Application of the Statistical Method to Convert Published PASI 50/75/90/100 into Absolute PASI Response Rate in Patients with Moderate-to-Severe Plaque Psoriasis Treated with Tildrakizumab Based on Data from the Two Pivotal Phase 3 Studies reSURFACE 1 and reSURFACE 2.

BACKGROUND: Absolute Psoriasis Area and Severity Index (PASI) is a key endpoint in psoriasis management. Petto et al. [Pharm Stat. 2019;18(1):4-21] developed a statistical method to estimate the proportion of patients reaching absolute PASI response given baseline PASI score and proportion of patients achieving relative improvements at predefined time points. OBJECTIVES: To test this method on clinical data from two phase 3 tildrakizumab trials (reSURFACE 1/2) comparing estimated absolute PASI ≤1/≤2/≤3/≤5 responses with reference responses from clinical databases. METHODS: Reference PASI responses of ≤1/≤2/≤3/≤5 were extracted from clinical databases. Estimation of absolute PASI ≤1/≤2/≤3/≤5 response rates at week (W) 12 and W28 by treatment and trial were performed. Differences between estimated and reference responses were analysed. Bland-Atman limits of agreement and Passing-Bablok regression to assess variations between estimated and reference responses were performed. RESULTS: Differences between estimated and reference absolute PASI ≤1/≤2/≤3/≤5 responses at W12 and W28 by treatment and trial were of little clinical relevance with an overall mean difference in PASI response proportion of -2.2% (e.g., for the tildrakizumab 100-mg arm, original proportions of patients achieving PASI of ≤1/≤2/≤3/≤5 at W28 were 38.5%/52.2%/63.5%/73.9% and 39.8%/54.8%/63.6%/76.9% [reSURFACE 1 and 2, respectively] vs. estimated proportions of 33.2%/49.8%/62.5%/78.3% and 34.3%/51.6%/64.5%/79.9%). Limits of agreement were -7.1% to 1.4% at W12 and -6.8% to 4.3% at W28. Scatterplots revealed linearity that stood the cusum test in Passing-Bablok regression with slope 1.14 (95% confidence intervals: 1.06 to 1.20). CONCLUSION: Good estimates of absolute PASI response rates were achieved with the application of the statistical method to tildrakizumab data reported in the phase 3 studies, in particular in the verum study arms. Our data support the method provided by Petto et al. [2019] to estimate proportions of psoriasis patients reaching absolute PASI value thresholds using relative PASI improvements.

Nabiximols in Chronic Neuropathic Pain: A Meta-Analysis of Randomized Placebo-Controlled Trials.

OBJECTIVE: Pooled analysis of nabiximols and placebo in randomized controlled studies (RCTs) of chronic neuropathic pain. DESIGN: Systematic review and meta-analysis. METHODS: A systematic literature search was conducted to identify double-blind placebo-controlled RCTs of nabiximols for chronic neuropathic pain. The clinical endpoint of interest was change from baseline in mean pain score on 11-point numerical rating scales. Mean difference (MD) and standardized mean difference (SMD, Hedges' g) were calculated using fixed effect (FE) and random effects (RE) models. Strength of evidence was assessed using the Cochrane Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool. Risk of bias was assessed using the revised Cochrane risk-of-bias tool (RoB 2). RESULTS: Nine RCTs with 1289 participants were included. Quality of evidence (GRADE) was moderate. One study had a high risk of bias (RoB 2) and five had some concerns. For the pooled endpoint of change from baseline in mean pain score, nabiximols was superior to placebo, with a MD of -0.40 (95% confidence interval [CI]: -.59 to -.21; FE, P < .0001) or -0.44 (95% CI: -.70 to -.19; RE, P = .0006). A SMD of -0.21 (95% CI: -.32 to -.10; FE) or -0.26 (95% CI: -.42 to -.10; RE) indicated an incremental benefit over background analgesia. Results in favor of nabiximols were maintained in sensitivity analyses. CONCLUSIONS: Nabiximols was superior to placebo for reduction of chronic neuropathic pain, with a small effect size. Larger RCTs designed to assess the effect of nabiximols in neuropathic pain are required to reach more definitive conclusions.

Individuals at risk for severe COVID-19 in whom ritonavir-containing therapies are contraindicated or may lead to interactions with concomitant medications: a retrospective analysis of German health insurance claims data.

Background: Nirmatrelvir/ritonavir is authorized for the treatment of COVID-19 but has several contraindications and potential drug-drug interactions (pDDIs) due to ritonavir-induced irreversible inhibition of cytochrome P450 3A4. We aimed to assess the prevalence of individuals with one or more risk factors for severe COVID-19 along with contraindications and pDDIs due to ritonavir-containing COVID-19 therapy. Methods: Retrospective observational study of individuals with one or more risk factors according to Robert Koch Institute criteria for severe COVID-19 according to German statutory health insurance (SHI) claims data from the pre-pandemic years 2018-2019 based on the German Analysis Database for Evaluation and Health Services Research. Prevalence was extrapolated to the entire SHI population using age-adjusted and sex-adjusted multiplication factors. Results: Nearly 2.5 million fully insured adults, representing 61 million people in the German SHI population, were included in the analysis. In 2019, prevalence of individuals that would have been at risk of severe COVID-19 was 56.4%. Amongst them, the prevalence of contraindications for treatment with ritonavir-containing COVID-19 therapy was approximately 2% according to presence of somatic comorbidities (severe liver or kidney disease). Prevalence of intake of medicines contraindicated for their potential interactions with ritonavir-containing COVID-19 therapy was 16.5% according to Summary of Product Characteristics and 31.8% according to previously published data. The prevalence of individuals at risk of pDDIs during ritonavir-containing COVID-19 therapy without adjustment of their concomitant therapy was 56.0% and 44.3%, respectively. Prevalence data for 2018 were similar. Conclusion: Administering ritonavir-containing COVID-19 therapy can be challenging as thorough medical record review and close monitoring are required. In some cases, ritonavir-containing treatment may not be appropriate due to contraindications, risk of pDDIs, or both. For those individuals, an alternative ritonavir-free treatment should be considered.

Systematic reviews of randomized controlled trials of cannabinoid products in chronic pain conditions and for symptoms associated with multiple sclerosis: what do they tell us?

INTRODUCTION: To investigate whether published systematic reviews of randomized controlled trials provide sufficient clarity to inform prescribing of medicinal cannabinoid products, we examined their features and findings in two well-researched areas: chronic cancer/noncancer pain and multiple sclerosis (MS)-related symptoms. AREAS COVERED: Structured searches from January 2011 to 2 February 2021 identified 31 systematic reviews (with/without meta-analyses) that met the inclusion criteria. Support for the efficacy of cannabinoids was minimal in cancer pain, and somewhat stronger in noncancer (especially neuropathic) pain and MS spasticity. All systematic reviews and most meta-analyses grouped cannabinoid products together without appropriate consideration of their differential attributes (active constituent(s), concentration/strength, dosage forms, administration route), dosing regimens or treatment durations. Patient populations and efficacy outcome measures were inhomogeneous, particularly for studies in noncancer pain and MS. Separate results for specific cannabinoid formulations were rarely provided. EXPERT OPINION: The therapeutic effect of cannabinoids, as already demonstrated for some products, is not reflected clearly in the current range of systematic reviews and meta-analyses in chronic pain and MS. To truly inform evidence-based practice, future publications should aim to present results by individual product from well-conducted clinical trials using appropriate and homogeneous outcome measures in well-defined patient populations.

Comparative Efficacy and Safety of Tirbanibulin for Actinic Keratosis of the Face and Scalp in Europe: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

Actinic keratosis (AK) is a chronic skin condition that may progress to cutaneous squamous cell carcinoma. We conducted a systematic review of efficacy and safety for key treatments for AK of the face and scalp, including the novel 5-day tirbanibulin 1% ointment. MEDLINE, PubMed, Embase, Cochrane Library, clinical trial registries and regulatory body websites were searched. The review included 46 studies, of which 35 studies included interventions commonly used in Europe and were sufficiently homogenous to inform a Bayesian network meta-analysis of complete clearance against topical placebo or vehicle. The network meta-analysis revealed the following odds ratios and 95% credible intervals: cryosurgery 13.4 (6.2-30.3); diclofenac 3% 2.9 (1.9-4.3); fluorouracil 0.5% + salicylic acid 7.6 (4.6-13.5); fluorouracil 4% 30.3 (9.1-144.7); fluorouracil 5% 35.0 (10.2-164.4); imiquimod 3.75% 8.5 (3.5-22.4); imiquimod 5% 17.9 (9.1-36.6); ingenol mebutate 0.015% 12.5 (8.1-19.9); photodynamic therapy with aminolevulinic acid 24.1 (10.9-52.8); photodynamic therapy with methyl aminolevulinate 11.7 (6.0-21.9); tirbanibulin 1% 11.1 (6.2-20.9). Four sensitivity analyses, from studies assessing efficacy after one treatment cycle only, for ≤25 cm2 treatment area, after 8 weeks post-treatment, and with single placebo/vehicle node confirmed the findings from the base case. Safety outcomes were assessed qualitatively. These results suggest that tirbanibulin 1% offers a novel treatment for AK, with a single short treatment period, favourable safety profile and efficacy, in line with existing topical treatments available in Europe.

Effects of SativexⓇ on cognitive function in patients with multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: Cognitive impairment is a common manifestation of multiple sclerosis (MS). OBJECTIVE: To assess by systematic review and meta-analysis available evidence regarding the impact of nabiximols oromucosal spray on cognition in patients with MS. METHODS: A systematic literature search of clinical studies (all types, any comparator) that measured cognitive function in patients with MS spasticity treated with nabiximols. Meta-analysis for cognitive endpoints was not possible due to heterogenous measurement instruments and outcomes. Meta-analysis was performed for adverse events (AEs) of special interest (cognition disorders) reported in randomized controlled trials (RCTs) of nabiximols versus placebo in patients with MS (with or without spasticity). Certainty of evidence and risk of bias were assessed. RESULTS: Seven clinical studies (three RCTs) directly assessing cognitive function were included in the qualitative analysis. There was no consistent evidence to suggest that nabiximols causes cognitive impairment as assessed by a range of specific psychometric instruments across cognitive domains. Thirteen double-blind, placebo-controlled RCTs (nabiximols, n = 964; placebo, n = 904) were included in the meta-analysis of cognitive AEs. Most cognitive AEs (30 of 32 events, 93.8%) reported with nabiximols in MS patients occurred with not in-label use, i.e., dosage >12 sprays per day and/or not administered primarily for treatment of spasticity. CONCLUSIONS: Within the limitations of the review, we can conclude that no detrimental effects of nabiximols on cognitive function were observed in patients with MS spasticity during up to 12 months follow-up and that cognitive AEs were rare and occurred only when nabiximols was not used according to its approved label.