Healthy
Conditions
Brief summary
The goal of this clinical trial is to compare drug exposure from two different products (AMZ001 and Diclofenac Sodium 1% Gel) in healthy participants on Day 7 after repeated topical administrations for 7 days. Participants will receive, in a crossover design, three different treatments * AMZ001 Low dose * AMZ001 High dose * Diclofenac Sodium 1% Gel Safety and tolerability of AMZ001 will be also investigated.
Detailed description
On their both knees, participants will apply once daily either low dose of AMZ001 or high dose of AMZ001 for 7 consecutive days. Participants will also apply Diclofenac Sodium 1% Gel as per label information on each knee. Intensive pharmacokinetic assessment (blood samplings) will be performed on the first day of application (Day 1) as well as on the last day of application (Day 7). Each participant will receive each of the three treatments in a randomized manner. Between each treatment, participant will not receive any of the three tested therapies between 3 weeks before receiving the next therapy. (washout period) Participants will stay on the clinical unit only during each period of treatment but not during washout period.
Interventions
Topical application on both knees
Sponsors
Amzell
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male or female participants 18-65 years of age (e.g., in general good physical health, as judged by the Investigator and no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12-lead ECG (electrocardiogram) or clinical laboratory tests) * Has a body mass index (BMI) between 18.0 and 35.0 kg/m\^2 (kilogram per square meter) at Screening. * In the case of females of child-bearing potential (\[FCBP) unless surgically sterilized \[hysterectomy, bilateral oophorectomy, bilateral tubal ligation\] or are postmenopausal for at least 12 months), are using two acceptable forms of birth control (hormonal contraceptives i.e., oral/implant/injectable/transdermal; intrauterine device (IUD) and/or barrier methods \[female condom, male condom, diaphragm, cervical cap, spermicide\]; note: 2 barrier methods are two acceptable forms of birth control)). Abstinence or partner's vasectomies are acceptable if the female participant agrees to implement two acceptable forms of birth control if her lifestyle/partner changes. * Females of child-bearing potential have a negative serum pregnancy test (SPT) at Screening and negative urine pregnancy test (UPT) on Day -1 of each period and at end of treatment (EOT) visit * Are free of any systemic or dermatologic disorder and chronic or acute infections, which, in the opinion of the Principal Investigator (PI), will interfere with the study results or increase the risk of adverse events (AEs) * Read, understand, and provide signed informed consent before any assessment is performed.
Exclusion criteria
* Participant has any visible skin disease, skin lesions, wounds, or a significant amount of hair at the application site (knee) * Use of an investigational medicinal product (IMP) within 30 days or 5 half-lives (if known), whichever is longer, of enrollment or during the study. * Treated with systemic or local diclofenac within 30 days of enrollment or during the study (except for study IMP) * Known hypersensitivity to diclofenac, aspirin, Xarelto, coumadin, or other non-steroidal anti-inflammatory drugs (NSAIDs), including Cyclooxygenase-2 (COX-2) inhibitors. * Any history of drug hypersensitivity, asthma, urticaria, or other significant allergic diathesis. Participants with uncomplicated seasonal allergic rhinitis can be accepted only if the expected allergy season is clearly outside enrollment / treatment periods. * Females who are pregnant and/or lactating * Of child-bearing potential but not willing to use adequate contraception for the duration of the study * Participant is a current smoker and unable to abstain from smoking during the treatment periods. * Use of any topical medication, cosmetics, cream, ointments, lotions on the treatment site 1 week prior to enrollment through EOT visit * Use of any medication (including over-the-counter medication, dietary supplements, and herbal remedies) within 2 weeks before first scheduled study drug administration or within less than 5 times the elimination half-life of the respective drug (whichever is longer) or is anticipated to require concomitant medication during the 2-week period or at any time throughout the study. Consumption of any drug metabolizing enzyme (e.g., cytochrome P450 3A4 (CYP3A4) or other cytochrome P450 enzymes) inducing or inhibiting beverages or food (e.g., broccoli, Brussel sprouts, grapefruit, grapefruit juice, star fruit) within 3 days prior to and during each treatment period * Participant has a known or suspected malignancy, excluding basal cell cancer unless it is associated with the treatment area. * Participant has a positive blood screen for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), hepatitis C antibody (Anti-HCV) * Participant has any acute or chronic condition or is using medications, which, in the investigator's opinion, would make it unsafe for the participant to participate in this study, including clinically significant abnormal laboratory values, vital signs, physical examination findings prior to randomization or during study participation. * History or current evidence of renal disease or impaired renal function at screening as indicated by abnormal levels of serum creatinine (greater than (\>) 1.43 mg/dL (milligram per deciliter)) or blood urea nitrogen (greater than or equal to (≥) 35 mg/dL) or the presence of clinical significant abnormal urinary constituents (e.g., albuminuria) * History or current evidence of ongoing hepatic disease or impaired hepatic function at screening. A participant will be excluded if more than one of the following lab value deviations are found: 1) aspartate aminotransferase (AST) (≥ 1.5 upper limit of normal (ULN)), alanine aminotransferase (ALT) (≥ 1.5 ULN), 2) Gamma-Glutamyl Transferase (GGT) (≥ 1.5 ULN), alkaline phosphatase (ALP) (≥ 1.5 ULN), 3) total bilirubin (\> 2.00 mg/dL) or creatine kinase (≥ 3 ULN). A single deviation from the above values is acceptable and will not exclude the participant, unless specifically advised by the Investigator. * Participant has clinically relevant chronic or acute infectious illnesses or febrile infections within 2 weeks prior to the first scheduled study drug administration * Participant has gastrointestinal bleeding issues, e.g., Gastroesophageal Reflux Disease (GERD), Peptic Ulcer Disease (PUD) * Participant has a hospital admission or major surgery within 30 days prior to randomization. * Participant has a donation or blood collection of more than 1 unit (approximately 450 mL(milliliter)) of blood (or blood products) or acute loss of blood during the 30 days prior to randomization. * Participant has a history of alcohol abuse, prescription drug abuse, or illicit drug use within 6 months prior to Screening. * Participant meets eligibility criteria, but study is filled * Participant who is an investigational site staff member directly involved in the conduct of the study and his/her family members, site staff member otherwise supervised by the Investigator, or participant who is a Amzell B.V. employee directly involved in the conduct of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Compare Exposure to Diclofenac | Day 7 | Area under the curve (AUC) from time zero to 24 hours |
| Pharmacokinetic Parameter - Cmax | Day 1 | Maximum plasma drug concentration (Cmax) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic Parameter - Ke | Day 7 | Terminal disposition rate constant (Ke) |
| Pharmacokinetic Parameter - Cmin | Day 7 | Minimum plasma drug concentration (Cmin) |
| Local Tolerability | Day 1 to Day 7 | Incidence of application site reactions according to the terminology of the International Contact Dermatitis Research Group |
| Pharmacokinetic Parameter - Cavg | Day 7 | Average plasma concentration (Cavg) |
| Pharmacokinetic Parameter - Tmax | Day 7 | Time to reach maximum plasma concentration (Tmax) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AMZ001 Low/AMZ001 High/Diclofenac Low/High/Diclofenac | 12 |
| Diclofenac/AMZ001 High/AMZ001 Low Diclofenac/High/Low | 12 |
| Diclofenac/AMZ001 Low/AMZ001 High Diclofenac/Low/High | 12 |
| AMZ001 High/AMZ001 Low/Diclofenac High/Low/Diclofenac | 13 |
| AMZ001 Low/Diclofenac/AMZ001 High Low/Diclofenac/High | 13 |
| AMZ001 High/Diclofenac/AMZ001 Low High/Diclofenac/Low | 12 |
| Total | 74 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| First Crossover Period | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 |
| First Crossover Period | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 0 |
| Second Crossover Period | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 |
| Third Crossover Period | Adverse Event | 0 | 0 | 0 | 0 | 1 | 0 |
| Third Crossover Period | failure to meet continuation criteria | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | AMZ001 Low/AMZ001 High/Diclofenac | Diclofenac/AMZ001 High/AMZ001 Low | Diclofenac/AMZ001 Low/AMZ001 High | AMZ001 High/AMZ001 Low/Diclofenac | AMZ001 Low/Diclofenac/AMZ001 High | AMZ001 High/Diclofenac/AMZ001 Low | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 44.0 years STANDARD_DEVIATION 11.2 | 42.3 years STANDARD_DEVIATION 14.69 | 36.4 years STANDARD_DEVIATION 12.35 | 42.3 years STANDARD_DEVIATION 10.6 | 39.8 years STANDARD_DEVIATION 11.98 | 41.8 years STANDARD_DEVIATION 13.47 | 41.1 years STANDARD_DEVIATION 12.69 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 3 Participants | 5 Participants | 8 Participants | 4 Participants | 4 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 9 Participants | 7 Participants | 5 Participants | 9 Participants | 8 Participants | 47 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 6 Participants | 7 Participants | 5 Participants | 6 Participants | 7 Participants | 37 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 6 Participants | 4 Participants | 7 Participants | 7 Participants | 3 Participants | 32 Participants |
| Sex: Female, Male Female | 7 Participants | 5 Participants | 5 Participants | 10 Participants | 7 Participants | 4 Participants | 38 Participants |
| Sex: Female, Male Male | 5 Participants | 7 Participants | 7 Participants | 3 Participants | 6 Participants | 8 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 71 | 0 / 72 | 0 / 72 |
| other Total, other adverse events | 7 / 71 | 8 / 72 | 5 / 72 |
| serious Total, serious adverse events | 0 / 71 | 0 / 72 | 0 / 72 |
Outcome results
Primary
Compare Exposure to Diclofenac
Area under the curve (AUC) from time zero to 24 hours
Time frame: Day 7
Population: All subjects for which at least AUC0-τ or Cmax can be determined for the reference treatment (Diclofenac Sodium 1% Gel) along with at least one of Treatments AMZ001 Low dose or AMZ001 High dose are included in the analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AMZ001 Low Dose | Compare Exposure to Diclofenac | 141.5 ng*hr/mL | Geometric Coefficient of Variation 89.8 |
| AMZ001 High Dose | Compare Exposure to Diclofenac | 166.1 ng*hr/mL | Geometric Coefficient of Variation 90.3 |
| Diclofenac Sodium 1% Gel | Compare Exposure to Diclofenac | 202.3 ng*hr/mL | Geometric Coefficient of Variation 79.4 |
Primary
Pharmacokinetic Parameter - Cmax
Maximum plasma drug concentration (Cmax)
Time frame: Day 1
Population: All subjects for which at least AUC0-τ or Cmax can be determined for the reference treatment (Diclofenac Sodium 1% Gel) along with at least one of Treatments AMZ001 Low dose or AMZ001 High dose are included in the analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AMZ001 Low Dose | Pharmacokinetic Parameter - Cmax | 4.66 ng/mL | Geometric Coefficient of Variation 122.4 |
| AMZ001 High Dose | Pharmacokinetic Parameter - Cmax | 6.22 ng/mL | Geometric Coefficient of Variation 128.9 |
| Diclofenac Sodium 1% Gel | Pharmacokinetic Parameter - Cmax | 3.85 ng/mL | Geometric Coefficient of Variation 122.2 |
Secondary
Local Tolerability
Incidence of application site reactions according to the terminology of the International Contact Dermatitis Research Group
Time frame: Day 1 to Day 7
Population: The Safety population includes randomized subjects who received at least one dose of AMZ001 Low dose or High dose or Diclofenac Sodium 1% Gel
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AMZ001 Low Dose | Local Tolerability | mild skin erythema | 1 Participants |
| AMZ001 Low Dose | Local Tolerability | doubtful skin reaction | 7 Participants |
| AMZ001 Low Dose | Local Tolerability | strong skin erythema | 1 Participants |
| AMZ001 Low Dose | Local Tolerability | no skin reaction | 62 Participants |
| AMZ001 High Dose | Local Tolerability | mild skin erythema | 4 Participants |
| AMZ001 High Dose | Local Tolerability | strong skin erythema | 0 Participants |
| AMZ001 High Dose | Local Tolerability | no skin reaction | 61 Participants |
| AMZ001 High Dose | Local Tolerability | doubtful skin reaction | 7 Participants |
| Diclofenac Sodium 1% Gel | Local Tolerability | strong skin erythema | 0 Participants |
| Diclofenac Sodium 1% Gel | Local Tolerability | mild skin erythema | 1 Participants |
| Diclofenac Sodium 1% Gel | Local Tolerability | doubtful skin reaction | 7 Participants |
| Diclofenac Sodium 1% Gel | Local Tolerability | no skin reaction | 64 Participants |
Secondary
Pharmacokinetic Parameter - Cavg
Average plasma concentration (Cavg)
Time frame: Day 7
Population: All subjects for which at least AUC0-τ or Cmax can be determined for the reference treatment (Diclofenac Sodium 1% Gel) along with at least one of Treatments AMZ001 Low dose or AMZ001 High dose are included in the analysis population.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AMZ001 Low Dose | Pharmacokinetic Parameter - Cavg | 5.90 ng/mL | Geometric Coefficient of Variation 89.8 |
| AMZ001 High Dose | Pharmacokinetic Parameter - Cavg | 6.92 ng/mL | Geometric Coefficient of Variation 90.3 |
| Diclofenac Sodium 1% Gel | Pharmacokinetic Parameter - Cavg | 8.43 ng/mL | Geometric Coefficient of Variation 79.4 |
Secondary
Pharmacokinetic Parameter - Cavg
Average plasma concentration (Cavg)
Time frame: Day 1
Population: All subjects for which at least AUC0-τ or Cmax can be determined for the reference treatment (Diclofenac Sodium 1% Gel) along with at least one of Treatments AMZ001 Low dose or AMZ001 High dose are included in the analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AMZ001 Low Dose | Pharmacokinetic Parameter - Cavg | 2.59 ng/mL | Geometric Coefficient of Variation 119.8 |
| AMZ001 High Dose | Pharmacokinetic Parameter - Cavg | 3.48 ng/mL | Geometric Coefficient of Variation 124.8 |
| Diclofenac Sodium 1% Gel | Pharmacokinetic Parameter - Cavg | 1.60 ng/mL | Geometric Coefficient of Variation 109.9 |
Secondary
Pharmacokinetic Parameter - Cmin
Minimum plasma drug concentration (Cmin)
Time frame: Day 7
Population: All subjects for which at least AUC0-τ or Cmax can be determined for the reference treatment (Diclofenac Sodium 1% Gel) along with at least one of Treatments AMZ001 Low dose or AMZ001 High dose are included in the analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AMZ001 Low Dose | Pharmacokinetic Parameter - Cmin | 3.09 ng/mL | Geometric Coefficient of Variation 96.3 |
| AMZ001 High Dose | Pharmacokinetic Parameter - Cmin | 3.38 ng/mL | Geometric Coefficient of Variation 90.1 |
| Diclofenac Sodium 1% Gel | Pharmacokinetic Parameter - Cmin | 5.03 ng/mL | Geometric Coefficient of Variation 80.1 |
Secondary
Pharmacokinetic Parameter - Ke
Terminal disposition rate constant (Ke)
Time frame: Day 7
Population: All subjects for which at least AUC0-τ or Cmax can be determined for the reference treatment (Diclofenac Sodium 1% Gel) along with at least one of Treatments AMZ001 Low dose or AMZ001 High dose are included in the analysis population.~Analysis specified that Ke would be determined whenever the elimination phase after the Day 7 dose appeared to be adequately sampled based on a visual inspection of the log-linear plots.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| AMZ001 Low Dose | Pharmacokinetic Parameter - Ke | NA 1/hr |
| AMZ001 High Dose | Pharmacokinetic Parameter - Ke | NA 1/hr |
| Diclofenac Sodium 1% Gel | Pharmacokinetic Parameter - Ke | NA 1/hr |
Secondary
Pharmacokinetic Parameter - Tmax
Time to reach maximum plasma concentration (Tmax)
Time frame: Day 7
Population: All subjects for which at least AUC0-τ or Cmax can be determined for the reference treatment (Diclofenac Sodium 1% Gel) along with at least one of Treatments AMZ001 Low dose or AMZ001 High dose are included in the analysis population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AMZ001 Low Dose | Pharmacokinetic Parameter - Tmax | 8 hr |
| AMZ001 High Dose | Pharmacokinetic Parameter - Tmax | 10 hr |
| Diclofenac Sodium 1% Gel | Pharmacokinetic Parameter - Tmax | 18 hr |
Secondary
Pharmacokinetic Parameter - Tmax
Time to reach maximum plasma concentration
Time frame: Day 1
Population: All subjects for which at least AUC0-τ or Cmax can be determined for the reference treatment (Diclofenac Sodium 1% Gel) along with at least one of Treatments AMZ001 Low dose or AMZ001 High dose are included in the analysis population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AMZ001 Low Dose | Pharmacokinetic Parameter - Tmax | 14 hr |
| AMZ001 High Dose | Pharmacokinetic Parameter - Tmax | 16 hr |
| Diclofenac Sodium 1% Gel | Pharmacokinetic Parameter - Tmax | 20 hr |