Efficacy and safety of Bacillus clausii (O/C, N/R, SIN, T) probiotic combined with oral rehydration therapy (ORT) and zinc in acute diarrhea in children: a randomized, double-blind, placebo-controlled study in India.

BACKGROUND: Childhood diarrhea remains a major disease burden, particularly in developing countries, and is a leading cause of death in children aged < 5 years, worldwide. Treatment of acute diarrhea now includes probiotics to potentially reduce the duration and severity of the illness. This phase 3, randomized, placebo-controlled, double-blind study assessed the efficacy and safety of four strains (O/C, N/R, SIN, T) of Bacillus clausii probiotic (Enterogermina®) plus oral rehydration therapy (ORT) and zinc, versus placebo plus ORT and zinc, in infants and children in India with acute moderate diarrhea. METHODS: Patients aged 6 months to 5 years with acute moderate diarrhea (WHO 2005 definition) of < 48 h' duration were randomly assigned to receive one mini bottle of either polyantibiotic-resistant B. clausii (oral suspension of 2 billion spores per 5 mL bottle) or matching placebo twice daily (morning and evening) for 5 days. Exclusion criteria included known hypersensitivity to B. clausii or excipients in the study treatment, or to other probiotics. Patients were admitted to hospital from Day 1 and discharged ≥6 h after diarrhea resolution, or a maximum of 5 days. The primary endpoint was duration of acute diarrhea from randomization to recovery. Secondary endpoints included frequency of stools, diapers with stools, or dehydration status. RESULTS: In total, 457 patients were randomized; 454 were treated. Similar proportions of patients showed recovery from diarrhea over the 120 h after randomization (97.0% in the B. clausii group [n = 227]; 98.0% on placebo [n = 227]). Median time to recovery was also similar: 42.83 (95% CI: 40.90-44.90) hours for B. clausii and 42.13 (95% CI: 39.80-43.87) hours for placebo. However, no statistically significant difference was observed between groups (hazard ratio = 0.93 [95% CI: 0.77-1.13]; p = 0.6968); nor were there statistically significant differences between groups for the secondary endpoints. Treatment with B. clausii was well tolerated with incidence of adverse events (9.7%) similar to that for placebo (12.3%). CONCLUSIONS: No significant difference in efficacy between B. clausii and placebo was demonstrated. Sample size may have been inadequate to allow detection of a between-group difference in efficacy, given the mild/moderate severity (only ~ 20% of patients had nausea/vomiting or abdominal pains) and short duration of disease among subjects, the relatively late start of treatment (most were already on Day 2 of their disease episode when study treatment started) and the effectiveness of the standard of care with ORT and zinc in both treatment groups. TRIAL REGISTRATION: CTRI number CTRI/2018/10/016053 . Registered on 17 October 2018. EudraCT number 2016-005165-31 . Registered 14 May 2020 (retrospectively registered).

Developing a Novel Measurement of Sleep in Rheumatoid Arthritis: Study Proposal for Approach and Considerations.

The development of novel digital endpoints (NDEs) using digital health technologies (DHTs) may provide opportunities to transform drug development. It requires a multidisciplinary, multi-study approach with strategic planning and a regulatory-guided pathway to achieve regulatory and clinical acceptance. Many NDEs have been explored; however, success has been limited. To advance industry use of NDEs to support drug development, we outline a theoretical, methodological study as a use-case proposal to describe the process and considerations when developing and obtaining regulatory acceptance for an NDE to assess sleep in patients with rheumatoid arthritis (RA). RA patients often suffer joint pain, fatigue, and sleep disturbances (SDs). Although many researchers have investigated the mobility of joint functions using wearable technologies, the research of SD in RA has been limited due to the availability of suitable technologies. We proposed measuring the improvement of sleep as the novel endpoint for an anti-TNF therapy and described the meaningfulness of the measure, considerations of tool selection, and the design of clinical validation. The recommendations from the FDA patient-focused drug development guidance, the Clinical Trials Transformation Initiative (CTTI) pathway for developing novel endpoints from DHTs, and the V3 framework developed by the Digital Medicine Society (DiMe) have been incorporated in the proposal. Regulatory strategy and engagement pathways are also discussed.

Baseline characteristics of participants in the LANDMARC trial: A 3-year, pan-india, prospective, longitudinal study to assess management and real-world outcomes of diabetes mellitus.

INTRODUCTION: Longitudinal data on progression, complications, and management of type 2 diabetes mellitus (T2DM) across India are scarce. LANDMARC (CTRI/2017/05/008452), the first pan-India, longitudinal, prospective, observational study, aims to understand the management and real-world outcomes of T2DM over 3 years. METHODS: Adults (≥25 to ≤60 years old at T2DM diagnosis; diabetes duration ≥2 years at enrollment; controlled/uncontrolled on ≥2 anti-diabetic agents) were enrolled. Baseline characteristics were analyzed using descriptive statistics. RESULTS: Of the 6279 recruited participants, 6236 were eligible for baseline assessment (56.6% [n/N = 3528/6236] men; mean ± SD age: 52.1 ± 9.2 years, diabetes duration: 8.6 ± 5.6 years). mean ± SD HbA1c, fasting plasma glucose, and postprandial glucose values were 64 ± 17 mmol/mol (8.1 ± 1.6%), 142.8 ± 50.4 mg/dl, and 205.7 ± 72.3 mg/dl, respectively. Only 25.1% (n/N = 1122/6236) participants had controlled glycemia (HbA1c < 53 mmol/mol, <7%). Macrovascular and microvascular complications were prevalent in 2.3% (n/N = 145/6236) and 14.5% (n/N = 902/6236) participants, respectively. Among those with complications, non-fatal myocardial infarction (n/N = 74/145, 51.0%) and neuropathy (n/N = 737/902, 81.7%) were the most reported macrovascular and microvascular complication, respectively. Hypertension (n/N = 2566/3281, 78.2%) and dyslipidemia (n/N = 1635/3281, 49.8%) were the most reported cardiovascular risks. Majority (74.5%; n/N = 4643/6236) were taking oral anti-diabetic drugs (OADs) only, while 24.4% (n/N = 1522/6236) participants were taking OADs+insulin. Biguanides (n/N = 5796/6236, 92.9%) and sulfonylureas (n/N = 4757/6236, 76.3%) were the most reported OADs. Basal (n/N = 837/6236, 13.4%) and premix (n/N = 684/6236, 11.0%) insulins were the most reported insulins. CONCLUSIONS: Baseline data from LANDMARC help understand the clinical/medical profile of study participants and underscore the extent of suboptimal glycemic control and prevalence of associated complications in a vast majority of Indians with T2DM.

Development and content validation of the Pediatric Oral Medicines Acceptability Questionnaires (P-OMAQ): patient-reported and caregiver-reported outcome measures.

BACKGROUND: Evolving regulatory guidelines recommend routine assessment of the acceptability of pediatric oral medicines throughout clinical development processes. However, such assessment is problematic owing to a lack of standard methods or criteria that define acceptability for children and their caregivers. This research aimed to identify the attributes of acceptability for targeted oral formulation types that are important to children, and to develop content-valid patient- and caregiver-reported outcome acceptability measures for use in the context of clinical drug development. METHODS: A concept-focused literature review and two advisory panel meetings involving researchers, clinicians, and measurement scientists were conducted to identify acceptability attributes that may be relevant to children taking targeted oral medicine formulations. The Pediatric Oral Medicines Acceptability Questionnaires (P-OMAQs), including patient (P-OMAQ-P) and caregiver (P-OMAQ-C) versions, were drafted to assess these attributes. Qualitative concept elicitation (CE) and cognitive debriefing (CD) patient and caregiver interviews were conducted to confirm key acceptability attribute concepts for measurement and to evaluate patient and caregiver ability to understand and respond to the questions. RESULTS: A full-text review of 40 articles identified 24 acceptability attributes that were categorized into 10 overarching domains and organized into a preliminary conceptual model. Feedback from the advisory panel refined the preliminary model. In total, 14 attributes were reported during the CE phase of the interviews (n = 23 pediatric patients, n = 13 caregivers); six attributes were included in the final model. The draft P-OMAQ was refined over four waves of CD interviews (n = 31 pediatric patients, n = 48 caregivers). The final version of the P-OMAQ-P is a 12-item questionnaire designed for young people aged 8-17 years. The P-OMAQ-C is a 19-item questionnaire designed for adult caregivers of young people aged 6 months to 17 years. There are two versions of each questionnaire: one with a 24-h recall period and one with a 7-day recall period. All items are answered on a 5-point numerical rating scale. CONCLUSIONS: This research supports the content validity of the patient and caregiver versions of the P-OMAQ. Both questionnaires appropriately assess the acceptability of oral medicine formulations from the perspective of pediatric patients and their caregivers.