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MethodsThis was a 12-week, randomized, double-blind, parallel-group, vehicle-controlled Phase 2b study of tofacitinib ointment (2% and 1%) applied once (QD) or twice (BID) daily in adults with mild to moderate plaque psoriasis. Primary endpoint: proportion of patients with Calculated Physician’s Global Assessment (PGA-C) clear or almost clear and ≥2 grade improvement from baseline at Weeks 8 and 12. Secondary endpoints: proportion of patients with PGA-C clear or almost clear; proportion achieving Psoriasis Area and Severity Index 75 (PASI75) response; percent change from baseline in PASI and body surface area; change from baseline in Itch Severity Item (ISI). Adverse events (AEs) were monitored and clinical laboratory parameters measured. ResultsOverall, 435 patients were randomized and 430 patients received treatment. The proportion of patients with PGA-C clear or almost clear and ≥2 grade improvement from baseline at Week 8 was 18.6% for 2% tofacitinib QD (80% confidence interval CI for difference from vehicle: 3.8, 18.2%) and 22.5% for 2% tofacitinib BID (80% CI: 3.1, 18.5%); this was significantly higher vs vehicle for both dosage regimens.
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No significant difference vs vehicle was seen at Week 12. Significantly more patients achieved PGA-C clear or almost clear with 2% tofacitinib QD and BID and 1% tofacitinib QD (not BID) at Week 8, and with 2% tofacitinib BID at Week 12. Pruritus was significantly reduced vs vehicle with 2% and 1% tofacitinib BID (starting Day 2), and 2% tofacitinib QD (starting Day 3). Overall, 44.2% of patients experienced AEs, 8.1% experienced application site AEs, and 2.3% experienced serious AEs. The highest incidence of AEs (including application site AEs) was in the vehicle QD group. BackgroundThe World Health Organization has described psoriasis as a ‘chronic, non-communicable, painful, disfiguring and disabling disease for which there is no cure’. The majority of people with plaque psoriasis (75–90%) are considered to have relatively limited mild to moderate disease ,.
Many treatments are available for mild to moderate psoriasis, including topical treatment with corticosteroids, often in combination with vitamin D analogues –. The use of mid to high potency corticosteroids can be limited by local and systemic adverse effects, particularly on the face and intertriginous areas ,. Irritation or burning can also occur with vitamin D analogues –. Topical therapy is also used in combination with phototherapy or systemic therapy in patients with moderate to severe psoriasis.A substantial proportion of patients with psoriasis are dissatisfied with their current treatment. The limited efficacy of non-steroidal topical monotherapy or low potency corticosteroids and the safety issues associated with long-term use of mid to high potency topical corticosteroids suggest an unmet need exists for additional topical therapeutic options.Tofacitinib (CP-690,550) is a small molecule Janus kinase (JAK) inhibitor; inhibition of JAK1 and JAK3 by tofacitinib blocks signaling of multiple cytokines implicated in immune response and inflammation. The oral formulation of tofacitinib is effective in patients with moderate to severe plaque psoriasis –. An ointment formulation of tofacitinib investigated for the topical treatment of psoriasis in a Phase 2a study showed the ointment (2% twice daily BID) was effective with acceptable tolerability for mild to moderate psoriasis.The primary objective of this Phase 2b study was to further characterize the efficacy and safety of tofacitinib ointment (2% and 1%) applied once daily (QD) or BID over 12 weeks in adult patients with mild or moderate chronic plaque psoriasis, compared with the corresponding vehicle.
Study design and treatmentThis randomized, double-blind, parallel-group, vehicle-controlled study , conducted at 52 centers in the United States, Canada, Denmark, and Poland, was initiated in May 2013 and completed in September 2014. Patients were randomized 1:1:1 to receive 1% (10 mg/g) tofacitinib ointment, 2% (20 mg/g) tofacitinib ointment or corresponding vehicle.
Randomization was stratified by baseline severity of psoriasis as defined by the Calculated Physician’s Global Assessment (PGA-C). Investigators, study staff and sponsor remained blinded to treatment and randomization information until after the conclusion of the study. Investigator sites were assigned to either QD or BID regimen, but not both; neither investigators nor patients were blinded to regimen.Tofacitinib ointment was provided in 60 g tubes at a strength of 2% (maximum feasible concentration) and 1%; the matching vehicle contained the same inactive ingredients as tofacitinib ointment.
Treatments were administered topically at a target application coverage of 3 mg/cm 2 to a treatment area corresponding to 2 to 20% of the patient’s body surface area (BSA). Patients were instructed to treat all treatment-eligible psoriatic areas identified at baseline for 12 weeks, regardless of clearing or improvement in psoriasis. On study visit days, showering or bathing, but not moisturizing, was permitted prior to attending, and study drug was applied in the clinic after study assessments were completed. After the final study treatment, the treatment areas were left untreated during the 4-week follow-up period.Use of shampoo containing tar, salicylic acid or low or least potent corticosteroid products (eg hydrocortisone and hydrocortisone acetate ≤1%) was permitted on hair-bearing scalp only throughout the study. The proprietary ointment formulation contained standard excipients for a topical formulation. AssessmentsClinical signs of plaque psoriasis (erythema, induration and scaling) were scored separately according to a 5-point severity scale: clear (0), almost clear (1), mild (2), moderate (3), and severe (4). These PGA subscores were then summed, averaged, and rounded to the nearest whole number to determine the PGA-C score and category.
Evaluation of the PGA-C excluded the scalp (even if the hairless scalp was being treated with study drug), palms, soles, and nails.The primary endpoint was the proportion of subjects achieving a PGA-C response of clear (0) or almost clear (1) with ≥2 grade improvement from baseline at Week 8 and Week 12, independently. Secondary endpoints included Week 8 and Week 12 assessments of the proportion of patients achieving a PGA-C response of clear (0) or almost clear (1); the proportion of patients achieving a ≥75% improvement from baseline in Psoriasis Area and Severity Index (PASI75); the percent change from baseline in PASI; and the percent change from baseline in affected BSA.Evaluation of patient-reported outcomes included change from baseline in itch severity and in the Dermatology Life Quality Index (DLQI).
The severity of itch was assessed via the Itch Severity Item (ISI), a single item instrument in which the patient records itching over the previous 24 h on a numerical rating scale of 0 (no itching) to 10 (worst possible itching). ISI was recorded in the clinic during Visit 1 (baseline/Day 1) and at Visits 3–7 (Weeks 2, 4, 8, 12, and 16), as well as once per day between Visit 1 and the day before Visit 3 by the patient in a diary prior to application of study treatment.
Patients in the BID treatment group recorded the ISI before applying either the morning or evening treatment, but at the same time throughout this period.Safety endpoints included the incidence of treatment-emergent adverse events (AEs), serious AEs (SAEs), and application site AEs, plus the proportion of patients who discontinued due to application site AEs. Physical examination, monitoring of vital signs, and clinical laboratory assessments (including hematology, fasting serum chemistry, fasting lipid panels, and urinalysis) were performed.Pharmacokinetic (PK) endpoints included tofacitinib PK concentrations for pre-dose and post-dose samples. Pre-dose blood samples were collected at baseline and at Weeks 2, 4, 8, and 12 (0 h). At selected sites, three PK samples were also collected at Week 4 post-dose between 30 min and 1 h, between 2 and 3 h, and between 4 and 10 h. Statistical analysisThis was an estimation study. A sample size of 70 subjects per treatment group was selected, such that the 80% confidence interval (CI) width of the difference between tofacitinib and vehicle was approximately 19%, assuming a 21% vehicle response and a 36% response in tofacitinib. Additionally, this sample size would yield approximately 76% power to establish the superiority of each strength and regimen of tofacitinib to its respective vehicle for the primary endpoint at the 0.10 (one-sided) significance level.
No adjustment for multiple comparisons was made.Patients with mild or moderate psoriasis at baseline (as defined by PGA-C) who were randomized and received at least one dose of study medication (tofacitinib or vehicle) were included in the analyses. Data at Week 8 and Week 12 were evaluated separately.For the primary endpoint, standard error (SE) and two-sided 80% CI were calculated using the normal approximation to the binomial proportions. A stratified analysis was conducted by summarizing the difference in proportions adjusted for the baseline PGA-C disease severity using the Cochran-Mantel-Haenszel approach ,. Patients with missing values were considered non-responders.PASI75 and PGA-C response of clear or almost clear were analyzed using a marginal logistic regression model fit by pseudo-likelihood (generalized linear mixed model for repeated measures).
Response proportions were estimated from the model and odds ratios for treatment contrasts along with 80% CI were determined. Continuous variables (eg percent change from baseline in PASI and BSA, and change from baseline in ISI) were analyzed using a linear mixed model for repeated measures. Least squares mean (LSM), difference in LSM, SE, and two-sided 80% CI were calculated. All analyses used observed data without imputation. Separate models were fit for the QD and BID data.For comparisons in response proportions between the active treatment and corresponding vehicle, statistical significance was declared if the lower limit of the two-sided 80% CI for the response difference was 0 for the primary efficacy endpoint, and if the lower limit of the two-sided 80% CI for the odds ratio was 1 for the secondary PGA-C and PASI75 endpoints.
For comparisons in LSMs between active treatment and corresponding vehicle, statistical significance was declared if the upper limit of the two-sided 80% CI was. Primary endpointsAt Week 8 only, significantly more patients receiving 2% tofacitinib QD and 2% tofacitinib BID achieved a PGA-C response of clear or almost clear and ≥2 grade improvement from baseline compared with the corresponding vehicle. Response rate was 18.6% and 8.1% for 2% tofacitinib QD and vehicle QD, respectively, and 22.5% and 11.3% for 2% tofacitinib BID and vehicle BID, respectively. The difference (80% CI) between response to active treatment and vehicle was 10.8% (3.1, 18.5) and 11.0% (3.8, 18.2) for 2% tofacitinib BID and QD administration, respectively (Fig. ). At Week 12, no statistically significant differences versus vehicle were seen for 2% or 1% tofacitinib by either dosing regimen (Fig. ). PGA-C response of clear (0)/almost clear (1) and ≥2 grade improvement at Week 16.Lower limit 80% CI of difference tofacitinib versus vehicle 0. Proportion (SE) of patients achieving a PGA-C response of clear (0) or almost clear (1) and ≥2 grade improvement from baseline through to Week 16 for patients applying 2% tofacitinib, 1% tofacitinib, or vehicle, once daily ( a) or twice daily ( b).
Patients who were discontinued or with missing values were considered non-responders. BID twice daily, BL baseline, CI confidence interval, PGA-C Calculated Physician’s Global Assessment, PGA-Cm Calculated Physician’s Global Assessment of patients with mild to moderate plaque psoriasis at baseline, QD once daily, SE standard error, tofa tofacitinib. ADifference active – vehicle; bmeets specification for statistical significancePASI excluded the scalp, palms, and soles from the assessment/scoring, even if these areas were being treated with study drug.
Patient-reported outcomes2% and 1% tofacitinib BID significantly reduced pruritus compared with vehicle BID as early as Day 2 (the day following the initial dose); these improvements were sustained through Day 14 (Fig. ). Numerically greater improvements in ISI were also seen in the 2% and 1% tofacitinib QD treatment groups compared with vehicle QD; these improvements were statistically significant for 2% tofacitinib QD on Days 3–14 (Fig. ). Significant improvements in pruritus were maintained for 2% BID, 1% BID, and 2% QD from Week 2 through Week 12 (except Week 8 and 12 for 2% QD). Change from baseline in Itch Severity Item score through Week 2. Least squares mean (SE) change from baseline in Itch Severity Item score through Week 2 for patients applying 2% tofacitinib, 1% tofacitinib, or vehicle, once daily ( a) or twice daily ( b). Changes from baseline in ISI were analyzed using a Mixed Model for Repeated Measures without imputation for missing values; QD and BID data were analyzed separately.
BID twice daily, ISI Itch Severity Item, LSM least squares mean, PGA-Cm Calculated Physician’s Global Assessment of patients with mild to moderate plaque psoriasis at baseline, QD once daily, SE standard error, tofa tofacitinibAt Week 8, 2% tofacitinib BID and QD significantly improved DLQI more than their respective vehicles (Additional file: Figure S1). At Week 12, 2% tofacitinib QD and 1% tofacitinib QD significantly improved DLQI more than the vehicle (Additional file: Figure S1). All adverse eventsOverall, 44.2% of patients experienced treatment-emergent AEs, most of which were mild or moderate in severity (Table ). The highest incidence of treatment-emergent AEs was in the vehicle QD group, with 54.1% of patients in this group reporting one or more treatment-emergent AE. The most frequently reported AEs by Medical Dictionary for Regulatory Activities (MedDRA; version 17.1) preferred term were nasopharyngitis (6.7%), upper respiratory tract infection (4.9%), and psoriasis (4.9%). 2% tofacitinib BID1% tofacitinib BIDVehicleBID2% tofacitinib QD1% tofacitinib QDVehicleQDN = 71N = 70N = 71N = 70N = 74N = 74Number of AEs62Patients with treatment-emergent AEs, n (%)30 (42.3)30 (42.9)28 (39.4)34 (48.6)28 (37.8)40 (54.1)Patients with application site AEs, n (%)4 (5.6)0 (0.0)4 (5.6)8 (11.4)7 (9.5)12 (16.2)Patients with SAEs, n (%)0 (0.0)5 (7.1)2 (2.8)0 (0.0)2 (2.7)1 (1.4)Patients discontinued due to AEs, n (%)0 (0.0)1 (1.4) a4 (5.6)6 (8.6)3 (4.1)7 (9.5)Deaths, n (%)0 (0.0)1 (1.4) a0 (0.0)0 (0.0)0 (0.0)0 (0.0). APatient had an AE of myocardial infarction and subsequently died; the patient is counted as a discontinuation due to AE and as a deathCategories of adverse events experienced include treatment-emergent, application site and serious adverse eventsAE adverse event, BID twice daily, QD once daily, SAE serious adverse eventA total of 11 SAEs were experienced by 10 (2.3%) patients.
No SAEs were reported in the 2% tofacitinib QD or BID treatment groups; SAEs were reported in five patients in the 1% tofacitinib BID group, in two patients in each of the 1% tofacitinib QD and vehicle BID groups, and in one patient in the vehicle QD group (Additional file: Table S1). No SAEs were assessed by the investigator as treatment-related, with the exception of one SAE of psoriatic arthropathy in the vehicle BID treatment group.Overall, 21 (4.9%) patients discontinued from the study due to AEs, most commonly psoriasis, which was reported by six (1.4%) patients. Seven patients discontinued due to AEs in the vehicle QD group, six with 2% tofacitinib QD, four with vehicle BID, three with 1% tofacitinib QD, and one with 1% tofacitinib BID (patient was discontinued from the study due to a fatal myocardial infarction as described below).One death (due to myocardial infarction) occurred in a 53-year-old white male receiving 1% tofacitinib BID. His final application of tofacitinib ointment was on Study Day 74 and he died on Study Day 86. Relevant medical history included prior myocardial infarction and stent placement, dyslipidemia, hypertension, and 18-year history of tobacco use.
The event was considered unrelated to study treatment by the investigator. Application site adverse eventsApplication site AEs were reported in 35 of the 190 (18.4%) patients who experienced treatment-emergent AEs (8.1% of total study population); no application site AEs were serious (Table ). The highest incidence was in the vehicle QD group (Table ). The most frequently reported application site AEs by MedDRA preferred term were psoriasis (reported by 18 4.2% patients), pruritus (9 2.1%), and application site pain (3 0.7%).A total of 12 (2.8%) patients discontinued the study due to application site AEs; seven were from the vehicle QD group, three from the 2% tofacitinib QD group, and one from each of the vehicle BID and 1% tofacitinib QD groups.
According to the information presented on the official website, you can install the application on Windows 95, 98, Me, XP, Vista, 7, and Windows 8.As you can see, there is no Windows 10 compatibility. You might have to wait until the developers release a compatible version for Windows 10. Additionally, try launching the application in Compatibility Mode. Right click it and then go to Properties Compatibility and choose an operating system from the ones mentioned above.For additional options, contact the developers of the application using. DO THE SAME LIKE HERE I HAVE DONE IT AND IT WORKS ON WINDOWS 10'Run time Error 75' messageWhen I start Janus 4.3 I get a 'run time error 75 path/file access error.'
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