Clinical trial NCT01729754: A Study to Evaluate the Efficacy and Safety/Tolerability of Subcutaneous Tildrakizumab (SCH 900222/MK-3222) in Participants With Moderate-to-Severe Chronic Plaque Psoriasis Followed by a Long-term Extension Study (MK-3222-011)
Official title: A 52-Week, Phase 3, Randomized, Active Comparator and Placebo-Controlled, Parallel Design Study to Evaluate the Efficacy and Safety/Tolerability of Subcutaneous Tildrakizumab (SCH 900222/MK-3222), Followed by an Optional Long-Term Safety Extension Study, in Subjects With Moderate-to-Severe Chronic Plaque Psoriasis (Protocol No. MK-3222-011)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Plaque Psoriasis
Lead sponsor: Sun Pharmaceutical Industries Limited
Sponsor class: INDUSTRY
First posted: 2012-11-20
Enrollment: 1090
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is being conducted to evaluate the efficacy and safety/tolerability of tildrakizumab (SCH 900222/MK-3222) in a population of participants with moderate-to-severe plaque psoriasis. The primary hypotheses of the study are that tildrakizumab is superior to placebo in the treatment of moderate-to-severe chronic plaque psoriasis as measured by the proportion of participants achieving \>= Psoriasis Area Sensitivity Index of 75% (PASI-75) response and the proportion of participants with a Physician's Global Assessment (PGA) score of "clear" or "minimal" with at least a 2 grade reduction from baseline at Week 12.

Detailed description: The base study consists of a screening phase of up to 4 weeks followed by a treatment period of 52 weeks, and a 20-week follow-up period. The base study treatment period is divided into 3 sequential parts.

In Part 1 of the base study (Week 0 to Week 12), participants will be randomized to one of 4 study arms (Arm A: tildrakizumab 200 mg + matching placebo to etanercept; Arm B: tildrakizumab 100 mg + matching placebo to etanercept; Arm C: matching placebo to tildrakizumab + matching placebo to etanercept; Arm D: matching placebo to tildrakizumab + etanercept 50 mg).

In Part 2 of the base study (Week 12 to Week 28), participants in Arm A and Arm B will receive matching placebo to tildrakizumab to maintain blinding at Week 12 and will receive either tildrakizumab 200 mg (Arm A) or tildrakizumab 100 mg (Arm B) at Weeks 12 and 16. Participants in Arm A and Arm B will also receive matching placebo to etanercept once weekly through study Week 28. At study Week 12, Arm C participants will be re-randomized to receive their first dose of tildrakizumab 200 mg or tildrakizumab 100 mg, and will receive additional doses of study medication according to their re-randomized treatment assignment at Week 16. Participants in Arm C will also receive matching placebo to etanercept through treatment Week 28. Participants in Arm D will continue with once weekly doses of etanercept through study Week 28 in combination with matching placebo to tildrakizumab.

In Part 3 of the base study (Week 28 to Week 52), participants in Arm A with \>= PASI-75 response at Week 28 will be re-randomized to either continue tildrakizumab 200 mg or receive tildrakizumab 100 mg at study Weeks 28, 40, and 52. Participants with \>= PASI-50 response but \< PASI-75 response will continue to receive tildrakizumab 200 mg every 12 weeks and those participants with \< PASI-50 response will be discontinued from the study. Participants in Arm B with \>= PASI-75 response at Week 28 will continue to receive tildrakizumab 100 mg every 12 weeks. Those with \>= PASI-50 response but \< PASI-75 response will be re-randomized to receive continued tildrakizumab 100 mg or tildrakizumab 200 mg every 12 weeks. Participants in Arm B with \< PASI-50 response will be discontinued from the study. Participants in Arm C will continue to receive treatment every 12 weeks according to their re-randomized treatment assignment. Participants in Arm D that achieve \>= PASI-75 response at Week 28 will be discontinued from the study. Those participants with \< PASI-75 response at Week 28 will be crossed over to tildrakizumab 200 mg to receive doses at Weeks 32, 36 and 48.

Eligible participants that choose to enroll in the extension study will have an additional treatment period of up to 192 weeks and will be monitored for an additional 20 weeks in the follow-up period. Each participant will receive tildrakizumab 200 mg or tildrakizumab 100 mg every 12 weeks up to study Week 244 according to their treatment assignment at the conclusion of Part 3 of the base study.

Eligibility criteria: Inclusion Criteria:

* Clinical diagnosis of moderate-to-severe plaque psoriasis for at least 6 months prior to enrollment;
* Candidate for phototherapy or systemic therapy;
* Premenopausal female participants must agree to abstain from heterosexual activity or use a medically approved method of contraception or use appropriate effective contraception as per local regulations or guidelines
* For the extension study: must have completed Part 3 of the base study
* For the extension study: must have achieved at least a PASI-50 response by the end of Part 3 of the base study

Exclusion Criteria:

* Non-plaque forms of psoriasis
* Presence or history of severe psoriatic arthritis and is well-controlled on current treatment regimen
* Women of childbearing potential who are pregnant, intend to become pregnant, or are lactating
* Participant is expected to require topical therapy, phototherapy, or systemic therapy during the trial
* Presence of any infection or history of recurrent infection requiring treatment with systemic antibiotics
* Previous use of entanercept, tildrakizumab (MK-3222), or other interleukin-23 (IL-23)/T- helper cell 17 (Th-17) pathway inhibitors including p40, p19, and IL-17 antagonists
* Latex allergy or sensitivity
* Active or untreated latent tuberculosis (TB)
* For the extension study: women of child-bearing potential who are pregnant, intend to become pregnant within 6 months of completing the trial, or are breast feeding
* For the extension study: active or uncontrolled significant organ dysfunction or clinically significant laboratory abnormalities
* For the extension study: expected to require topical treatment, phototherapy, or systemic treatment during the extension study

Primary outcomes:
measure: Percentage of Participants Achieving a Psoriasis Area Sensitivity Index 75% (PASI-75) Response at Week 12 (Part 1)
timeFrame: Week 12
measure: Percentage of Participants With a Physician's Global Assessment (PGA) Score of Clear or Minimal With at Least a 2 Grade Reduction From Baseline at Week 12 (Part 1)
timeFrame: Week 12
measure: Percentage of Participants Experiencing an Adverse Event (AE) Up to Week 12 (Part 1)
timeFrame: Up to Week 12
measure: Percentage of Participants Discontinuing Study Treatment Due to an AE Up to Week 12 (Part 1)
timeFrame: Up to Week 12
Secondary outcomes:
measure: Percentage of Participants Achieving a PASI-75 Response at Week 28 (Part 2)
timeFrame: Week 28
measure: Percentage of Participants Achieving a PASI-75 Response at Week 40 (Part 3)
timeFrame: Week 40
measure: Percentage of Participants Achieving a PASI-75 Response at Week 52 (Part 3)
timeFrame: Week 52
measure: Percentage of Participants With a PGA Score of Clear or Minimal With at Least a 2 Grade Reduction From Baseline at Week 28 (Part 2)
timeFrame: Week 28
measure: Percentage of Participants With a PGA Score of Clear or Minimal With at Least a 2 Grade Reduction From Baseline at Week 40 (Part 3)
timeFrame: Week 40
measure: Percentage of Participants With a PGA Score of Clear or Minimal With at Least a 2 Grade Reduction From Baseline at Week 52 (Part 3)
timeFrame: Week 52
measure: Percentage of Participants Achieving a PASI-90 Response at Week 12 (Part 1)
timeFrame: Week 12
measure: Percentage of Participants Achieving a PASI-90 Response at Week 28 (Part 2)
timeFrame: Week 28
measure: Percentage of Participants Achieving a PASI-90 Response at Week 40 (Part 3)
timeFrame: Week 40
measure: Percentage of Participants Achieving a PASI-90 Response at Week 52 (Part 3)
timeFrame: Week 52
measure: Percentage of Participants Achieving a PASI-100 Response at Week 12 (Part 1)
timeFrame: Week 12
measure: Percentage of Participants Achieving a PASI-100 Response at Week 28 (Part 2)
timeFrame: Week 28
measure: Percentage of Participants Achieving a PASI-100 Response at Week 40 (Part 3)
timeFrame: Week 40
measure: Percentage of Participants Achieving a PASI-100 Response at Week 52 (Part 3)
timeFrame: Week 52
measure: Baseline Dermatology Life Quality Index (DLQI)
timeFrame: Baseline
measure: Change From Baseline in the DLQI at Week 12 (Part 1)
timeFrame: Baseline and Week 12
measure: Change From Baseline in the DLQI at Week 28 (Part 2)
timeFrame: Baseline and Week 28
measure: Change From Baseline in the DLQI at Week 40 (Part 3)
timeFrame: Baseline and Week 40
measure: Change From Baseline in the DLQI at Week 52 (Part 3)
timeFrame: Baseline and Week 52
measure: Percentage of Participants With a DLQI Score of 0 or 1 at Week 12 (Part 1)
timeFrame: Week 12
measure: Percentage of Participants With a DLQI Score of 0 or 1 at Week 28 (Part 2)
timeFrame: Week 28
measure: Percentage of Participants With a DLQI Score of 0 or 1 at Week 40 (Part 3)
timeFrame: Week 40
measure: Percentage of Participants With a DLQI Score of 0 or 1 at Week 52 (Part 3)
timeFrame: Week 52
measure: Mean Change From Baseline in PASI Score Over Time (Part 1)
timeFrame: Baseline and Week 4, Week 8 or Week 12
measure: Mean Change From Baseline in PASI Score Over Time (Part 2)
timeFrame: Baseline and Week 16, Week 22 or Week 28
measure: Mean Change From Baseline in PASI Score Over Time (Part 3)
timeFrame: Baseline and Week 32, Week 36, Week 40, Week 46 and Week 52
measure: Mean Percent Change From Baseline in PASI Score Over Time (Part 1)
timeFrame: Baseline and Week 4, Week 8 or Week 12
measure: Mean Percent Change From Baseline in PASI Score Over Time (Part 2)
timeFrame: Baseline and Week 16, Week 22 or Week 28
measure: Mean Percent Change From Baseline in PASI Score Over Time (Part 3)
timeFrame: Baseline and Week 32, Week 36, Week 40, Week 46 and Week 52
Other outcomes:
Locations:
Study officials:
References:
citation: Reich K, Papp KA, Blauvelt A, Tyring SK, Sinclair R, Thaci D, Nograles K, Mehta A, Cichanowitz N, Li Q, Liu K, La Rosa C, Green S, Kimball AB. Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials. Lancet. 2017 Jul 15;390(10091):276-288. doi: 10.1016/S0140-6736(17)31279-5. Epub 2017 Jun 6.
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citation: Kerbusch T, Li H, Wada R, Jauslin PM, Wenning L. Exposure-response characterisation of tildrakizumab in chronic plaque psoriasis: Pooled analysis of 3 randomised controlled trials. Br J Clin Pharmacol. 2020 Sep;86(9):1795-1806. doi: 10.1111/bcp.14280. Epub 2020 Mar 25.
citation: Elewski B, Menter A, Crowley J, Tyring S, Zhao Y, Lowry S, Rozzo S, Mendelsohn AM, Parno J, Gordon K. Sustained and continuously improved efficacy of tildrakizumab in patients with moderate-to-severe plaque psoriasis. J Dermatolog Treat. 2020 Dec;31(8):763-768. doi: 10.1080/09546634.2019.1640348. Epub 2019 Jul 22.
citation: Reich K, Warren RB, Iversen L, Puig L, Pau-Charles I, Igarashi A, Ohtsuki M, Falques M, Harmut M, Rozzo S, Lebwohl MG, Cantrell W, Blauvelt A, Thaci D. Long-term efficacy and safety of tildrakizumab for moderate-to-severe psoriasis: pooled analyses of two randomized phase III clinical trials (reSURFACE 1 and reSURFACE 2) through 148 weeks. Br J Dermatol. 2020 Mar;182(3):605-617. doi: 10.1111/bjd.18232. Epub 2019 Jul 18.
citation: Jauslin P, Kulkarni P, Li H, Vatakuti S, Hussain A, Wenning L, Kerbusch T. Population-Pharmacokinetic Modeling of Tildrakizumab (MK-3222), an Anti-Interleukin-23-p19 Monoclonal Antibody, in Healthy Volunteers and Subjects with Psoriasis. Clin Pharmacokinet. 2019 Aug;58(8):1059-1068. doi: 10.1007/s40262-019-00743-7.