A Double Blind Study in Pediatric Subjects With Chronic Plaque Psoriasis, Studying Adalimumab vs. Methotrexate

Study Overview
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Brief Summary
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This study will compare how well adalimumab works versus methotrexate (MTX) in children with moderate to severe psoriasis in the short term. It will also study how safe and how well adalimumab works in the long term and how long disease response can be maintained after stopping therapy.

Detailed Description
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The study had a 30-day screening period and a multi-period study design, as described below: Period A - Primary Treatment Phase: Participants were randomized to receive adalimumab 0.8 mg/kg, adalimumab 0.4 mg/kg, or MTX in 1:1:1 ratio for 16 weeks. Period B - Treatment Withdrawal Phase: Responders were withdrawn from active treatment and monitored for loss of disease control for up to 36 weeks. Period C - Re-Treatment Phase: Participants who had experienced loss of disease control in Period B were re-treated with adalimumab for 16 weeks. Period D - Long-Term Follow-Up Phase: Participants received adalimumab or were observed off-treatment (if disease remained under control) for 52 weeks.

Official Title
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A Multicenter, Randomized, Double-dummy, Double-blind Study Evaluating Two Doses of Adalimumab Versus Methotrexate (MTX) in Pediatric Subjects With Chronic Plaque Psoriasis (Ps)

Conditions
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Plaque Psoriasis

Intervention / Treatment
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* Biological: Adalimumab
* Drug: Methotrexate
* Biological: Placebo to Adalimumab
* Drug: Placebo to Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is ≥ 4 years and < 18 years of age; Subject weighs ≥ 13 kg; Subject must have failed to respond to topical therapy; Subject must need systemic treatment to control his/her disease and meet one of the following: Physician's Global Assessment (PGA) ≥ 4 Body surface area (BSA) involved > 20% Very thick lesions with BSA > 10% Psoriasis Area and Severity Index (PASI) > 20 PASI > 10 and at least one of the following: Active psoriatic arthritis unresponsive to non-steroid anti-inflammatory drugs (NSAIDs) Clinically relevant facial involvement Clinically relevant genital involvement Clinically relevant hand and/or foot involvement Children's Dermatology Life Quality Index (CDLQI) > 10 If subject is < 12 years of age and resides in a geographic region where heliotherapy is practical, subject must have failed to respond, be intolerant, or have a contraindication to heliotherapy, or is not a suitable candidate for heliotherapy; If ≥ 12 years of age, subject must have failed to respond, be intolerant, or have a contraindication to phototherapy, or is not a suitable candidate for phototherapy; Subject must have a clinical diagnosis of psoriasis for at least 6 months as determined by the subject's medical history and confirmation of diagnosis through physical examination by the Investigator; Subject must have stable plaque psoriasis for at least 2 months prior to Baseline Exclusion Criteria: Prior biologic use other than prior treatment with etanercept; Treatment with etanercept therapy within 4 weeks prior to the Baseline visit; 3. Methotrexate (MTX) use within the past year or prior MTX use at any time where the subject did not respond, or did not tolerate MTX; 4. Contraindication for treatment with MTX during the study; 5. Erythrodermic psoriasis, generalized or localized pustular psoriasis, medication-induced or medication exacerbated psoriasis or new onset guttate psoriasis; 6. Infection(s) requiring treatment with intravenous (IV) anti-infectives within 30 days prior to the Baseline Visit or oral anti-infectives within 14 days prior to the Baseline Visit; 7. Treatment of psoriasis with topical therapies such as corticosteroids, vitamin D analogs, or retinoids within 7 days prior to the Baseline visit; 8. Treatment of psoriasis with ultraviolet (UV)B phototherapy, excessive sun exposure, or the use of tanning beds within 7 days prior to the Baseline visit; 9. Treatment of psoriasis with ultraviolet A with psoralen (PUVA) phototherapy, non-biologic systemic therapies for the treatment of psoriasis, or systemic therapies known to improve psoriasis within 14 days prior to the Baseline visit.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Adalimumab 0.4 mg/kg<br>In Period A participants received a single subcutaneous loading dose of adalimumab 0.4 mg/kg (up to a maximum of 20 mg) at Week 0 followed by every other week dosing beginning at Week 1. To maintain the blind, participants also received weekly dosing of methotrexate placebo tablets. Participants who were non-responders in Period A entered Period D directly and received open-label adalimumab at 0.8 mg/kg eow for up to 52 weeks. Participants who responded in Period A entered the Treatment Withdrawal Phase (Period B) for up to 36 weeks. Participants who experienced a loss of disease control in Period B entered the Re-treatment Phase (Period C) and received blinded adalimumab 0.4 mg/kg eow for 16 weeks. Participants who completed Period B with no loss of disease control entered Period D and were observed off study medication for up to 52 weeks. Participants who completed Period C entered Period D for an additional 52 weeks of treatment with blinded adalimumab 0.4 mg/kg eow. | Biological: Adalimumab<br>* Adalimumab by subcutaneous injection every other week (eow)<br>* Other names: Humira;Drug: Placebo to Methotrexate<br>* Orally once a week<br>|
| Experimental: Adalimumab 0.8 mg/kg<br>In Period A participants received a single subcutaneous loading dose of adalimumab 0.8 mg/kg (up to a maximum of 40 mg) at Week 0 followed by every other week dosing beginning at Week 1. To maintain the blind, participants also received weekly dosing of methotrexate placebo tablets. Participants who were non-responders in Period A entered Period D directly and received open-label adalimumab at 0.8 mg/kg eow for up to 52 weeks. Participants who responded in Period A entered the Treatment Withdrawal Phase (Period B) for up to 36 weeks. Participants who experienced a loss of disease control in Period B entered the Re-treatment Phase (Period C) and received blinded adalimumab 0.8 mg/kg eow for 16 weeks. Participants who completed Period B with no loss of disease control entered Period D and were observed off study medication for up to 52 weeks. Participants who completed Period C entered Period D for an additional 52 weeks of treatment with blinded adalimumab 0.8 mg/kg eow. | Biological: Adalimumab<br>* Adalimumab by subcutaneous injection every other week (eow)<br>* Other names: Humira;Drug: Placebo to Methotrexate<br>* Orally once a week<br>|
| Active Comparator: Methotrexate<br>Participants received 0.1 mg/kg methotrexate at Baseline (Week 0), and up to 0.4 mg/kg weekly (maximum dose of 25 mg/week) in Period A. Participants also received adalimumab placebo as a single subcutaneous loading dose at Week 0, followed by every other week (eow) dosing from Week 1. Participants who were non-responders in period A entered Period D directly and received open-label adalimumab at 0.8 mg/kg eow for up to 52 weeks. Participants who responded in Period A entered the Treatment Withdrawal Phase (Period B) for up to 36 weeks. Participants who experienced a loss of disease control in Period B entered the Re-treatment Phase (Period C) and received blinded adalimumab 0.8 mg/kg eow for 16 weeks. Participants who completed Period B with no loss of disease control entered Period D and were observed off study medication for up to 52 weeks. Participants who completed Period C entered Period D for an additional 52 weeks of treatment with blinded adalimumab 0.8 mg/kg eow. | Drug: Methotrexate<br>* Methotrexate 0.1 mg/kg at Week 0 and up to 0.4 mg/kg per week (maximum dose of 25 mg/week) orally.<br>Biological: Placebo to Adalimumab<br>* A single subcutaneous loading dose at Week 0 followed by eow dosing beginning at Week 1.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved a Psoriasis Area and Severity Index (PASI) 75 Response at Week 16 | PASI is a composite score based on the degree of effect on body surface area of psoriasis and the extension of erythema (reddening), induration (plaque thickness), desquamation (scaling) of the lesions and area affected as observed on the day of examination. The score ranges from 0 (no psoriasis) to 72 (very severe psoriasis). A PASI 75 response is defined as at least a 75% reduction (improvement) from Baseline in PASI score at Week 16. | Baseline and Week 16 | 
| Percentage of Participants Achieving a Physician's Global Assessment of Disease Activity (PGA) of Cleared (0) or Minimal (1) at Week 16 | The PGA is a 6-point scale used to measure the severity of disease at the time of the evaluation. The degree of overall lesion severity was evaluated using the following categories: 0 (Cleared): No evidence of scaling, erythema, or plaque elevation; 1 (Minimal): Occasional fine scale over <5% of lesions, faint erythema, minimal plaque elevation; 2 (Mild): Fine scale dominates, light red coloration, mild plaque elevation; 3 (Moderate): Course scale dominates, moderate red coloration, moderate plaque elevation; 4 (Marked): Thick non-tenacious scale dominates, bright red coloration, marked plaque elevation; 5 (Severe): Very thick tenacious scale predominates, dusky to deep red coloration, severe plaque elevation. The percentage of participants achieving a score of clear (0) or minimal (1) is reported. | Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved a PASI 90 Response at Week 16 | PASI is a composite score based on the degree of effect on body surface area of psoriasis and the extension of erythema (reddening), induration (plaque thickness), desquamation (scaling) of the lesions and area affected as observed on the day of examination. The score ranges from 0 (no psoriasis) to 72 (very severe psoriasis). A PASI 90 response is at least a 90% reduction (improvement) from Baseline in PASI score at Week 16. | Baseline and Week 16 | 
| Percentage of Participants Who Achieved a PASI 100 Response at Week 16 | PASI is a composite score based on the degree of effect on body surface area of psoriasis and the extension of erythema (reddening), induration (plaque thickness), desquamation (scaling) of the lesions and area affected as observed on the day of examination. The score ranges from 0 (no psoriasis) to 72 (very severe psoriasis). A PASI 100 response is a 100% reduction (improvement) from Baseline in PASI score at Week 16. | Baseline and Week 16 | 
| Change From Baseline in the Children's Dermatology Life Quality Index (CDLQI) Score at Week 16 | The Children's Dermatology Life Quality Index (CDLQI) is a 10-item questionnaire to measure the quality of life in children aged from 4 to 16 years. Each question is scored from 0 (not at all) to 3 (very much). The CDLQI is calculated by summing the score of each question resulting in a maximum of 30 and a minimum of 0. The higher the score, the more quality of life is impaired. | Baseline and Week 16 | 
| Change From Baseline in the Pediatric Quality of Life Inventory (PedsQL) Score at Week 16 | The PedsQL Measurement Model measures health-related quality of life (HRQOL) in children and adolescents. The 23-item PedsQL Generic Core Scale includes Physical, Emotional, Social, School Functioning dimensions. Each item is scored from 0 (never) to 4 (almost always). Items are reversed scored and linearly transformed to a 0-100 scale, so that higher scores indicate better HRQOL; the total score therefore ranges from 0 (worst) to 100 (best). | Baseline and Week 16 | 
| Percentage of Participants Achieving a PGA of Cleared (0) or Minimal (1) Upon Re-Treatment in Period C | The PGA is a 6-point scale used to measure the severity of disease at the time of the evaluation. The degree of overall lesion severity was evaluated using the following categories: 0 (Cleared): No evidence of scaling, erythema, or plaque elevation; 1 (Minimal): Occasional fine scale over < 5% of lesions, faint erythema, minimal plaque elevation; 2 (Mild): Fine scale dominates, light red coloration, mild plaque elevation; 3 (Moderate): Course scale dominates, moderate red coloration, moderate plaque elevation; 4 (Marked): Thick non-tenacious scale dominates, bright red coloration, marked plaque elevation; 5 (Severe): Very thick tenacious scale predominates, dusky to deep red coloration, severe plaque elevation. The percentage of participants achieving a score of clear (0) or minimal (1) is reported. | Period C, Week 16 | 
| Time to Loss of Disease Control for Participants Who Entered Period B | Loss of disease control was defined as a worsening of PGA scores in comparison to Week 16 of Period A by at least 2 grades after treatment withdrawal. The PGA is a 6-point scale used to measure the severity of disease at the time of the evaluation. Scores range from 0 (no evidence of scaling, erythema, or plaque elevation) to 5 (very thick tenacious scale predominates, dusky to deep red coloration, severe plaque elevation). Participants who did not lose disease control in period B continued off drug into period D and were observed off-drug until they finally lost disease control or until the end of the 52 weeks of period D. | Period B (36 weeks) and Period D (52 weeks) | 
| Percentage of Participants Achieving a PGA of Cleared (0) or Minimal (1) Over Time | The PGA is a 6-point scale used to measure the severity of disease at the time of the evaluation. The degree of overall lesion severity was evaluated using the following categories: 0 (Cleared): No evidence of scaling, erythema, or plaque elevation; 1 (Minimal): Occasional fine scale over <5% of lesions, faint erythema, minimal plaque elevation; 2 (Mild): Fine scale dominates, light red coloration, mild plaque elevation; 3 (Moderate): Course scale dominates, moderate red coloration, moderate plaque elevation; 4 (Marked): Thick non-tenacious scale dominates, bright red coloration, marked plaque elevation; 5 (Severe): Very thick tenacious scale predominates, dusky to deep red coloration, severe plaque elevation. The percentage of participants achieving a score of clear (0) or minimal (1) is reported. | Period A, Weeks 4, 8 and 11, Period C, Weeks 0 and 16, Period D, Weeks 0, 16, 28, 40 and 52 | 
| Percentage of Participants Achieving a PGA of Cleared (0) Over Time | The PGA is a 6-point scale used to measure the severity of disease at the time of the evaluation. The degree of overall lesion severity was evaluated using the following categories: 0 (Cleared): No evidence of scaling, erythema, or plaque elevation; 1 (Minimal): Occasional fine scale over <5% of lesions, faint erythema, minimal plaque elevation; 2 (Mild): Fine scale dominates, light red coloration, mild plaque elevation; 3 (Moderate): Course scale dominates, moderate red coloration, moderate plaque elevation; 4 (Marked): Thick non-tenacious scale dominates, bright red coloration, marked plaque elevation; 5 (Severe): Very thick tenacious scale predominates, dusky to deep red coloration, severe plaque elevation. The percentage of participants achieving a score of clear (0) is reported. | Period A, Weeks 4, 8, 11 and 16, Period C, Weeks 0 and 16, Period D, Weeks 0, 16, 28, 40 and 52 | 
| Percentage of Participants Who Achieved a PASI 50 Response Over Time | PASI is a composite score based on the degree of effect on body surface area of psoriasis and the extension of erythema (reddening), induration (plaque thickness), desquamation (scaling) of the lesions and area affected as observed on the day of examination. The score ranges from 0 (no psoriasis) to 72 (very severe psoriasis). A PASI 50 response is at least a 50% reduction (improvement) from Baseline in PASI score. | Baseline, Period A, Weeks 4, 8, 11 and 16, Period C, Weeks 0 and 16, Period D, Weeks 0, 16, 28, 40 and 52 | 
| Percentage of Participants Who Achieved a PASI 75 Response Over Time | PASI is a composite score based on the degree of effect on body surface area of psoriasis and the extension of erythema (reddening), induration (plaque thickness), desquamation (scaling) of the lesions and area affected as observed on the day of examination. The score ranges from 0 (no psoriasis) to 72 (very severe psoriasis). A PASI 75 response is at least a 75% reduction (improvement) from Baseline in PASI score. | Baseline, Period A, Weeks 4, 8, and 11, Period C, Weeks 0 and 16, Period D, Weeks 0, 16, 28, 40 and 52 | 
| Percentage of Participants Who Achieved a PASI 90 Response Over Time | PASI is a composite score based on the degree of effect on body surface area of psoriasis and the extension of erythema (reddening), induration (plaque thickness), desquamation (scaling) of the lesions and area affected as observed on the day of examination. The score ranges from 0 (no psoriasis) to 72 (very severe psoriasis). A PASI 90 response is at least a 90% reduction (improvement) from Baseline in PASI score. | Baseline, Period A, Weeks 4, 8 and 11, Period C, Weeks 0 and 16, Period D, Weeks 0, 16, 28, 40 and 52 | 
| Percentage of Participants Who Achieved a PASI 100 Response Over Time | PASI is a composite score based on the degree of effect on body surface area of psoriasis and the extension of erythema (reddening), induration (plaque thickness), desquamation (scaling) of the lesions and area affected as observed on the day of examination. The score ranges from 0 (no psoriasis) to 72 (very severe psoriasis). A PASI 100 response is a 100% reduction (improvement) from Baseline in PASI score. | Baseline, Period A, Weeks 4, 8, and 11, Period C, Weeks 0 and 16, Period D, Weeks 0, 16, 28, 40 and 52 | 
| Percent Change From Baseline in PASI Score Over Time | PASI is a composite score based on the degree of effect on body surface area of psoriasis and the extension of erythema (reddening), induration (plaque thickness), desquamation (scaling) of the lesions and area affected as observed on the day of examination. The score ranges from 0 (no psoriasis) to 72 (very severe psoriasis). | Baseline, Period A, Weeks 4, 8, 11 and 16, Period C, Weeks 0 and 16, Period D, Weeks 0, 16, 28, 40 and 52 | 
| Change From Baseline in CDLQI Over Time | The Children's Dermatology Life Quality Index (CDLQI) is a 10-item questionnaire to measure the quality of life in children aged from 4 to 16 years. Each question is scored from 0 (not at all) to 3 (very much). The CDLQI is calculated by summing the score of each question resulting in a maximum of 30 and a minimum of 0. The higher the score, the more quality of life is impaired. | Baseline, Period A, Weeks 4, and 8, Period C, Weeks 0 and 4, Period D, Weeks 0, 11, 28, and 52 | 
| Percentage of Participants With CDLQI = 0 Over Time | The Children's Dermatology Life Quality Index (CDLQI) is a 10-item questionnaire to measure the quality of life in children aged from 4 to 16 years. Each question is scored from 0 (not at all) to 3 (very much). The CDLQI is calculated by summing the score of each question resulting in a maximum of 30 and a minimum of 0. The higher the score, the more quality of life is impaired and a score of 0 indicates no impairment in quality of life. | Period A, Weeks 4, 8 and 16, Period C, Weeks 0 and 4, Period D, Weeks 0, 11, 28, and 52 | 
| Time to PASI 50/75/90/100 Response in Period A | Participants who did not have a response during Period A were censored. | Period A, 16 weeks | 
| Change From Baseline in PedsQL Over Time | The PedsQL Measurement Model measures health-related quality of life (HRQOL) in children and adolescents. The 23-item PedsQL Generic Core Scale includes Physical, Emotional, Social, School Functioning dimensions. Each item is scored from 0 (never) to 4 (almost always). Items are reversed scored and linearly transformed to a 0-100 scale, so that higher scores indicate better HRQOL; the total score therefore ranges from 0 (worst) to 100 (best). | Baseline, Period A, Weeks 4 and 8, Period C, Weeks 0 and 4, Period D, Weeks 0, 11, 28, and 52 | 
| Change From Baseline in the Children's Depression Inventory: Short (CDI:S) | The CDI:S is a short 10-item self-rated symptom-oriented scale used to screen for depressive symptoms. CDI:S scores range from 0 to 100, with a lower score indicating fewer depressive symptoms. | Baseline, Period A, Weeks 4, 8, and 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Randomized, Double-blind, Chronic plaque psoriasis, Pediatric