Using dichotomized survival data to construct a prior distribution for a Bayesian seamless Phase II/III clinical trial

Master protocol designs allow for simultaneous comparison of multiple treatments or disease subgroups. Master protocols can also be designed as seamless studies, in which two or more clinical phases are considered within the same trial. They can be divided into two categories: operationally seamless, in which the two phases are separated into two independent studies, and inferentially seamless, in which the interim analysis is considered an adaptation of the study. Bayesian designs are scarcely studied. Our aim is to propose and compare Bayesian operationally seamless Phase II/III designs using a binary endpoint for the first stage and a time-to-event endpoint for the second stage. At the end of Phase II, arm selection is based on posterior (futility) and predictive (selection) probabilities. The results of the first phase are then incorporated into prior distributions of a time-to-event model. Simulation studies showed that Bayesian operationally seamless designs can approach the inferentially seamless counterpart, allowing for an increasing simulated power with respect to the operationally frequentist design

Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A <i>ND4</i> Mutation: Systematic Review and Indirect Comparison.

Objective: This work aimed to compare the evolution of visual outcomes in Leber hereditary optic neuropathy (LHON) patients treated with intravitreal gene therapy to the spontaneous evolution in prior natural history (NH) studies. Design: A combined analysis of two phase three randomized, double-masked, sham-controlled studies (REVERSE and RESCUE) and their joint long-term extension trial (CLIN06) evaluated the efficacy of rAAV2/2-ND4 vs. 11 pooled NH studies used as an external control. Subjects: The LHON subjects carried the m.11778G>A ND4 mutation and were aged ≥15 years at onset of vision loss. Methods: A total of 76 subjects received a single intravitreal rAAV2/2-ND4 injection in one eye and sham injection in the fellow eye within 1 year after vision loss in REVERSE and RESCUE. Both eyes were considered as treated due to the rAAV2/2-ND4 treatment efficacy observed in the contralateral eyes. Best corrected visual acuity (BCVA) from REVERSE, RESCUE, and CLIN06 up to 4.3 years after vision loss was compared to the visual acuity of 208 NH subjects matched for age and ND4 genotype. The NH subjects were from a LHON registry (REALITY) and from 10 NH studies. A locally estimated scatterplot smoothing (LOESS), non-parametric, local regression model was used to modelize visual acuity curves over time, and linear mixed model was used for statistical inferences. Main Outcome Measures: The main outcome measure was evolution of visual acuity from 12 months after vision loss, when REVERSE and RESCUE patients had been treated with rAAV2/2-ND4. Results: The LOESS curves showed that the BCVA of the treated patients progressively improved from month 12 to 52 after vision loss. At month 48, there was a statistically and clinically relevant difference in visual acuity of -0.33 logarithm of the minimal angle of resolution (LogMAR) (16.5 ETDRS letters equivalent) in favor of treated eyes vs. NH eyes (p p p Conclusions: The m.11778G>A LHON patients treated with rAAV2/2-ND4 exhibited an improvement of visual acuity over more than 4 years after vision loss to a degree not demonstrated in NH studies. Clinical Trial Registration: NCT02652767, NCT02652780, NCT03406104, and NCT03295071

Indirect Comparison of Lenadogene Nolparvovec Gene Therapy Versus Natural History in Patients with Leber Hereditary Optic Neuropathy Carrying the m.11778G\u3eA MT-ND4 Mutation

INTRODUCTION: Lenadogene nolparvovec is a promising novel gene therapy for patients with Leber hereditary optic neuropathy (LHON) carrying the m.11778G\u3eA ND4 mutation (MT-ND4). A previous pooled analysis of phase 3 studies showed an improvement in visual acuity of patients injected with lenadogene nolparvovec compared to natural history. Here, we report updated results by incorporating data from the latest phase 3 trial REFLECT in the pool, increasing the number of treated patients from 76 to 174. METHODS: The visual acuity of 174 MT-ND4-carrying patients with LHON injected in one or both eyes with lenadogene nolparvovec from four pooled phase 3 studies (REVERSE, RESCUE and their long-term extension trial RESTORE; and REFLECT trial) was compared to the spontaneous evolution of an external control group of 208 matched patients from 11 natural history studies. RESULTS: Treated patients showed a clinically relevant and sustained improvement in their visual acuity when compared to natural history. Mean improvement versus natural history was - 0.30 logMAR (+ 15 ETDRS letters equivalent) at last observation (P \u3c 0.01) with a maximal follow-up of 3.9 years after injection. Most treated eyes were on-chart as compared to less than half of natural history eyes at 48 months after vision loss (89.6% versus 48.1%; P \u3c 0.01) and at last observation (76.1% versus 44.4%; P \u3c 0.01). When we adjusted for covariates of interest (gender, age of onset, ethnicity, and duration of follow-up), the estimated mean gain was - 0.43 logMAR (+ 21.5 ETDRS letters equivalent) versus natural history at last observation (P \u3c 0.0001). Treatment effect was consistent across all phase 3 clinical trials. Analyses from REFLECT suggest a larger treatment effect in patients receiving bilateral injection compared to unilateral injection. CONCLUSION: The efficacy of lenadogene nolparvovec in improving visual acuity in MT-ND4 LHON was confirmed in a large cohort of patients, compared to the spontaneous natural history decline. Bilateral injection of gene therapy may offer added benefits over unilateral injection. TRIAL REGISTRATION NUMBERS: NCT02652780 (REVERSE); NCT02652767 (RESCUE); NCT03406104 (RESTORE); NCT03293524 (REFLECT); NCT03295071 (REALITY)

Depression in Patients with Mastocytosis: Prevalence, Features and Effects of Masitinib Therapy

Depression in patients with mastocytosis is often reported but its prevalence and characteristics are not precisely described. In addition, the impact of therapies targeting mast cells proliferation, differentiation and degranulation on psychic symptoms of depression have never been investigated. Our objective was to determine the prevalence and to describe features of depression in a large cohort of mastocytosis patients (n = 288) and to investigate the therapeutic impact of the protein kinase inhibitor masitinib in depression symptoms. The description of depression was based on the analysis of a database with Hamilton scores using Principal Component Analysis (PCA). Efficacy of masitinib therapy was evaluated using non parametric Wilcoxon test for paired data within a three months period (n = 35). Our results show that patients with indolent mastocytosis present an elevated prevalence of depression (64%). Depression was moderate in 56% but severe in 8% of cases. Core symptoms (such as psychic anxiety, depressed mood, work and interests) characterized depression in mastocytosis patients. Masitinib therapy was associated with significant improvement (67% of the cases) of overall depression, with 75% of recovery cases. Global Quality of Life slightly improved after masitinib therapy and did not predicted depression improvement. In conclusion, depression is very frequent in mastocytosis patients and masitinib therapy is associated with the reduction its psychic experiences. We conclude that depression in mastocytosis may originate from processes related to mast cells activation. Masitinib could therefore be a useful treatment for mastocytosis patients with depression and anxiety symptoms

Résultats de l'étude observationnelle EPIGRAM : prise en charge de l'obésité et du surpoids en médecine générale, suivi de la cohorte traitée par l'orlistat

L'étude pharmacoépidémiologique EPIGRAM a été mise en place auprès de médecins généralistes (MG) prescripteurs d'orlistat (Xenical®) dans le but de décrire, en situation réelle, la prise en charge des patients obèses ou en surpoids et le suivi sur un an des patients traités par orlistat. Sept cent quatorze MG ont participé à cette étude et ont inclus 6801 patients dont 40 % traités par orlistat, 76 % étaient des femmes et 63 % souffraient de comorbidités. Avec un indice de masse corporelle (IMC) moyen de 33,1 ± 5,1 kg/m2, les patients traités par orlistat correspondaient pour 85 % aux indications du médicament. La comparaison des patients traités ou non par orlistat n'a permis d'identifier aucun facteur majeur prédictif de la prescription du traitement. Les patients traités par orlistat à l'inclusion et revus au moins une fois par leur médecin ont été suivis par celui-ci 11 mois en moyenne avec un maximum de 23 mois. Entre 64 % et 77 % des patients ont arrêté le traitement par orlistat sur la période de suivi. Le coût thérapeutique était une raison d'arrêt plus fréquente avec 50 % des cas. La perte de poids était en moyenne de 5 % et 9 % à 3 mois et 12 mois de traitement, respectivement

Diet and Disease Activity in Patients with Axial Spondyloarthritis: SpondyloArthritis and NUTrition Study (SANUT)

Axial Spondyloarthritis (axSpA) patients with inflamed intestines have higher SpA activity. Diets that modulate microbiota may influence inflammation and SpA activity. Today, data concerning the impact of diet on SpA activity are scarce. SANUT was a single-center, noninterventional, cohort study that assessed dietetic profiles associated with SpA activity in axSpA. Demographic, clinical, SpA-related, quality of life (QoL), fatigue, physical activity, and dietary data were collected. SpA activity was assessed by Ankylosing Spondylitis Disease Activity Score (ASDAS) and by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). We assessed whether high SpA activity was associated with nutriment consumption. Between 12 February 2018 and 12 February 2020, 278 patients participated. High SpA activity, as measured by ASDAS and BASDAI, was significantly associated with higher body mass index and waist circumference, negative HLA-B27, lower QoL, higher fatigue, and higher digestive-symptom scores. Furthermore, high SpA activity, as measured by BASDAI, was associated with female sex, smoking status, patients who were not actively employed, reduced physical activity, and high intake of ultra-transformed foods, while high SpA activity, as measured by ASDAS, was associated with low intake of omega-3 PUFAs and fiber. Therefore, low intakes of omega-3 PUFAs and fiber, and high intake of ultra-transformed foods, are associated with high SpA activity

Citrulline in the management of patients with urea cycle disorders

Abstract Background Treatment recommendations for urea cycle disorders (UCDs) include supplementation with amino acids involved in the urea cycle (arginine and/or citrulline, depending on the enzyme deficiency), to maximize ammonia excretion through the urea cycle, but limited data are available regarding the use of citrulline. This study retrospectively reviewed clinical and biological data from patients with UCDs treated with citrulline and/or arginine at a reference center since 1990. The aim was to describe the prescription, impact, and safety of these therapies. Data collection included patient background, treatment details, changes in biochemical parameters (plasma ammonia and amino acids concentrations), decompensations, and patient outcomes. Results Overall, 79 patients (median age at diagnosis, 0.9 months) received citrulline and/or arginine in combination with a restricted protein diet, most with ornithine transcarbamylase (n = 57, 73%) or carbamoyl phosphate synthetase 1 (n = 15, 19%) deficiencies. Most patients also received ammonium scavengers. Median follow-up was 9.5 years and median exposure to first treatment with arginine + citrulline, citrulline monotherapy, or arginine monotherapy was 5.5, 2.5, or 0.3 years, respectively. During follow-up, arginine or citrulline was administered at least once (as monotherapy or in combination) in the same proportion of patients (86.1%); the overall median duration of exposure was 5.9 years for arginine + citrulline, 3.1 years for citrulline monotherapy, and 0.6 years for arginine monotherapy. The most common switch was from monotherapy to combination therapy (41 of 75 switches, 54.7%). During treatment, mean ammonia concentrations were 35.9 µmol/L with citrulline, 49.8 µmol/L with arginine, and 53.0 µmol/L with arginine + citrulline. Mean plasma arginine concentrations increased significantly from the beginning to the end of citrulline treatment periods (from 67.6 µmol/L to 84.9 µmol/L, P < 0.05). At last evaluation, mean height and weight for age were normal and most patients showed normal or adapted behavior (98.7%) and normal social life (79.0%). Two patients (2.5%) experienced three treatment-related gastrointestinal adverse reactions. Conclusions This study underlines the importance of citrulline supplementation, either alone or together with arginine, in the management of patients with UCDs. When a monotherapy is considered, citrulline would be the preferred option in terms of increasing plasma arginine concentrations

Identification of Cx43 variants predisposing to ventricular fibrillation in the acute phase of ST-elevation myocardial infarction

International audienceAbstract Aims Ventricular fibrillation (VF) occurring in the acute phase of ST-elevation myocardial infarction (STEMI) is the leading cause of sudden cardiac death worldwide. Several studies showed that reduced connexin 43 (Cx43) expression and reduced conduction velocity increase the risk of VF in acute myocardial infarction (MI). Furthermore, genetic background might predispose individuals to primary VF (PVF). The primary objective was to evaluate the presence of GJA1 variants in STEMI patients. The secondary objective was to evaluate the arrhythmogenic impact of GJA1 variants in STEMI patients with VF. Methods and results The MAP-IDM prospective cohort study included 966 STEMI patients and was designed to identify genetic predisposition to VF. A total of 483 (50.0%) STEMI patients with PVF were included. The presence of GJA1 variants increased the risk of VF in STEMI patients [from 49.1 to 70.8%, P = 0.0423; odds ratio (OR): 0.40; 95% confidence interval: 0.16–0.97; P = 0.04]. The risk of PVF decreased with beta-blocker intake (from 53.5 to 44.8%, P = 0.0085), atrial fibrillation (from 50.7 to 26.4%, P = 0.0022), and with left ventricular ejection fraction &gt;50% (from 60.2 to 41.4%, P &lt; 0.0001). Among 16 GJA1 variants, three novel heterozygous missense variants were identified in three patients: V236I, H248R, and I327M. In vitro studies of these variants showed altered Cx43 localization and decreased cellular communication, mainly during acidosis. Conclusion Connexin 43 variants are associated with increased VF susceptibility in STEMI patients. Restoring Cx43 function may be a potential therapeutic target to prevent PVF in patients with acute MI. Clinical trial registration Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT0085930