A SAS Program Combining R Functionalities to Implement Pattern-Mixture Models

Pattern-mixture models have gained considerable interest in recent years. Patternmixture modeling allows the analysis of incomplete longitudinal outcomes under a variety of missingness mechanisms. In this manuscript, we describe a SAS program which combines R functionalities to fit pattern-mixture models, considering the cases that missingness mechanisms are at random and not at random. Patterns are defined based on missingness at every time point and parameter estimation is based on a full group-bytime interaction. The program implements a multiple imputation method under so-called identifying restrictions. The code is illustrated using data from a placebo-controlled clinical trial. This manuscript and the program are directed to SAS users with minimal knowledge of the R language

Rationale and protocol for the efficacy, safety and tolerability of nangibotide in patients with septic shock (ASTONISH) phase IIb randomised controlled trial.

INTRODUCTION: Septic shock is the subgroup of patients with sepsis, which presents as vasopressor dependence, an elevated blood lactate concentration and is associated with a mortality of at least 30%. Expression of the triggering receptor expressed on myeloid cells 1 (TREM-1) pathway, measured using a serum biomarker of pathway activation (soluble TREM-1, sTREM-1) has been associated with outcome in septic shock. Preclinical and early phase patient data suggest that therapeutic modulation of this pathway may improve survival. METHODS AND ANALYSIS: Efficacy, Safety and Tolerability of Nangibotide in Patients with Septic Shock is a phase IIb randomised controlled trial that will take place in up to 50 centres in seven countries and recruit 450 patients with septic shock to receive either placebo or one of two doses of nangibotide, a novel regulator of the TREM-1 pathway. The primary outcome will be the impact of nangibotide therapy on the change in Sequential Organ Failure Assessment score from a baseline determined before initiation of study drug therapy. This will be assessed first in the patients with an elevated sTREM-1 level and then in the study population as a whole. In addition to safety, secondary outcomes of the study will include efficacy of nangibotide in relation to sTREM-1 levels in terms of organ function, mortality and long-term morbidity. This study will also facilitate the development of a novel platform for the measurement of sTREM-1 at the point of care. ETHICS AND DISSEMINATION: The study has been approved by the responsible ethics committees/institutional review boards in all study countries: Belgium: Universitair Ziekenhuis Antwerpen, France: CPP Ile de France II, Denmark: Region Hovedstaden, Spain: ethics committee from Valld'Hebron Hospital, Barcelona, Finland: Tukija, Ireland: St. James' Hospital (SJH) / Tallaght University Hospital (TUH) Joint Research Ethics Committee, USA: Lifespan, Providence TRIAL REGISTRATION NUMBERS: EudraCT Number: 2018-004827-36 and NCT04055909

Rubus idaeus extract improves symptoms in knee osteoarthritis patients: results from a phase II double-blind randomized controlled trial.

peer reviewed[en] BACKGROUND: Osteoarthritis (OA) is the most frequent cause of disability in elderly people. In daily practice, the main objective of the physician is to reduce patient symptoms using treatments without adverse effects. However, the most prescribed treatment to manage OA symptoms remains nonsteroidal anti-inflammatory drugs which are associated with severe adverse effects. Therefore, we need a safe alternative to managing OA. One candidate is Rubus idaeus leaf extracts known to inhibit inflammatory responses. OBJECTIVE: This study aimed to evaluate the effects of a 12-weeks intervention with an ethanolic extract from Rubus idaeus leaf on symptoms of knee osteoarthritis. METHOD: The study was a randomized, double-blind, placebo-controlled, monocentric trial of 198 participants with femorotibial osteoarthritis. Participants were randomized equally to receive one daily during 3 months either 1 capsule of Rubus idaeus leaf extract 400 mg, 1 capsule of Rubus idaeus leaf extract 200 mg, or 1 capsule of placebo. The participants were assessed at baseline and after one and three months of treatment. The primary endpoint was an absolute change of the Western Ontario McMaster osteoarthritis index (WOMAC) pain subscale. The secondary endpoints were WOMAC global score, stiffness and function sub-scales, knee pain VAS score at walking, the Short Form (SF)-36, the Short Physical Performance Battery (SPPB), the 20-m walk test, and the International Physical Activity Questionnaire (IPAQ) and Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) responders rate. Statistical analyses were conducted on the intent-to-treat (ITT) population. RESULTS: In the Intention-to-treat population, WOMAC pain was not significantly modified by Rubus idaeus leaf extract compared to placebo. In contrast, Rubus idaeus leaf extract 400 mg after 12 weeks of treatment significantly reduced pain measured by the VAS. The mean pain decrease induced by Rubus ideaus leaf extract was over -7 mm which is clinically relevant and reached a clinically statistical difference compared to placebo with the highest dose. Rubus Ideaus was not significantly more efficient than the placebo on WOMAC global score, stiffness, and physical function subscores, IPAQ, SF-36, walking distance in treadmill test, SPPB, and evaluation of associated treatments needed to manage OA. CONCLUSION: Rubus idaeus leaf extract was well tolerated and effective to relieve pain in a patient with knee osteoarthritis. TRIAL REGISTRATION: NCT03703024  (11/10/2018)

Comparative effectiveness of bimekizumab and ustekinumab in patients with psoriatic arthritis at 52 weeks assessed using a matching-adjusted indirect comparison

Introduction: A matching-adjusted indirect comparison (MAIC) was conducted to assess the relative efficacy at 52 weeks (Wk52) of bimekizumab 160 mg every 4 weeks (Q4W) and ustekinumab 45 or 90 mg every 12 weeks (Q12W) in patients with psoriatic arthritis (PsA) who were biologic disease-modifying anti-rheumatic drug naïve (bDMARD naïve) or who had a previous inadequate response or an intolerance to tumor necrosis factor inhibitors (TNFi-IR). Methods: Relevant trials were systematically identified. Individual patient data from the bimekizumab trials BE OPTIMAL (NCT03895203; N = 431) and BE COMPLETE (NCT03896581; N = 267) were matched with summary data on patients receiving ustekinumab in the PSUMMIT 1 trial (NCT01009086; 45 mg, N = 205; 90 mg; N = 204) and a subgroup of TNFi-IR patients receiving ustekinumab in the PSUMMIT 2 trial (NCT01077362; 45 mg, N = 60; 90 mg, N = 58), respectively. Patients from the bimekizumab trials were re-weighted using propensity scores to match the baseline characteristics of the ustekinumab trial patients. Adjustment variables were selected based on expert consensus (n = 5) and adherence to established MAIC guidelines. Non-placebo-adjusted comparisons of recalculated bimekizumab and ustekinumab outcomes for the American College of Rheumatology (ACR) 20/50/70 response criteria (non-responder imputation) were analyzed. Results: In patients who were bDMARD naïve, bimekizumab had a greater likelihood of response than ustekinumab at Wk52 for ACR20 (odds ratio [95% confidence interval] 45 mg: 2.14 [1.35, 3.40]; 90 mg: 1.98 [1.24, 3.16]), ACR50 (45 mg: 2.74 [1.75, 4.29]; 90 mg: 2.29 [1.48, 3.55]), and ACR70 (45 mg: 3.33 [2.04, 5.46]; 90 mg: 3.05 [1.89, 4.91]). In patients who were TNFi-IR, bimekizumab had a greater likelihood of response than ustekinumab at Wk52 for ACR20 (45 mg: 4.17 [2.13, 8.16]; 90 mg: 4.19 [2.07, 8.49]), ACR50 (45 mg: 5.00 [2.26, 11.05]; 90 mg: 3.86 [1.70, 8.79]), and ACR70 (45 mg: 9.85 [2.79, 34.79]; 90 mg: 6.29 [1.98, 20.04]). Conclusions: Using MAIC, bimekizumab showed greater efficacy than ustekinumab in achieving all ACR responses in patients with PsA who were bDMARD naïve and TNFi-IR at Wk52. Trial Registration: NCT03895203, NCT03896581, NCT01009086, NCT01077362

Comparative effectiveness of bimekizumab and secukinumab in patients with psoriatic arthritis at 52 weeks using a matching-adjusted indirect comparison

Introduction: Matching-adjusted indirect comparisons (MAICs) were used to compare the efficacy of bimekizumab and secukinumab 150 mg and 300 mg at 52 weeks for the treatment of psoriatic arthritis (PsA) in patients who were biologic disease-modifying anti-rheumatic drug-naı¨ve (bDMARD-naı¨ve) or with previous inadequate response or intolerance to tumor necrosis factor inhibitors (TNFi-IR). Methods: Relevant trials were systematically identified. Individual patient data from bimekizumab randomized controlled trials, BE OPTIMAL (N = 431) and BE COMPLETE (N = 267), were matched to aggregate data from bDMARDnaı¨ve and TNFi-IR patient subgroups from FUTURE 2 using secukinumab 150 mg and 300 mg doses (bDMARD-naı¨ve: N = 63/37; TNFiIR:N = 67/33). To adjust for cross-trial differences, patients from the bimekizumab trials were reweighted using propensity scores to match the baseline characteristics of patients in the secukinumab trials. Unanchored comparisons of recalculated bimekizumab and secukinumab 52-week non-responder imputation outcomes for 20/50/70% improvement in American College of Rheumatology score (ACR20/50/70) and minimal disease activity (MDA) index were analyzed. Results: In patients who were bDMARD-naı¨ve, bimekizumab had a greater likelihood of ACR70 response than secukinumab 150 mg (odds ratio [95% confidence interval] 2.39 [1.26, 4.53]; p = 0.008) and secukinumab 300 mg (2.03 [1.11, 3.72]; p = 0.021) at 52 weeks. In patients who were TNFi-IR, bimekizumab had a greater likelihood of response compared to secukinumab 150 mg for ACR20 (3.50 [1.64–7.49]; p = 0.001), ACR50 (3.32 [1.41, 7.80]; p = 0.006), ACR70 (2.95 [1.08, 8.07]; p = 0.035) and MDA (3.52 [1.38, 8.99]; p = 0.009), and a greater likelihood of response compared to secukinumab 300 mg for ACR50 (2.44 [1.06, 5.65]; p = 0.037) and MDA (2.92 [1.20, 7.09]; p = 0.018) at 52 weeks. Conclusion: In this MAIC analysis, the efficacy of bimekizumab, as demonstrated by the likelihood of ACR20/50/70 and MDA response at 52 weeks, was greater or comparable to secukinumab 150 mg and 300 mg for patients with PsA who were bDMARD-naive and TNFi-IR

Comparative effectiveness of bimekizumab and risankizumab in patients with psoriatic arthritis at 52 weeks assessed using a matching-adjusted indirect comparison

Introduction: The relative efficacy of bimekizumab and risankizumab in patients with PsA who were biologic disease-modifying anti-rheumatic drug naïve (bDMARD naïve) or with previous inadequate response or intolerance to tumor necrosis factor inhibitors (TNFi-IR) was assessed at 52 weeks (Wk52) using matching-adjusted indirect comparisons (MAIC). Methods: Relevant trials were systematically identified. For patients who were bDMARD naïve, individual patient data (IPD) from BE OPTIMAL (NCT03895203; N = 431) were matched with summary data from KEEPsAKE-1 (NCT03675308; N = 483). For patients who were TNFi-IR, IPD from BE COMPLETE (NCT03896581; N = 267) were matched with summary data from the TNFi-IR patient subgroup in KEEPsAKE-2 (NCT03671148; N = 106). To adjust for cross-trial differences, patients from the bimekizumab trials were re-weighted to match the baseline characteristics of patients in the risankizumab trials. Adjustment variables were selected based on expert consensus (n = 5) and adherence to established MAIC guidelines. Recalculated bimekizumab Wk52 outcomes for American College of Rheumatology (ACR) 20/50/70 response criteria and minimal disease activity (MDA) index (non-responder imputation) were compared with risankizumab outcomes via non-placebo-adjusted comparisons. Results: In patients who were bDMARD naïve, bimekizumab had a significantly greater likelihood of response than risankizumab at Wk52 for ACR50 (odds ratio [95% confidence interval]: 1.52 [1.11, 2.09]) and ACR70 (1.80 [1.29, 2.51]). In patients who were TNFi-IR, bimekizumab had a significantly greater likelihood of response than risankizumab at Wk52 for ACR20 (1.78 [1.08, 2.96]), ACR50 (3.05 [1.74, 5.32]), ACR70 (3.69 [1.82, 7.46]), and MDA (2.43 [1.37, 4.32]). Conclusions: Using MAIC, bimekizumab demonstrated a greater likelihood of efficacy in most ACR and MDA outcomes than risankizumab in patients with PsA who were bDMARD naïve and TNFi-IR at Wk52. Trial Registration NCT03895203, NCT03896581, NCT03675308, NCT03671148

Bayesian sample size determination in non-sequential clinical trials: statistical aspects and some regulatory considerations?

International audienceThe most common Bayesian methods for sample size determination (SSD) are reviewed in the non-sequential context of a confirmatory phase III trial in drug development. After recalling the regulatory viewpoint on SSD, we discuss the relevance of the various priors applied to the planning of clinical trials. We then investigate whether these Bayesian methods could compete with the usual frequentist approach to SSD and be considered as acceptable from a regulatory viewpoint

Efficacy and safety of imeglimin in Japanese patients with type 2 diabetes: A 24-week, randomized, double-blind, placebo-controlled, dose-ranging phase 2b trial

International audienceAIMS: The aim of this study was to assess the efficacy and safety of imeglimin monotherapy compared to placebo for 24 weeks in Japanese patients with type 2 diabetes mellitus (T2DM).MATERIAL AND METHODS: In this 24-week, randomized, double-blind, placebo-controlled, parallel group, dose ranging, phase 2b clinical trial, Japanese adults (age ? 20 years) with T2DM either treatment-na�ve or previously treated with one oral anti-diabetes agent were eligible for participation. Patients were randomly assigned (1:1:1:1) to receive orally imeglimin 500 mg or imeglimin 1000 mg or imeglimin 1500 mg, or placebo twice daily over a 24-week period. The primary endpoint was the placebo-adjusted change at week 24 in HbA1c. Safety outcomes were assessed in all patients that received at least one dose of study drug. This trial is registered at JAPIC (JapicCTI-153086).RESULTS: A total of 299 patients were randomized to receive double-blind treatment with orally twice-daily placebo (n= 75), imeglimin 500 mg (n=75), 1000 mg (n=74) or 1500 mg (n=75). At week 24, imeglimin significantly decreased HbA1c (difference vs placebo: imeglimin 500 mg -0.52% (95% CI: -0.77, -0.27), imeglimin 1000 mg -0.94% (95% CI: -1.19, -0.68), imeglimin 1500 mg -1.00% (95% CI: -1.26, -0.75) (p < 0.0001 for all). Treatment-emergent adverse events (TEAE) were reported for 68.0%, 62.2%, 73.3% and 68.0% of patients receiving imeglimin 500 mg, imeglimin 1000 mg, imeglimin 1500 mg and placebo, respectively. A small increase in gastrointestinal adverse effects (e.g. diarrhea) occurred with the 1500 mg dose level. Hypoglycemia was balanced between groups.CONCLUSIONS: Imeglimin as monotherapy in Japanese patients with T2DM was well tolerated and significantly improved glycemic control with no significant increase in hypoglycemic events versus placebo. Given the marginal increase in efficacy with the 1500 mg vs. 1000 mg dose (along with the potential for gastrointestinal tolerability issues), a dose of 1000 mg BID was selected for subsequent Phase III studies

A SAS

Pattern-mixture models have gained considerable interest in recent years. Patternmixture modeling allows the analysis of incomplete longitudinal outcomes under a variety of missingness mechanisms. In this manuscript, we describe a SAS program which combines R functionalities to fit pattern-mixture models, considering the cases that missingness mechanisms are at random and not at random. Patterns are defined based on missingness at every time point and parameter estimation is based on a full group-bytime interaction. The program implements a multiple imputation method under so-called identifying restrictions. The code is illustrated using data from a placebo-controlled clinical trial. This manuscript and the program are directed to SAS users with minimal knowledge of the R language

Relative Bioavailability Study of Midazolam Intramuscularly Administered with the Needle-Free Auto-Injector ZENEO® in Healthy Adults

Abstract Introduction Intramuscular (IM) midazolam is indicated for the treatment of status epilepticus. Administration must be efficient to rapidly terminate prolonged seizures and prevent complications. The objective of this study was to compare, in terms of relative bioavailability and bioequivalence, IM midazolam injection by needle-free auto-injector, in different settings, to IM midazolam injection by a conventional syringe and needle. Methods In this open-label, randomized, four-period crossover study, healthy adults received single doses of midazolam (10 mg) under fasting conditions. The reference treatment (conventional syringe) was administered once, on bare skin in the thigh. The tested treatment (the needle-free auto-injector ZENEO®) was administered three times: on bare skin in the thigh, on bare skin in the ventrogluteal area, and through clothing in the thigh. Repeated plasma samples were collected to obtain 36-h pharmacokinetic (PK) profiles. Primary PK parameters were area under the plasma concentration–time curve, from time zero to the last measurable time point (AUC0−t) and from time zero to infinity (AUC0–∞), and the maximum observed plasma concentration (C max). Results Forty adults were enrolled and included in the PK analysis set. In all comparisons, the 90% confidence interval (CI) of the least-squares geometric mean ratios for AUC0−t and AUC0−∞ were within the bioequivalence range of 80–125%, with low intra-individual coefficients of variation (< 20.5% for all parameters in all comparisons). Bioequivalence was also met for C max in all comparisons except when comparing the tested treatment through clothing versus the reference treatment, where the 90% CI lower limit was slightly outside the bioequivalence range (78.8%). With all tested treatments C max was slightly lower, but early mean plasma concentrations (first 10 min post-dosing) were higher when compared to the reference treatment. In general, all treatments were well tolerated, with maximum sedation 0.5–1 h post-injection. Discussion/Conclusion This study establishes that IM midazolam injection on bare skin in the thigh with the ZENEO® is bioequivalent to IM midazolam injection with a syringe and needle. An acceptable relative bioavailability, compatible with emergency practice, was also shown in multiple settings. Higher mean concentrations within the first 10 min with the ZENEO® device, and quicker two-step injection suggest a faster onset of action, and thereby an earlier seizure termination, thus preventing the occurrence of prolonged seizure and neurological complications. Trial Registration Information ClinicalTrials.gov identifier: NCT05026567. Registration first posted August 30, 2021, first patient enrolled May 9, 2022