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The purpose of this study is to evaluate the effect of nemolizumab (CD14152) on the pharmacokinetics (PK) of a drug "cocktail" representative of CYP450 (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5 sensitive index substrates) in adult participants with moderate to- severe atopic dermatitis (AD).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| CYP 450 Substrates plus Nemolizumab | Experimental | Participants will receive 1 single oral dose of selected, commercially available, cytochrome P450 substrates (CYP450-S) on Day 1 and after a 1-week washout period, participants will receive a 60 milligram (mg) loading dose of nemolizumab via 2 consecutive subcutaneous (SC) 30-mg injections at the Week 1 visit, followed by a single 30-mg injection once in every 4 weeks (Q4W) at Week 5 and Week 9. Participants will receive a second oral dosing of CYP450-S at Week 10. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Nemolizumab | Drug | Nemolizumab 30 mg will be administered as SC injections. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in Area Under the Concentration-time Curve From Time Zero to Infinity (AUC[0-infinity]) of Each of the 5 Probe Drugs Before and After 9-week Nemolizumab Treatment | AUC (0-infinity) was defined as AUC from time 0 to infinity, calculated as the sum of AUC (0-last) and C(last)/lambda(z); where C(last) was the last observed measurable (non-BQL) concentration; and lambda(z) was apparent terminal elimination rate constant. Probe drugs included Caffeine, Metoprolol Tartrate, Midazolam, Omeprazole and Warfarin Sodium. Change in AUC(0-infinity) of each of the 5 probe drugs before (Baseline) and after 9-week nemolizumab treatment is reported. | Baseline (before nemolizumab injection, at Week 0) and Week 10 (after nemolizumab injection): Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 72 and 120 hours post-dose |
| Change in Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUC [0-last]) of Each of the 5 Probe Drugs Before and After 9-week Nemolizumab Treatment | AUC (0-last) was defined as AUC from time 0 to the time of the last measurable (non-BQL) concentration, calculated by linear-linear trapezoidal summation. Probe drugs included Caffeine, Metoprolol Tartrate, Midazolam, Omeprazole and Warfarin Sodium. Change of AUC(0-last) of each of the 5 probe drugs before (Baseline) and after 9-week nemolizumab treatment is reported. | Baseline (before nemolizumab injection, at Week 0) and Week 10 (after nemolizumab injection): Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 72 and 120 hours post-dose |
| Maximum Observed Plasma Concentration (Cmax) of Each of the 5 Probe Drugs Before and After 9-week Nemolizumab Treatment | Cmax was defined as the maximum observed plasma concentration. Probe drugs included Caffeine, Metoprolol Tartrate, Midazolam, Omeprazole and Warfarin Sodium. Cmax of each of the 5 probe drugs before (Baseline) and after 9-week nemolizumab treatment is reported. | Baseline (before nemolizumab injection, at Week 0) and Week 10 (after nemolizumab injection): Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 72 and 120 hours post-dose |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), AEs of Special Interest (AESIs), and Serious AEs (SAEs) | An AE is defined as any untoward medical occurrence in a study participant administered a medicinal product which does not necessarily have a causal relationship with this treatment. SAE is any untoward medical occurrence that at any dose may results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is a suspected transmission of any infectious agent via a medicinal product. A TEAE is defined as an AE that occurs on or after the first date of study drug(s) administration until the date of last study visit. An AESI is a noteworthy treatment-emergent event for the study drug that should be monitored closely and reported promptly. |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| 8894 Galderma Investigational Site | North Hollywood | California | 91606 | United States | ||
| 9954 Galderma Investigational Site |
A total of 48 participants were screened, out of which 17 participants were enrolled in this study and 16 participants received at least 1 dose of nemolizumab.
The study was conducted at 2 sites in the United States and Bulgaria from 08 December 2021 to 07 June 2023.
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| ID | Title | Description |
|---|---|---|
| FG000 | CYP 450 Substrates Plus Nemolizumab | Participants received a single oral dose of selected, commercially available, cytochrome P450 substrates (CYP450-S) (caffeine 100 milligrams [mg], warfarin sodium 10 mg, midazolam 2 mg, omeprazole 20 mg, and metoprolol tartrate 100 mg) on Day 1. After a 1-week washout period, participants received a 60 mg loading dose of nemolizumab via 2 consecutive subcutaneous (SC) 30-mg injections at the Week 1 visit, followed by a single 30-mg injection once every 4 weeks (Q4W) at Week 5 and Week 9. Participants received a second oral dosing of CYP450-S at Week 10. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jul 15, 2024 | Nov 11, 2024 |
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| CYP 450 Substrates | Drug | CYP substrates (Caffeine, Warfarin Sodium, Midazolam, Omeprazole, and Metoprolol Tartrate) will administered orally at Week 0 (Day 1) and Week 10 as per the commercially available prescribing information. |
|
| Up to 24 weeks |
| Hallandale |
| Florida |
| 33009 |
| United States |
| 9923 Galderma Investigational Site | Miami | Florida | 33147 | United States |
| 8030 Galderma Investigational Site | Raleigh | North Carolina | 27612 | United States |
| 8076 Galderma Investigational Site | Austin | Texas | 78759 | United States |
| 5952 Galderma Investigational Site | Sofia | 1612 | Bulgaria |
| Safety Population | Safety population included all participants who received at least 1 dose of Nemolizumab. |
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| COMPLETED |
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| NOT COMPLETED |
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Enrolled population included all participants who signed the informed consent form and are enrolled in the study.
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| ID | Title | Description |
|---|---|---|
| BG000 | CYP 450 Substrates Plus Nemolizumab | Participants received a single oral dose of selected, commercially available, CYP450-S (caffeine 100 mg, warfarin sodium 10 mg, midazolam 2 mg, omeprazole 20 mg, and metoprolol tartrate 100 mg) on Day 1. After a 1-week washout period, participants received a 60 mg loading dose of nemolizumab via 2 consecutive SC 30-mg injections at the Week 1 visit, followed by a single 30-mg injection Q4W at Week 5 and Week 9. Participants received a second oral dosing of CYP450-S at Week 10. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Area Under the Concentration-time Curve From Time Zero to Infinity (AUC[0-infinity]) of Each of the 5 Probe Drugs Before and After 9-week Nemolizumab Treatment | AUC (0-infinity) was defined as AUC from time 0 to infinity, calculated as the sum of AUC (0-last) and C(last)/lambda(z); where C(last) was the last observed measurable (non-BQL) concentration; and lambda(z) was apparent terminal elimination rate constant. Probe drugs included Caffeine, Metoprolol Tartrate, Midazolam, Omeprazole and Warfarin Sodium. Change in AUC(0-infinity) of each of the 5 probe drugs before (Baseline) and after 9-week nemolizumab treatment is reported. | Analysis was performed on the per-protocol population, which included all participants who completed the treatment period without any major protocol deviations or any other event that could render the probe drugs plasma concentration-time profiles unreliable. Here, number analyzed signifies the number of participants evaluable for each specified category. | Posted | Mean | Standard Deviation | hour*microgram per liter | Baseline (before nemolizumab injection, at Week 0) and Week 10 (after nemolizumab injection): Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 72 and 120 hours post-dose |
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| Primary | Change in Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUC [0-last]) of Each of the 5 Probe Drugs Before and After 9-week Nemolizumab Treatment | AUC (0-last) was defined as AUC from time 0 to the time of the last measurable (non-BQL) concentration, calculated by linear-linear trapezoidal summation. Probe drugs included Caffeine, Metoprolol Tartrate, Midazolam, Omeprazole and Warfarin Sodium. Change of AUC(0-last) of each of the 5 probe drugs before (Baseline) and after 9-week nemolizumab treatment is reported. | Analysis was performed on the per-protocol population, which included all participants who completed the treatment period without any major protocol deviations or any other event that could render the probe drugs plasma concentration-time profiles unreliable. | Posted | Mean | Standard Deviation | hour*microgram per liter | Baseline (before nemolizumab injection, at Week 0) and Week 10 (after nemolizumab injection): Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 72 and 120 hours post-dose |
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| Primary | Maximum Observed Plasma Concentration (Cmax) of Each of the 5 Probe Drugs Before and After 9-week Nemolizumab Treatment | Cmax was defined as the maximum observed plasma concentration. Probe drugs included Caffeine, Metoprolol Tartrate, Midazolam, Omeprazole and Warfarin Sodium. Cmax of each of the 5 probe drugs before (Baseline) and after 9-week nemolizumab treatment is reported. | Analysis was performed on the per-protocol population, which included all participants who completed the treatment period without any major protocol deviations or any other event that could render the probe drugs plasma concentration-time profiles unreliable. | Posted | Mean | Standard Deviation | micrograms per liter | Baseline (before nemolizumab injection, at Week 0) and Week 10 (after nemolizumab injection): Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 72 and 120 hours post-dose |
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| Secondary | Number of Participants With Treatment Emergent Adverse Events (TEAEs), AEs of Special Interest (AESIs), and Serious AEs (SAEs) | An AE is defined as any untoward medical occurrence in a study participant administered a medicinal product which does not necessarily have a causal relationship with this treatment. SAE is any untoward medical occurrence that at any dose may results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is a suspected transmission of any infectious agent via a medicinal product. A TEAE is defined as an AE that occurs on or after the first date of study drug(s) administration until the date of last study visit. An AESI is a noteworthy treatment-emergent event for the study drug that should be monitored closely and reported promptly. | Analysis was performed on the safety population. The safety population included all participants who received at least 1 dose of nemolizumab. | Posted | Count of Participants | Participants | Up to 24 weeks |
|
Up to 24 weeks
Analysis was performed on safety population which included all participants who received at least 1 dose of nemolizumab.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | CYP 450 Substrates Plus Nemolizumab | Participants received a single oral dose of selected, commercially available, CYP450-S (caffeine 100 mg, warfarin sodium 10 mg, midazolam 2 mg, omeprazole 20 mg, and metoprolol tartrate 100 mg) on Day 1. After a 1-week washout period, participants received a 60 mg loading dose of nemolizumab via 2 consecutive SC 30-mg injections at the Week 1 visit, followed by a single 30-mg injection Q4W at Week 5 and Week 9. Participants received a second oral dosing of CYP450-S at Week 10. | 0 | 16 | 0 | 16 | 0 | 16 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Clinical Operations | Galderma | 08179615000 | 1 | Clinical.Studies@galderma.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jul 15, 2024 | Nov 11, 2024 | SAP_001.pdf |
| ID | Term |
|---|---|
| D003876 | Dermatitis, Atopic |
| ID | Term |
|---|---|
| D012873 | Skin Diseases, Genetic |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D003872 | Dermatitis |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D017443 | Skin Diseases, Eczematous |
| D006969 | Hypersensitivity, Immediate |
| D006967 | Hypersensitivity |
| D007154 | Immune System Diseases |
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| ID | Term |
|---|---|
| C000612881 | nemolizumab |
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| Unknown or Not Reported |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Metoprolol Tartrate |
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| Midazolam |
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| Omeprazole |
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| Warfarin Sodium |
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Metoprolol Tartrate |
| Mixed Models Analysis |
| 0.9468 |
A linear mixed-effect model was used to compare the natural log-transformed of the value, with substrate with or without Nemolizumab as the fixed effect and subject as a random effect. |
| Ratio |
| 99.34 |
| 2-Sided |
| 90 |
| 83.66 |
| 117.96 |
| Other |
| Midazolam | Mixed Models Analysis | 0.1364 | A linear mixed-effect model was used to compare the natural log-transformed of the value, with substrate with or without Nemolizumab as the fixed effect and subject as a random effect. | Ratio | 107.81 | 2-Sided | 90 | 99.14 | 117.24 | Other |
| Omeprazole | Mixed Models Analysis | 0.1915 | A linear mixed-effect model was used to compare the natural log-transformed of the value, with substrate with or without Nemolizumab as the fixed effect and subject as a random effect. | Ratio | 92.13 | 2-Sided | 90 | 82.85 | 102.44 | Other |
| Warfarin Sodium | Mixed Models Analysis | 0.5059 | A linear mixed-effect model was used to compare the natural log-transformed of the value, with substrate with or without Nemolizumab as the fixed effect and subject as a random effect. | Ratio | 101.67 | 2-Sided | 90 | 97.41 | 106.12 | Other |
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