Healthy Volunteers
Conditions
Brief summary
This was a phase 1, double-blind, 4-way crossover study in healthy male and female volunteers. Subjects received 4 formulations of intranasal ketorolac tromethamine 30 mg. There was a wash-out period of 3-7 days between each dose. On Day 1 of each period subjects were randomised to receive either a single intranasal dose of 30 mg ketorolac tromethamine alone or single intranasal dose of 30 mg ketorolac tromethamine with 4%, 5% or 6% lidocaine hydrochloride. At the end of the study each subject had received all 4 treatments. The primary objective of this study in healthy volunteers was to compare the safety, tolerability, and pharmacokinetics of 4 formulations of ketorolac tromethamine. A secondary objective was to monitor lidocaine hydrochloride plasma levels.
Interventions
DRUGKetorolac Tromethamine
30 mg Ketorolac Tromethamine intranasal (IN)
DRUGKetorolac Tromethamine with 4% Lidocaine hydrochloride (HCl)
30 mg Ketorolac Tromethamine with 4% Lidocaine HCl IN
DRUGKetorolac Tromethamine with 5% Lidocaine HCl
30 mg Ketorolac Tromethamine with 5% Lidocaine HCl IN
DRUG30 mg Ketorolac Tromethamine with 6% Lidocaine HCl
30 mg Ketorolac Tromethamine with 6% Lidocaine HCl IN
Sponsors
Egalet Ltd
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
* Male or female volunteers, aged 18 to 60 years inclusive * Female subjects of child bearing potential must have had 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 use 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. 1999) * 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 range 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 was at least 70 kg
Exclusion criteria
* Subject had a clinically significant illness in the 4 weeks before screening * Use of prescribed medications in the 3 weeks prior to dosing or over-the-counter preparations for 7 days prior to dosing, except paracetamol which was allowed up to 48 hours prior to dosing. However, 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 * Subject had history of alcohol abuse or drank in excess of 28 units per week (males) or 21 units per week (females) * Current tobacco use or a history of smoking within the past 5 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 3 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 with a serious adverse reaction or significant hypersensitivity to any drug * Subjects who has donated 500 mL or more of blood within the 3 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 could have interfered with the absorption of the nasal spray or with the assessment of AEs * 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 * 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Maximum Observed Plasma Concentration (Cmax) | Anytime at pre-dose, 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours (ketorolac tromethamine only), and 24 hours (ketorolac tromethamine only) post-dose |
| Area Under the Plasma Concentration-time Profile From Time Zero to the Last Quantifiable Post-dose (AUC 0-t) | Anytime at pre-dose, 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours (ketorolac tromethamine only), and 24 hours (ketorolac tromethamine only) post-dose |
| Area Under the Plasma Concentration-time Profile From Time Zero to Infinity (AUC 0-∞) | Anytime at pre-dose, 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours (ketorolac tromethamine only), and 24 hours (ketorolac tromethamine only) post-dose |
Secondary
| Measure | Time frame |
|---|---|
| Time to Reach Maximum Plasma Concentration (Tmax) | Anytime at pre-dose, 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours (ketorolac tromethamine only), and 24 hours (ketorolac tromethamine only) post-dose |
Countries
United Kingdom
Participant flow
Recruitment details
1 month and 2 weeks; Medeval Limited Skelton House, Manchester Science Park, Lloyd Street North, Manchester M15 6SH, U.K.
Participants by arm
| Arm | Count |
|---|---|
| Treatment A, Treatment C, Treatment D, Treatment B Treatment A: Ketorolac Tromethamine : 30 mg Ketorolac Tromethamine intranasal (IN), then; Treatment C: Ketorolac Tromethamine with 5% Lidocaine HCl : 30 mg Ketorolac Tromethamine with 5% Lidocaine HCl IN, then; Treatment D: 30 mg Ketorolac Tromethamine with 6% Lidocaine HCl : 30 mg Ketorolac Tromethamine with 6% Lidocaine HCl IN, then; Treatment B: Ketorolac Tromethamine with 4% Lidocaine hydrochloride (HCl) : 30 mg Ketorolac Tromethamine with 4% Lidocaine HCl IN | 4 |
| Treatment B, Treatment D, Treatment C, Treatment A Treatment B: Ketorolac Tromethamine with 4% Lidocaine hydrochloride (HCl) : 30 mg Ketorolac Tromethamine with 4% Lidocaine HCl IN, then; Treatment D: 30 mg Ketorolac Tromethamine with 6% Lidocaine HCl : 30 mg Ketorolac Tromethamine with 6% Lidocaine HCl IN, then; Treatment C: Ketorolac Tromethamine with 5% Lidocaine HCl : 30 mg Ketorolac Tromethamine with 5% Lidocaine HCl IN, then; Treatment A: Ketorolac Tromethamine : 30 mg Ketorolac Tromethamine intranasal (IN) | 4 |
| Treatment C, Treatment B, Treatment A, Treatment D Treatment C: Ketorolac Tromethamine with 5% Lidocaine HCl : 30 mg Ketorolac Tromethamine with 5% Lidocaine HCl IN, then; Treatment B: Ketorolac Tromethamine with 4% Lidocaine hydrochloride (HCl) : 30 mg Ketorolac Tromethamine with 4% Lidocaine HCl IN, then; Treatment A: Ketorolac Tromethamine : 30 mg Ketorolac Tromethamine intranasal (IN), then; Treatment D: 30 mg Ketorolac Tromethamine with 6% Lidocaine HCl : 30 mg Ketorolac Tromethamine with 6% Lidocaine HCl IN | 4 |
| Treatment D, Treatment A, Treatment B, Treatment C Treatment D: 30 mg Ketorolac Tromethamine with 6% Lidocaine HCl : 30 mg Ketorolac Tromethamine with 6% Lidocaine HCl IN, then; Treatment A: Ketorolac Tromethamine : 30 mg Ketorolac Tromethamine intranasal (IN), then; Treatment B: Ketorolac Tromethamine with 4% Lidocaine hydrochloride (HCl) : 30 mg Ketorolac Tromethamine with 4% Lidocaine HCl IN, then; Treatment C: Ketorolac Tromethamine with 5% Lidocaine HCl : 30 mg Ketorolac Tromethamine with 5% Lidocaine HCl IN | 4 |
| Total | 16 |
Baseline characteristics
| Characteristic | Treatment B, Treatment D, Treatment C, Treatment A | Treatment C, Treatment B, Treatment A, Treatment D | Treatment A, Treatment C, Treatment D, Treatment B | Treatment D, Treatment A, Treatment B, Treatment C | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 16 Participants |
| Age, Continuous | 40.75 years STANDARD_DEVIATION 19.97 | 34.0 years STANDARD_DEVIATION 15.9 | 34.25 years STANDARD_DEVIATION 17.21 | 50.25 years STANDARD_DEVIATION 10.31 | 39.8 years STANDARD_DEVIATION 16 |
| Region of Enrollment United Kingdom | 4 participants | 4 participants | 4 participants | 4 participants | 16 participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 2 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 4 Participants | 3 Participants | 2 Participants | 2 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 11 / 16 | 9 / 16 | 9 / 16 | 8 / 16 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 16 |
Outcome results
Primary
Area Under the Plasma Concentration-time Profile From Time Zero to Infinity (AUC 0-∞)
Time frame: Anytime at pre-dose, 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours (ketorolac tromethamine only), and 24 hours (ketorolac tromethamine only) post-dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketorolac Tromethamine | Area Under the Plasma Concentration-time Profile From Time Zero to Infinity (AUC 0-∞) | 9061.9 ng*h/mL | Standard Deviation 4526.8 |
| Ketorolac Tromethamine With 4% Lidocaine Hydrochloride (HCl) | Area Under the Plasma Concentration-time Profile From Time Zero to Infinity (AUC 0-∞) | 8694.5 ng*h/mL | Standard Deviation 4477.1 |
| Ketorolac Tromethamine With 5% Lidocaine HCl | Area Under the Plasma Concentration-time Profile From Time Zero to Infinity (AUC 0-∞) | 8086.8 ng*h/mL | Standard Deviation 4608.2 |
| Ketorolac Tromethamine With 6% Lidocaine HCl | Area Under the Plasma Concentration-time Profile From Time Zero to Infinity (AUC 0-∞) | 8677.6 ng*h/mL | Standard Deviation 4301 |
Primary
Area Under the Plasma Concentration-time Profile From Time Zero to the Last Quantifiable Post-dose (AUC 0-t)
Time frame: Anytime at pre-dose, 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours (ketorolac tromethamine only), and 24 hours (ketorolac tromethamine only) post-dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketorolac Tromethamine | Area Under the Plasma Concentration-time Profile From Time Zero to the Last Quantifiable Post-dose (AUC 0-t) | 8440.6 ng*h/mL | Standard Deviation 4021.2 |
| Ketorolac Tromethamine With 4% Lidocaine Hydrochloride (HCl) | Area Under the Plasma Concentration-time Profile From Time Zero to the Last Quantifiable Post-dose (AUC 0-t) | 7856.0 ng*h/mL | Standard Deviation 4211.8 |
| Ketorolac Tromethamine With 5% Lidocaine HCl | Area Under the Plasma Concentration-time Profile From Time Zero to the Last Quantifiable Post-dose (AUC 0-t) | 7561.5 ng*h/mL | Standard Deviation 4051.2 |
| Ketorolac Tromethamine With 6% Lidocaine HCl | Area Under the Plasma Concentration-time Profile From Time Zero to the Last Quantifiable Post-dose (AUC 0-t) | 8103.8 ng*h/mL | Standard Deviation 3786.3 |
Primary
Maximum Observed Plasma Concentration (Cmax)
Time frame: Anytime at pre-dose, 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours (ketorolac tromethamine only), and 24 hours (ketorolac tromethamine only) post-dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketorolac Tromethamine | Maximum Observed Plasma Concentration (Cmax) | 2059.6 ng/mL | Standard Deviation 801.7 |
| Ketorolac Tromethamine With 4% Lidocaine Hydrochloride (HCl) | Maximum Observed Plasma Concentration (Cmax) | 1963.1 ng/mL | Standard Deviation 1020.8 |
| Ketorolac Tromethamine With 5% Lidocaine HCl | Maximum Observed Plasma Concentration (Cmax) | 1799.9 ng/mL | Standard Deviation 714.1 |
| Ketorolac Tromethamine With 6% Lidocaine HCl | Maximum Observed Plasma Concentration (Cmax) | 2048.5 ng/mL | Standard Deviation 817.6 |
Secondary
Time to Reach Maximum Plasma Concentration (Tmax)
Time frame: Anytime at pre-dose, 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours (ketorolac tromethamine only), and 24 hours (ketorolac tromethamine only) post-dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ketorolac Tromethamine | Time to Reach Maximum Plasma Concentration (Tmax) | 0.510 hours |
| Ketorolac Tromethamine With 4% Lidocaine Hydrochloride (HCl) | Time to Reach Maximum Plasma Concentration (Tmax) | 0.500 hours |
| Ketorolac Tromethamine With 5% Lidocaine HCl | Time to Reach Maximum Plasma Concentration (Tmax) | 0.390 hours |
| Ketorolac Tromethamine With 6% Lidocaine HCl | Time to Reach Maximum Plasma Concentration (Tmax) | 0.410 hours |