PLANETA is the ongoing international, multicentre, phase 3, double-blind, placebo-controlled clinical study conducted in 24 investigational sites in the Russian Federation and the Republic of Belarus according to the Declaration of Helsinki following Good Clinical Practice guidelines. The study was approved by the Central Regulatory Authorities of the Russian Federation and the Republic of Belarus and Ethical Review Boards of each of the participating sites. The trial was registered at the US National Institutes of Health (ClinicalTrials.gov; NCT03390101).
Eligible patients were 18 years and older, had an established diagnosis of moderate-to-severe plaque psoriasis for at least 6 months, were candidates for or had received at least one course of phototherapy or systemic therapy, had at least a 10% body surface area (BSA) affected by psoriasis, a Psoriasis Area and Severity Index (PASI) score ≥ 10, and a static Physician’s Global Assessment (sPGA) score ≥ 3 at screening.
Patients were ineligible to participate in the study if they had other forms of psoriasis (e.g. guttate, erythrodermic or pustular) or any other skin diseases (e.g. eczema), previously used mAbs targeting IL-17 or its receptor, or received more than one drug containing mAbs or their fragments. Any mAb had to be withdrawn for at least 12 weeks; systemic therapy and phototherapy within 4 weeks; and the range of topical medications within 2 weeks before signing the informed consent (IC). All patients were given adequate time to reflect on the information, had their questions answered, gave free and voluntary consent to participate and signed an IC form.
All patients underwent chest x-ray and tuberculosis test (T-SPOT.TB test/QuantiFERON-TB Gold test/TB skin test) at screening. In case of ambiguous tuberculosis test results, patient underwent consultation with a specialized physician. If active/latent infection was excluded, the patient could be included in the study.
Eligible patients were stratified by body weight (< 100 kg/≥ 100 kg), previous treatment of psoriasis with mAb (previously treated/naive), PASI score (< 20/≥ 20) and presence of psoriatic arthritis (yes/no) and randomly assigned in a 2:2:1 ratio to receive NTK 120 mg Q2W (NTK Q2W group), NTK 120 mg Q4W (NTK Q4W group) or placebo. The randomization was performed with random sequence using an electronic centralized randomization system. The study investigators, trial team and patients were blinded to the treatment allocation during the first 12 weeks of the study.
The main treatment period included the blinded phase (weeks 0–12) followed by an open-label phase up to 54 weeks. The study was extended up to 3 years. During the first 3 weeks, all patients received subcutaneous injections of NTK or placebo (according to the allocation) once a week (induction phase). Patients in the NTK Q2W group then received the study drug at weeks 4, 6, 8 and 10. Subjects in the NTK Q4W group received NTK at weeks 6 and 10 and placebo at weeks 4 and 8 to preserve blinding. Patients in the placebo group received injections containing placebo at weeks 4, 6, 8 and 10.
The treatment was unblinded at week 12. During the open-label phase, patients in both NTK groups continued to receive the study drug Q4W (NTK Q2W/Q4W and NTK Q4W groups). Patients who received placebo were switched to the active treatment and were administered NTK at weeks 12, 13 and 14 (induction) and then Q4W through weeks 18–50 (placebo/NTK Q4W group). Patients were followed up for 4 weeks after the last injection of the study drug.
NTK was administered as two subcutaneous injections (1.0 ml containing NTK 60 mg); placebo was administered as two indistinguishable subcutaneous injections (1.0 ml each).
The primary efficacy endpoint was the proportion of patients who achieved a ≥ 75% reduction from baseline in PASI (PASI 75) at week 12. The secondary endpoints included the proportion of patients attaining PASI 75 at weeks 8, 16, 24, 42 and 52, PASI 90 and PASI 100 at weeks 8, 12, 16, 24, 42 and 52; the change from baseline in PASI, the proportion of patients with sPGA 0 or 1 and sPGA 0 at weeks 8, 12, 16, 24, 42 and 52; the proportion of patients with Dermatology Life Quality Index (DLQI) 0 or 1 at weeks 24, 42 and 52; the change from baseline in itch severity (measured by visual analogue scale [VAS], 0–100 mm) at weeks 1, 12, 24 and 52; Nail Psoriasis Severity Index (NAPSI) at weeks 12, 24 and 52; and DLQI at weeks 8, 12, 24, 42 and 52.
The safety analysis included all data obtained after the first injection of NTK/placebo. Adverse events (AEs) were reported according to Common Terminology Criteria for Adverse Events (CTCAE) v. 4.03 .
Blood samples for the immunogenicity analysis were obtained before the first dose of NTK/placebo, at weeks 12, 24, and 54. The samples were analyzed using a validated enzyme-linked immunosorbent assay (ELISA; drug-tolerant method). In case of detection of NTK-binding antibodies, we performed the analysis for the antibodies with neutralizing activity. The immunogenicity endpoint was the proportion of patients with binding/neutralizing anti-drug antibodies at weeks 12, 24 and 54.
This trial tested three hypotheses. The main study hypothesis stated the non-inferiority of NTK Q4W vs. Q2W at a significance level of 0.05. The second and the third hypotheses stated the superiority of NTK over placebo for each of the dosing regimens, Q4W and Q2W, respectively, each at a significance level of 0.05.
To calculate the sample size, we used literature data about the efficacy of ixekizumab in patients with moderate-to-severe plaque psoriasis . Assuming 89.1% and 82.6% PASI 75 response rate at week 12 in the Q2W and Q4W groups, respectively, a sample size of 154 patients (77 in each NTK group) would provide approximately 80% power to demonstrate non-inferiority with a 20.4% margin and 5% type I error rate. Non-inferiority margin was calculated as 0.25 of the lower boundary 95% confidence interval (CI) (81.5%; 88.9%) for the difference between assumed PASI 75 response rate at week 12 in the Q2W and placebo groups, assuming the response rate of 3.9% in the placebo group. Also, a sample size of 193 patients (77 in each NTK group and 39 in the placebo group) would provide > 80% power to demonstrate the superiority of NTK over placebo for each group with a 0% margin and 5% type I error rate. With a potential withdrawal rate of 10%, the study should involve 213 patients.
The statistical analysis was performed using two-sided hypothesis tests. The statistical significance level was set as 0.05.
Quantitative data were tested for normality using the Shapiro-Wilk test. Normally distributed quantitative data were analysed using the two-sample Student’s t-test and analysis of variance. Non-normally distributed data were analysed using the Mann-Whitney, Wilcoxon, Kruskal-Wallis and Friedman tests. Benjamini-Yekutieli adjustment was used for multiple comparisons. The categorical data were processed using frequency tables, Fisher’s exact test and Pearson’s chi-squared test.
Statistical hypotheses were tested by two steps:
Superiority hypotheses of NTK Q2W and NTK Q4W groups over placebo group;
Non-inferiority hypothesis of NTK Q4W and NTK Q2W.
A statistical comparison of all secondary efficacy endpoints was performed between the NTK Q2W/Q4W and NTK Q4W groups. Secondary efficacy endpoints in the placebo/NTK Q4W group were assessed descriptively because comparison with the NTK Q2W/Q4W and NTK Q4W groups was not feasible because of the difference in NTK treatment durations.
The efficacy and safety analyses were performed according to the intention-to-treat (ITT) principle and included all patients randomized in the study (n = 213). For dichotomous responder-type endpoints, missing responses at a post-baseline visit were imputed as a non-responder. For continuous endpoints, no missing data imputation rules were applied.