]	3.368 (0.056)

Adverse Events

Time Frame	1 month and 3 weeks
Arm/Group Title	Ketorolac Tromethamine
Arm/Group Description	Ketorolac tromethamine : Subjects received intranasal ketorolac tromethamine (30 mg) three times daily (t.i.d.) for three days (seven doses in total). Doses were administered every eight hours.
All Cause Mortality
	Ketorolac Tromethamine
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Ketorolac Tromethamine
	Affected / at Risk (%)	# Events
Total	0/15 (0%)
Other (Not Including Serious) Adverse Events
	Ketorolac Tromethamine
	Affected / at Risk (%)	# Events
Total	14/15 (93.3%)
Eye disorders
Lacrimation increased	2/15 (13.3%)	4
Gastrointestinal disorders
Lip dry	1/15 (6.7%)	1
Nausea	1/15 (6.7%)	1
General disorders
Catheter site haematoma	1/15 (6.7%)	1
Feeling cold	1/15 (6.7%)	1
Infections and infestations
Rhinitis	1/15 (6.7%)	2
Musculoskeletal and connective tissue disorders
Myalgia	1/15 (6.7%)	1
Nervous system disorders
Dizziness	1/15 (6.7%)	1
Headache	3/15 (20%)	4
Paraesthesia	1/15 (6.7%)	1
Psychiatric disorders
Anxiety	1/15 (6.7%)	1
Respiratory, thoracic and mediastinal disorders
Nasal discomfort	4/15 (26.7%)	10
Rhinorrhoea	1/15 (6.7%)	1
Sneezing	2/15 (13.3%)	2
Throat irritation	2/15 (13.3%)	3
Vascular disorders
Orthostatic hypotension	1/15 (6.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.