Secukinumab Dosage Optimisation in Partial Responders With Moderate to Severe Plaque-type Psoriasis

A Randomized, Double-blind, Multicenter Study to Assess the Efficacy and Safety of 16 Weeks Secukinumab Dosage Interval Shortening in Comparison to Continued Standard Treatment (4-weekly 300 mg s.c.) in Patients With Moderate-severe Plaque Type Psoriasis Who Achieved Less Than Almost Clear Skin After 16 Weeks Under the Standard Dose of Secukinumab

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02474069

Acronym

GAIN

Enrollment

772

Registered

2015-06-17

Start date

2015-02-08

Completion date

2016-09-15

Last updated

2019-07-05

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Moderate to Severe Plaque-type Psoriasis

Keywords

skin condition, skin disease, itching condition, psoriasis vulgaris, relapsing psoriasis, remitting psoriasis, immune-mediated systemic disease, skin lesions, red skin lesions, scaly patches, papules, plaques, itching, auto-immune, plaque-type psoriasis, plaque

Brief summary

This study is designed to support the optimal use of secukinumab by providing data to refine guidance on dosing flexibility in patients with psoriasis. The purpose of the study is to explore the effects of dosage interval shorteng to achieve PASI 90 at week 32 for patients who had less than almost clear skin at week 16.

Interventions

DRUGSecukinumab

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Intervention model description

This was a multicenter, double-blind, randomized study in 772 patients with moderate to severe chronic plaque-type psoriasis. Patients were enrolled at 89 study sites in Germany. The study was divided into 3 phases: screening, selection phase (SP), and comparative dosing phase (CDP). In the screening phase, inclusion and exclusion criteria were confirmed. Eligible patients rolled over into a selection phase (SP) where all patients received 300 mg s.c. open-label secukinumab at baseline, Weeks 1, 2, 3, 4, 8, and 12. At Week 16, PASI response was assessed as a basis for further treatment: 300 mg s.c. secukinumab treatment every 4 weeks vesus 300 mg s.c. secukinumab treatment every 2 weeks. Patients who achieved at least clear or almost clear skin (≥ PASI 90) at Week 16 discontinued the study

Eligibility

Sex/Gender

ALL

Healthy volunteers

Inclusion criteria

Subjects eligible for inclusion in this study must fulfill all of the following criteria: 1. Subjects must be able to understand and communicate with the investigator and must give a written, signed and dated informed consent before any study related activity is performed and who are willing and capable to comply with all study procedures. 2. Men or women at least 18 years of age at time of screening. 3. Chronic plaque type psoriasis diagnosed for at least 6 months prior to baseline 4. Moderate to severe plaque type psoriasis at baseline derived from the European consensus (Mrowietz et al., 2011): BSA (Body Surface Area) \>10% and PASI\>10 and DLQI\>10. 5. Candidates for biologic therapy who failed to respond to, or who had a contraindication to or were intolerant to previous conventional systemic therapies. 6. According to local guidelines, to exclude chest infection before initiation of a biologic immunomodulating therapy, it is necessary to have obtained an image of the chest (X-ray, computerized tomography or magnetic resonance imaging) within 12 weeks prior to screening and have this evaluated by a qualified physician.

Exclusion criteria

1. Forms of psoriasis other than chronic plaque-type (e.g., pustular, erythrodermic and guttata psoriasis). 2. Drug-induced psoriasis (i.e., new onset or current exacerbation from beta-blockers, calcium channel inhibitors or lithium). 3. Ongoing use of prohibited psoriasis and non-psoriasis treatments. Washout periods have to be adhered to. 4. Subjects not willing to limit UV light exposure (e.g., sunbathing and/or the use of tanning devices) during the course of the study. 5. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer. 6. Previous exposure to secukinumab (AIN457) or any other biologic drug directly targeting IL-17A or the IL-17A receptor (e.g. brodalumab, ixekizumab). 7. History of hypersensitivity to any of the study drugs or to drugs with similar chemical structures. 8. Study personnel or first degree relatives of investigator(s) must not be included in the study. 9. Women who are pregnant or breast feeding (pregnancy defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (\> 5 mIU/ml)) who are menstruating and capable of becoming pregnant\* and not practicing a medically approved method of contraception (Pearl Index \<1\*\*) during and up to at least 4 weeks after the end of treatment. A negative pregnancy test (serum) for all women and for girls entering menarche is required with sufficient lead time before inclusion \*definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels \>40 mIU/m or 6 weeks post- surgical bilateral oophorectomy with or without hysterectomy \*\*examples of particularly reliable methods with Pearl Index (PI) \<1, according to guidelines of Deutsche Gesellschaft für Gynakologie und Geburtshilfe: * hormonal oral contraception (Combination of estrogen and gestagen, PI=0.1-0.9) hormonal vaginal ring (combination of estrogen and gestagen, PI=0.65 uncorr.; 0.4 corr.) * hormonal transdermal patch (combination of estrogen and gestagen, PI= 0.72 uncorr.; 0.9 corr.) * Estrogen-free ovulation inhibitors containing desogestrel (PI=0.14) * Implanted hormones containing etonogestrel (PI=0-0.08) * Injectable 3-month depot progestins (PI=0.3-1.4; 0.88 corr.) * Intra-uterine progestine device (synthetic progestin containing IUDs,PI=0.16) * Oral contraceptives without estrogen (e.g. mini-pills), nonsynthetic progesterone only IUDs, female condoms, cervical shield, periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. 10. Active ongoing inflammatory diseases other than psoriasis that might confound the evaluation of the benefit of secukinumab therapy. Patients with psoriatic arthritis are not excluded. 11. Underlying condition (including, but not limited to metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, cardiac, infectious or gastrointestinal) which in the opinion of the investigator significantly immunocompromises the subject and/or places the subject at unacceptable risk for receiving an immunomodulatory therapy. 12. Subjects with preexisting or recent-onset central or peripheral nervous system demyelinating disorders at discretion of the investigator. 13. Significant medical problems, including but not limited to the following: uncontrolled hypertension (≥160 systolic and/or 95 diastolic mmHg), congestive heart failure \[New York Heart Association status of class III or IV\]. 14. Subjects with a serum creatinine level exceeding 2.0 mg/dl (176.8μmol/l) at screening. 15. Screening total white blood cell (WBC) count \<2,500/μl, or platelets \<100,000/μl or neutrophils \<1,500/μl or hemoglobin \<8.5 g/dl. 16. Active systemic infections during the last two weeks (exception: common cold) prior to screening or any infection that reoccurs on a regular basis. 17. History of an ongoing, chronic or recurrent infectious disease including recurrent respiratory and/or urinary tract infections or evidence of tuberculosis infection as defined by a positive QuantiFERON TB-Gold test at screening. Subjects with a positive or indeterminate QuantiFERON TB-Gold test may participate in the study if further full tuberculosis work up (according to local practice/guidelines) completed at least 12 weeks prior to first study drug administration establishes conclusively that the subject has no evidence of active tuberculosis. If presence of latent tuberculosis is established, then treatment must have been initiated and maintained according to local country guidelines for at least 4 weeks prior to screening. 18. Past medical history record of infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C prior to screening. 19. History of lymphoproliferative disease or any known malignancy or history of malignancy of any organ system within the past 5 years (except for skin Bowen's disease, or basal cell carcinoma or actinic keratoses that have been treated with no evidence of recurrence in the past 12 weeks; carcinoma in situ of the cervix or non-invasive malignant colon polyps that have been removed). 20. Current severe progressive or uncontrolled disease which in the judgment of the clinical investigator renders the subject unsuitable for the trial or puts the subject at increased risk. 21. Inability or unwillingness to undergo repeated venipuncture (e.g. because of poor tolerability or lack of access to veins). 22. Any medical or psychiatric condition which, in the investigator's opinion, would preclude the participant from adhering to the protocol or completing the study per protocol. 23. History or evidence of ongoing alcohol or drug abuse, within the last six months before screening. 24. Plans for administration of live vaccines during the study period or 6 weeks prior to screening. No additional exclusions may be applied by the investigator, in order to ensure that the study population will be representative of all eligible subjects.

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With PASI 90 Response at Week 32	at 32 weeks	Number of participants with at least 90% improvement from baseline. PASI is a 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, arms, trunk, legs; 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, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area\* area score weight of section (head: 0.1, arms: 0.2 body: 0.3 legs: 0.4).
Number of Participants With PASI 90 Response at Week 32 for PPS	at week 32	Number of participants with at least 90% improvement from baseline. PASI is a 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, arms, trunk, legs; 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, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area\* area score weight of section (head: 0.1, arms: 0.2 body: 0.3 legs: 0.4).

Secondary

Measure	Time frame	Description
Selection Phase:Summary of PASI Total Score	at weeks 1,2,3,4,8, 12, 16	PASI is a 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, arms, trunk, legs; 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, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area\* area score weight of section (head: 0.1, arms: 0.2 body: 0.3 legs: 0.4).
Comparative Dose Phase: Summary of PASI Total Score	Weeks 18, 22, 26, 30 and 32	PASI is a 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, arms, trunk, legs; 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, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area\* area score weight of section (head: 0.1, arms: 0.2 body: 0.3 legs: 0.4).
Number of Patients Achieving Dermatology Life Quality Index (DLQI) Scores of 0 or 1 by Visits in the CDP	Weeks 4, 16, 18, 22, 26, 30, 32	The DLQI is a ten item general dermatology disability index designed to assess health-related quality of life in adult participants with skin diseases such as eczema, psoriasis, acne and viral worts. It is a self-administered questionnaire which includes domains of daily activity, leisure, personal relationships, symptoms and feelings, treatment and school/work activities. Each domain has 4 response categories ranging from 0 (not at all) to 3 (very much). Not relevant is a valid score also and is scored as 0. The DLQI total score is a sum of all 10 responses. Scores range from 0 to 30 with higher scores indicating greater health-related quality of life impairment. The DLQI was designed to assess health-related quality of life (HRQoL) in adult patients with skin diseases including psoriasis.
Number of Patients Achieving DLQI Total Score <= 5 in the CDP	Weeks 4, 16, 18, 22, 26, 30, 32	The DLQI is a ten item general dermatology disability index designed to assess health-related quality of life in adult participants with skin diseases such as eczema, psoriasis, acne and viral worts. It is a self-administered questionnaire which includes domains of daily activity, leisure, personal relationships, symptoms and feelings, treatment and school/work activities. Each domain has 4 response categories ranging from 0 (not at all) to 3 (very much). Not relevant is a valid score also and is scored as 0. The DLQI total score is a sum of all 10 responses. Scores range from 0 to 30 with higher scores indicating greater health-related quality of life impairment.
Selection Phase: Number of Participants Achieving (Psoriasis Area and Severity Index Score)PASI 50, 75, 90, 100	at weeks 1, 2, 3, 4, 8, 12 and 16	Number of participants with at least 50, 75, 90 or 100% improvement from baseline. PASI is a 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, arms, trunk, legs; 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, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area\* area score weight of section (head: 0.1, arms: 0.2 body: 0.3 legs: 0.4).
Comparative Dose Phase: Number of Patients Achieving Investigator Global Assessment (IGA) 0 or 1	Weeks 18, 22, 26, 30, 32	The IGA scale is static, i.e. it referred exclusively to the participant's disease at the time of the assessment, and did not compare with any of the participant's previous disease states at previous visits. The scores are: 0 = clear, 1 = almost clear, 2 = mild, 3 = moderate, 4 = severe and 5 = very severe.
Selection Phase: Summary of IGA Score	Weeks 4, 16	The IGA scale is static, i.e. it referred exclusively to the participant's disease at the time of the assessment, and did not compare with any of the participant's previous disease states at previous visits. The scores are: 0 = clear, 1 = almost clear, 2 = mild, 3 = moderate, 4 = severe and 5 = very severe.
Comparative Dose Phase:Summary of IGA Score	Weeks 18, 22, 26, 30, 32	The IGA scale is static, i.e. it referred exclusively to the participant's disease at the time of the assessment, and did not compare with any of the participant's previous disease states at previous visits. The scores are: 0 = clear, 1 = almost clear, 2 = mild, 3 = moderate, 4 = severe and 5 = very severe.
Selection Phase: Number of Patients Achieving Investigator Global Assessment (IGA) 0 or 1	Weeks 4, 16	The IGA scale is static, i.e. it referred exclusively to the participant's disease at the time of the assessment, and did not compare with any of the participant's previous disease states at previous visits. The scores are: 0 = clear, 1 = almost clear, 2 = mild, 3 = moderate, 4 = severe and 5 = very severe.
Comparative Dose Phase: Number of Participants Achieving Psoriasis Area and Severity Index Score (PASI) 90 and 100	at weeks 18, 22, 30, 32	Number of participants with at least 90 or 100% improvement from baseline. PASI is a 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, arms, trunk, legs; 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, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area\* area score weight of section (head: 0.1, arms: 0.2 body: 0.3 legs: 0.4).

Countries

Germany

Participant flow

Recruitment details

860 screened (not shown here). In selection phase (SP), 772 received 300 mg s.c. open-label secukinumab at baseline to wk 12. Those who did not achieve ≥Psoriasis Area and Severity Index (PASI) 75 at wk 16 discontinued. Those who had ≤ clear or almost clear skin (≥PASI75 but not PASI90) rolled over into double blind comparative dosing phase (CDP).

Pre-assignment details

and randomized 1:1 to: a.standard treatment: 300 mg s.c. secukinumab treatment every 4 weeks (weeks 16, 20, 24, & 28) and, to maintain the blind, placebo every 4 weeks b. OR dosage interval shortening: 300 mg s.c. secukinumab treatment every 2 weeks Those who achieved at least clear or almost clear skin (≥ PASI 90) at week 16 discontinued study

Participants by arm

Arm	Count
SP - Secukinumab 300 mg s.c. (4-weekly In the SP, all patients were treated with open-label secukinumab 300 mg s.c. at baseline, Weeks 1, 2, 3, 4, 8, and 12. At Week 16	772
Total	772

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Comparative Dosing Phase (CDP)	Adverse Event	0	3	2
Comparative Dosing Phase (CDP)	Lost to Follow-up	0	4	1
Comparative Dosing Phase (CDP)	Withdrawal by Subject	0	0	1
Comparative Dosing Phase (CDP)	Withdrawal of informed Consent	0	2	2
Selection Phase (SP)	Adverse Event	8	0	0
Selection Phase (SP)	Lack of Efficacy	1	0	0
Selection Phase (SP)	Lost to Follow-up	4	0	0
Selection Phase (SP)	No longer requires treatment	1	0	0
Selection Phase (SP)	Physician Decision	1	0	0
Selection Phase (SP)	Protocol Violation	1	0	0
Selection Phase (SP)	Technical Problem	1	0	0
Selection Phase (SP)	Withdrawal by Subject	3	0	0
Selection Phase (SP)	Withdrawal of Informed Consent	3	0	0

Baseline characteristics

Characteristic	SP - Secukinumab 300 mg s.c. (4-weekly
Age, Continuous	45.8 Years STANDARD_DEVIATION 13.72
Sex/Gender, Customized Female	222 Participants
Sex/Gender, Customized Male	550 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	510 / 772	85 / 162	87 / 163
serious Total, serious adverse events	32 / 772	8 / 162	4 / 163

Outcome results

Primary

Number of Participants With PASI 90 Response at Week 32

Number of participants with at least 90% improvement from baseline. PASI is a 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, arms, trunk, legs; 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, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area\* area score weight of section (head: 0.1, arms: 0.2 body: 0.3 legs: 0.4).

Time frame: at 32 weeks

Population: Full Analysis Set (FAS) - Comparative Dosing Phase (CDP): consisted of all patients who were randomized and received at least one dose of study drug during the CDP and had at least one post-randomization assessment. Patients with missing PASI at week 32 were counted as non-responders, unless they were responders already at their last reported PASI.

Arm	Measure	Value (NUMBER)
CDP - Secukinumab 300 mg s.c. (4-weekly)	Number of Participants With PASI 90 Response at Week 32	93 participants
CDP - Secukinumab 300 mg s.c. (2-weekly)	Number of Participants With PASI 90 Response at Week 32	105 participants

Comparison: Logistic regression model: Logit (proportion) = treatment + PASI Score at baseline + PASI score at randomization + errorp-value: 0.08795% CI: [0.39, 1.07]ANCOVA

Primary

Number of Participants With PASI 90 Response at Week 32 for PPS

Time frame: at week 32

Population: PPS: consisted of all patients from the FAS-CDP who completed the study without any major protocol deviation.

Arm	Measure	Value (NUMBER)
CDP - Secukinumab 300 mg s.c. (4-weekly)	Number of Participants With PASI 90 Response at Week 32 for PPS	81 participants
CDP - Secukinumab 300 mg s.c. (2-weekly)	Number of Participants With PASI 90 Response at Week 32 for PPS	85 participants

Comparison: Logistic regression model: Logit (proportion) = treatment + PASI Score at baseline + PASI score at randomization + errorp-value: 0.28195% CI: [0.43, 1.28]ANCOVA

Secondary

Comparative Dose Phase: Number of Participants Achieving Psoriasis Area and Severity Index Score (PASI) 90 and 100

Number of participants with at least 90 or 100% improvement from baseline. PASI is a 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, arms, trunk, legs; 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, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area\* area score weight of section (head: 0.1, arms: 0.2 body: 0.3 legs: 0.4).

Time frame: at weeks 18, 22, 30, 32