Moderate to Severe Chronic Plaque-type Psoriasis
Conditions
Keywords
pediatric, secukinumab, plaque psoriasis, AIN457A, Skin condition, skin disease, itching condition, psoriasis vulgaris, relapsing/remitting psoriasis, immune-mediated systemic disease, skin lesions, red skin lesions, scaly patches, papules, plaques, itching
Brief summary
This was an open-label, parallel-group, two-arm, multicenter study in pediatric subjects aged 6 years to less than 18 years, at randomization, with moderate to severe chronic plaque psoriasis. 84 subjects (most with moderate severity) were enrolled. Subjects were stratified by weight and disease severity.
Detailed description
This was an open-label, parallel group, two-arm, multi-center, trial in pediatric subjects aged 6 years to less than 18 years, at randomization, with moderate to severe chronic, plaque psoriasis. The study consists of 3 periods: screening (up to 4 weeks), treatment (Week 208) and post-treatment follow-up (Week 224). Approximately 80 subjects (at least 60 subjects with moderate psoriasis) were planned to be enrolled in about 40 centers worldwide and targeted to have at least 5 subjects in the \< 25kg body weight, and at least 10 subjects in each of the other two weight groups (25-\< 50 kg and ≥ 50 kg). Adolescents (12-\< 18 years) and children (6-\< 12 years) were included from the beginning of this study, since the DMC had approved already the enrollment of children (6-\< 12 years) in the study CAIN457A2310 (NCT02471144). Subjects received the appropriate dose based on their body weight category. For the statistical analysis for outcome measures 1 and 2, there was no 'within study' control arm. A historical placebo control was obtained using data from qualifying trials and used as the comparator for the primary and key secondary endpoint analysis. This was in line with the guidance from and discussions with Health Authorities including FDA and EMA (PDCO), which suggested reducing placebo exposure as well as overall clinical trial burden for the pediatric population and accepted an extrapolation approach (EMA 2012). Historical placebo data included in this study were based on clinical appropriateness and alignment of definitions (endpoints, clinical disease population and time point of assessment). Integrated in the analysis were placebo data from Novartis-reported secukinumab adult placebo-controlled studies (CAIN457A2302 (NCT01544595 and NCT01365455), CAIN457A2303 (NCT01544595 and NCT01358578), CAIN457A2308 (NCT01555125) and CAIN457A2309 (NCT01636687)) and pediatric placebo-controlled study CAIN457A2310. In addition, pediatric placebo-controlled study data from the literature on other biologics (e.g. etanercept, ustekinumab) were utilized (Paller et al 2008, Landells et al 2015). If the subject moved into a higher or lower weight group at two consecutive visits with weight measurements during the maintenance (from Week 12 onwards as assessed at 4 weekly visits or during extension treatment period (as assessed at scheduled site visits), then the subject was dosed according to the new (higher or lower) weight group respectively.
Interventions
DRUGsecukinumab low dose
dose depends on the weight group
DRUGsecukinumab high dose
dose depends on the weight group
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
1. Written informed assent and parental permission (age as per local law) obtained at screening before any assessment is performed. 2. Must be 6 to less than 18 years of age at the time of randomization 3. Moderate to Severe plaque psoriasis, defined as a PASI score ≥ 12, and IGA mod 2011 score of ≥ 3, and BSA involvement of ≥10%, at randomization. 4. Subject being regarded by the investigator to be a candidate for systemic therapy.
Exclusion criteria
1. Forms of psoriasis other than chronic plaque-type active at randomization 2. Drug-induced psoriasis 3. Ongoing use of prohibited treatments 4. Female subjects of childbearing potential defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing and for 16 weeks after stopping study treatment 5. Pregnant or nursing (lactating) females 6. Subjects with total WBC count \<2,500/μL, or platelets \<100,000/μL or neutrophils \<1,500/μL or hemoglobin \<8.5 g/dL at screening 7. Previous exposure to secukinumab or any other biologic drug directly targeting IL-17 or the IL-17 receptor
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number and Percentage of Participants With PASI 75 Response | Week 12 | Psoriasis Area and Severity Index (PASI):Combined assessment of lesion severity and affected area into a single score: 0 (no disease) to 72(maximal disease). Body is divided into 4 areas for scoring (head, trunk, upper limbs and lower limbs); each area is scored by itself and scores are combined for final PASI. For each area, percent of skin involved is estimated: 0 (0%) to 6 (90-100%), and severity is estimated by clinical signs, Erythema,Thickening (plaque elevation, induration) & Scaling(desquamation). Scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area\* area score weight of section(head: 0.1, upper limbs: 0.2 body: 0.3 lower limbs: 0.4). Psoriasis Area and Severity Index (PASI) will be assessed/calculated as per standard procedure. PASI 75 represents the percentage (or number)of patients who have achieved a 75% or more reduction in their PASI score from baseline. PASI 100 indicates patients who have achieved a complete resolution of all disease. |
| Number and Percentage of Participants With IGA Mod 2011 0 or 1 Response | Week 12 | Investigator will assess the disease using the validated Investigator Global Assessment (IGA) mod 2011 and rate the disease from a score of 0 (clear skin) to 4 (severe disease) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number and Percentage of Participants With PASI 90 Response | Week 12 | Psoriasis Area and Severity Index (PASI) was assessed/calculated as per the standard procedure. PASI 90 represents the percentage (or number) of patients who have achieved a 90% or more reduction in their PASI score from baseline. PASI 100 indicates patients who have achieved a complete resolution of all disease. |
| Secukinumab Concentration in Serum | Baleine, Weeks 4, 12, 13, 14, 15, 16, 24, 52, 104, 156, 208 | Mean (Standard Deviation) Secukinumab concentration levels in serum over time. |
| Summary Table of Adverse Events | Adverse events are reported from the first dose of study-drug until the end of the treatment period (at Week 208) plus 16 weeks additional follow up reporting, for a maximum timeframe of approximately 224 weeks. | An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study. Treatment emergent adverse events in this study are events that started after the first dose of study treatment and until 84 days after the last study treatment, or events present prior to the first dose of treatment which increased in severity based on preferred term within 84 days after the last study treatment. |
Countries
Belgium, Czechia, Estonia, Germany, Peru, Poland, Russia, Spain, United States
Participant flow
Recruitment details
A total of 92 subjects were screened of which 84 subjects completed the screening phase and were randomized to the Secukinumab Low dose and High dose groups in a 1:1 ratio.
Pre-assignment details
A total of 92 subjects were screened of which 84 subjects completed the screening phase and were randomized to the Secukinumab Low dose and High dose groups in a 1:1 ratio.
Participants by arm
| Arm | Count |
|---|---|
| AIN457 Low Dose Subcutaneous (s.c.) secukinumab injections at randomization and weekly until Week 4, thereafter every 4 weeks until Wk 204. Patients received secukinumab 75 mg (if weighing \< 50kg) or 150 mg (if weighing \>= 50kg) | 42 |
| AIN457 High Dose Subcutaneous (s.c.) secukinumab injections at randomization and weekly until Week 4, thereafter every 4 weeks until Wk 204. Patients received secukinumab 75 mg (if weighing \< 25kg) or 150mg (if weighing 25 to \< 50kg) or 300 mg (if weighing \>=50 kg) | 42 |
| Total | 84 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Guardian decision | 1 | 0 |
| Overall Study | Lack of Efficacy | 5 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Pregnancy | 0 | 2 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Total | AIN457 Low Dose | AIN457 High Dose |
|---|---|---|---|
| Age, Customized 12 to <18 years | 51 Participants | 25 Participants | 26 Participants |
| Age, Customized 6 to <12 years | 33 Participants | 17 Participants | 16 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 5 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 77 Participants | 39 Participants | 38 Participants |
| Sex: Female, Male Female | 45 Participants | 20 Participants | 25 Participants |
| Sex: Female, Male Male | 39 Participants | 22 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 42 | 0 / 42 |
| other Total, other adverse events | 30 / 42 | 27 / 42 |
| serious Total, serious adverse events | 4 / 42 | 2 / 42 |
Outcome results
Primary
Number and Percentage of Participants With IGA Mod 2011 0 or 1 Response
Investigator will assess the disease using the validated Investigator Global Assessment (IGA) mod 2011 and rate the disease from a score of 0 (clear skin) to 4 (severe disease)
Time frame: Week 12
Population: Full Analysis Set: The FAS comprised all patients from the randomized set to whom study treatment had been assigned
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AIN457 Low Dose | Number and Percentage of Participants With IGA Mod 2011 0 or 1 Response | 33 Participants |
| AIN457 High Dose | Number and Percentage of Participants With IGA Mod 2011 0 or 1 Response | 35 Participants |
Comparison: Compared to historical placebo95% CI: [2.638, 6.513]Bayesian method using (MAP)
Comparison: Compared to historical placebo95% CI: [2.919, 6.78]Bayesian method using (MAP)
Primary
Number and Percentage of Participants With PASI 75 Response
Psoriasis Area and Severity Index (PASI):Combined assessment of lesion severity and affected area into a single score: 0 (no disease) to 72(maximal disease). Body is divided into 4 areas for scoring (head, trunk, upper limbs and lower limbs); each area is scored by itself and scores are combined for final PASI. For each area, percent of skin involved is estimated: 0 (0%) to 6 (90-100%), and severity is estimated by clinical signs, Erythema,Thickening (plaque elevation, induration) & Scaling(desquamation). Scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area\* area score weight of section(head: 0.1, upper limbs: 0.2 body: 0.3 lower limbs: 0.4). Psoriasis Area and Severity Index (PASI) will be assessed/calculated as per standard procedure. PASI 75 represents the percentage (or number)of patients who have achieved a 75% or more reduction in their PASI score from baseline. PASI 100 indicates patients who have achieved a complete resolution of all disease.
Time frame: Week 12
Population: Full Analysis Set: The FAS comprised all patients from the randomized set to whom study treatment had been assigned
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AIN457 Low Dose | Number and Percentage of Participants With PASI 75 Response | 39 Participants |
| AIN457 High Dose | Number and Percentage of Participants With PASI 75 Response | 39 Participants |
Comparison: Compared to historical placebo95% CI: [3.422, 6.782]Bayesian method using (MAP)
Comparison: Compared to historical placebo95% CI: [3.422, 6.772]Bayesian method using (MAP)
Secondary
Number and Percentage of Participants With PASI 90 Response
Psoriasis Area and Severity Index (PASI) was assessed/calculated as per the standard procedure. PASI 90 represents the percentage (or number) of patients who have achieved a 90% or more reduction in their PASI score from baseline. PASI 100 indicates patients who have achieved a complete resolution of all disease.
Time frame: Week 12
Population: Full Analysis Set: The FAS comprised all patients from the randomized set to whom study treatment had been assigned
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AIN457 Low Dose | Number and Percentage of Participants With PASI 90 Response | 29 Participants |
| AIN457 High Dose | Number and Percentage of Participants With PASI 90 Response | 32 Participants |
95% CI: [3.201, 6.58]Bayesian method using (MAP)
95% CI: [2.916, 6.202]Bayesian method using (MAP)
Secondary
Secukinumab Concentration in Serum
Mean (Standard Deviation) Secukinumab concentration levels in serum over time.
Time frame: Baleine, Weeks 4, 12, 13, 14, 15, 16, 24, 52, 104, 156, 208
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AIN457 Low Dose | Secukinumab Concentration in Serum | Baseline | 0.00 mcg/mL | Standard Deviation 0 |
| AIN457 Low Dose | Secukinumab Concentration in Serum | Week 15 (n=38,35) | 34.6 mcg/mL | Standard Deviation 12.4 |
| AIN457 Low Dose | Secukinumab Concentration in Serum | Week 16 (n=40,37) | 30.9 mcg/mL | Standard Deviation 11.2 |
| AIN457 Low Dose | Secukinumab Concentration in Serum | Week 104 (n=39,33) | 21.9 mcg/mL | Standard Deviation 10.8 |
| AIN457 Low Dose | Secukinumab Concentration in Serum | Week 4 (n=40,40) | 74.2 mcg/mL | Standard Deviation 33 |
| AIN457 Low Dose | Secukinumab Concentration in Serum | Week 12 (n=40, 39) | 34.8 mcg/mL | Standard Deviation 10.9 |
| AIN457 Low Dose | Secukinumab Concentration in Serum | Week 13 (n=38,33) | 47.1 mcg/mL | Standard Deviation 17.4 |
| AIN457 Low Dose | Secukinumab Concentration in Serum | Week 14 (n=40, 39) | 40.9 mcg/mL | Standard Deviation 15.5 |
| AIN457 Low Dose | Secukinumab Concentration in Serum | Week 24 (n=42, 38) | 26.0 mcg/mL | Standard Deviation 10.8 |
| AIN457 Low Dose | Secukinumab Concentration in Serum | Week 52 (n=37,38) | 25.0 mcg/mL | Standard Deviation 9.01 |
| AIN457 Low Dose | Secukinumab Concentration in Serum | Week 156 (n=34,32) | 19.3 mcg/mL | Standard Deviation 8.68 |
| AIN457 Low Dose | Secukinumab Concentration in Serum | Week 208 (n=25,28) | 16.7 mcg/mL | Standard Deviation 6.25 |
| AIN457 High Dose | Secukinumab Concentration in Serum | Week 104 (n=39,33) | 39.3 mcg/mL | Standard Deviation 12.1 |
| AIN457 High Dose | Secukinumab Concentration in Serum | Week 14 (n=40, 39) | 78.4 mcg/mL | Standard Deviation 29.8 |
| AIN457 High Dose | Secukinumab Concentration in Serum | Week 15 (n=38,35) | 65.7 mcg/mL | Standard Deviation 28.9 |
| AIN457 High Dose | Secukinumab Concentration in Serum | Week 16 (n=40,37) | 55.2 mcg/mL | Standard Deviation 24.9 |
| AIN457 High Dose | Secukinumab Concentration in Serum | Week 208 (n=25,28) | 38.8 mcg/mL | Standard Deviation 17.2 |
| AIN457 High Dose | Secukinumab Concentration in Serum | Baseline | 0.00 mcg/mL | Standard Deviation 0 |
| AIN457 High Dose | Secukinumab Concentration in Serum | Week 24 (n=42, 38) | 48.0 mcg/mL | Standard Deviation 21.4 |
| AIN457 High Dose | Secukinumab Concentration in Serum | Week 4 (n=40,40) | 135 mcg/mL | Standard Deviation 45.3 |
| AIN457 High Dose | Secukinumab Concentration in Serum | Week 156 (n=34,32) | 35.0 mcg/mL | Standard Deviation 14.1 |
| AIN457 High Dose | Secukinumab Concentration in Serum | Week 12 (n=40, 39) | 69.6 mcg/mL | Standard Deviation 29.2 |
| AIN457 High Dose | Secukinumab Concentration in Serum | Week 52 (n=37,38) | 42.7 mcg/mL | Standard Deviation 17 |
| AIN457 High Dose | Secukinumab Concentration in Serum | Week 13 (n=38,33) | 91.2 mcg/mL | Standard Deviation 34.1 |
Secondary
Summary Table of Adverse Events
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study. Treatment emergent adverse events in this study are events that started after the first dose of study treatment and until 84 days after the last study treatment, or events present prior to the first dose of treatment which increased in severity based on preferred term within 84 days after the last study treatment.
Time frame: Adverse events are reported from the first dose of study-drug until the end of the treatment period (at Week 208) plus 16 weeks additional follow up reporting, for a maximum timeframe of approximately 224 weeks.
Population: Safety set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AIN457 Low Dose | Summary Table of Adverse Events | Subjects with any AE(s) | 33 Participants |
| AIN457 Low Dose | Summary Table of Adverse Events | Subjects with serious or other significant events - Death | 0 Participants |
| AIN457 Low Dose | Summary Table of Adverse Events | Subjects with serious or other significant events - Non-fatal SAE(s) | 4 Participants |
| AIN457 Low Dose | Summary Table of Adverse Events | Subjects with serious or other significant events - Discontinued study treatment due to any AE(s) | 1 Participants |
| AIN457 High Dose | Summary Table of Adverse Events | Subjects with serious or other significant events - Discontinued study treatment due to any AE(s) | 2 Participants |
| AIN457 High Dose | Summary Table of Adverse Events | Subjects with any AE(s) | 35 Participants |
| AIN457 High Dose | Summary Table of Adverse Events | Subjects with serious or other significant events - Non-fatal SAE(s) | 2 Participants |
| AIN457 High Dose | Summary Table of Adverse Events | Subjects with serious or other significant events - Death | 0 Participants |