Treatment Strategy for Rifampin-Susceptible Tuberculosis.

BACKGROUND: Tuberculosis is usually treated with a 6-month rifampin-based regimen. Whether a strategy involving shorter initial treatment may lead to similar outcomes is unclear. METHODS: In this adaptive, open-label, noninferiority trial, we randomly assigned participants with rifampin-susceptible pulmonary tuberculosis to undergo either standard treatment (rifampin and isoniazid for 24 weeks with pyrazinamide and ethambutol for the first 8 weeks) or a strategy involving initial treatment with an 8-week regimen, extended treatment for persistent clinical disease, monitoring after treatment, and retreatment for relapse. There were four strategy groups with different initial regimens; noninferiority was assessed in the two strategy groups with complete enrollment, which had initial regimens of high-dose rifampin-linezolid and bedaquiline-linezolid (each with isoniazid, pyrazinamide, and ethambutol). The primary outcome was a composite of death, ongoing treatment, or active disease at week 96. The noninferiority margin was 12 percentage points. RESULTS: Of the 674 participants in the intention-to-treat population, 4 (0.6%) withdrew consent or were lost to follow-up. A primary-outcome event occurred in 7 of the 181 participants (3.9%) in the standard-treatment group, as compared with 21 of the 184 participants (11.4%) in the strategy group with an initial rifampin-linezolid regimen (adjusted difference, 7.4 percentage points; 97.5% confidence interval [CI], 1.7 to 13.2; noninferiority not met) and 11 of the 189 participants (5.8%) in the strategy group with an initial bedaquiline-linezolid regimen (adjusted difference, 0.8 percentage points; 97.5% CI, -3.4 to 5.1; noninferiority met). The mean total duration of treatment was 180 days in the standard-treatment group, 106 days in the rifampin-linezolid strategy group, and 85 days in the bedaquiline-linezolid strategy group. The incidences of grade 3 or 4 adverse events and serious adverse events were similar in the three groups. CONCLUSIONS: A strategy involving initial treatment with an 8-week bedaquiline-linezolid regimen was noninferior to standard treatment for tuberculosis with respect to clinical outcomes. The strategy was associated with a shorter total duration of treatment and with no evident safety concerns. (Funded by the Singapore National Medical Research Council and others; TRUNCATE-TB ClinicalTrials.gov number, NCT03474198.).

Adjunctive pascolizumab in rifampicin-susceptible pulmonary tuberculosis: proof-of-concept, partially-randomised, double-blind, placebo-controlled, dose-escalation trial.

BACKGROUND: Interleukin-4 (IL-4), increased in tuberculosis infection, may impair bacterial killing. Blocking IL-4 confers benefit in animal models. We evaluated safety and efficacy of pascolizumab (humanised anti-IL-4 monoclonal antibody) as adjunctive tuberculosis treatment. METHODS: Participants with rifampicin-susceptible pulmonary tuberculosis received a single intravenous infusion of pascolizumab or placebo; and standard 6-month tuberculosis treatment. Pascolizumab dose increased in successive cohorts: [1] non-randomised 0.05 mg/kg (n = 4); [2] non-randomised 0.5 mg/kg (n = 4); [3] randomised 2.5 mg/kg (n = 9) or placebo (n = 3); [4] randomised 10 mg/kg (n = 9) or placebo (n = 3). Co-primary safety outcome was study-drug-related grade 4 or serious adverse event (G4/SAE); in all cohorts (1-4). Co-primary efficacy outcome was week-8 sputum culture time-to-positivity (TTP); in randomised cohorts (3-4) combined. RESULTS: Pascolizumab levels exceeded IL-4 50% neutralising dose for 8 weeks in 78-100% of participants in cohorts 3-4. There were no study-drug-related G4/SAEs. Median week-8 TTP was 42 days in pascolizumab and placebo groups (p = 0.185). Rate of TTP increase was greater with pascolizumab (difference from placebo 0.011 [95% Bayesian credible interval 0.006 to 0.015] log10TTP/day. CONCLUSIONS: There was no evidence to suggest blocking IL-4 was unsafe. Preliminary efficacy findings are consistent with animal models. This supports further investigation of adjunctive anti-IL-4 interventions for tuberculosis in larger phase 2 trials.

Effects of Increasing Concentrations of Rifampicin on Different Mycobacterium tuberculosis Lineages in a Whole-Blood Bactericidal Activity Assay.

High-dose rifampicin improved bactericidal activity and culture conversion in early-phase tuberculosis (TB) trials, done mainly in Africa. We performed a whole-blood bactericidal activity (WBA) study to determine whether the effects of high-dose rifampicin differ across globally relevant TB strains and whether effects are similar in dormant bacilli that will be required for enhancing cure. Whole blood from healthy volunteers was spiked with rifampicin (range, 0.63 to 60 mg/L) and incubated with one of four Mycobacterium tuberculosis clinical strains (Haarlem, Latin American-Mediterranean [LAM], East African-Indian [EAI], and Beijing lineages) or a dormant strain (streptomycin-starved 18b [ss18b]). Change in bacterial CFU was estimated after inoculation of WBA cultures in MGIT. WBA increased with higher concentrations of rifampicin in all strains. At rifampicin concentrations up to 5 mg/L, the rates of increase in WBA per unit increase in rifampicin concentration were similar in all 4 clinical strains (P > 0.51). Above 5 mg/L, EAI (P < 0.001) and Beijing (P = 0.007) strains showed greater increases in WBA than did LAM; Haarlem was similar to LAM. The dormant strain showed a lower rate of increase in WBA than clinical strains at rifampicin concentrations up to 5 mg/L; above 5 mg/L, the rate of increase was similar to those in the LAM, Beijing, and Haarlem strains. Increasing rifampicin concentration enhanced WBA in all strains; the greatest effects were seen in strains common in Asia, suggesting that early-phase trial findings may be generalizable beyond Africa. Similar effects of high concentrations of rifampicin on the dormant strain support the concept that this intervention may enhance sterilizing activity.

The Singapore Asymptomatic Narrow Angles Laser Iridotomy Study: Five-Year Results of a Randomized Controlled Trial.

PURPOSE: To examine the efficacy of laser peripheral iridotomy (LPI) in patients who received a diagnosis of primary angle-closure suspect (PACS). DESIGN: Prospective, randomized controlled trial. PARTICIPANTS: This multicenter, randomized controlled trial (ClinicalTrials.gov identifier, NCT00347178) enrolled 480 patients older than 50 years from glaucoma clinics in Singapore with bilateral asymptomatic PACS (defined as having ≥2 quadrants of appositional angle closure on gonioscopy). METHODS: Each participant underwent prophylactic LPI in 1 randomly selected eye, whereas the fellow eye served as a control. Patients were followed up yearly for 5 years. MAIN OUTCOME MEASURES: The primary outcome measure was development of primary angle closure (PAC; defined as presence of peripheral anterior synechiae, intraocular pressure [IOP] of >21 mmHg, or both or acute angle closure [AAC]) or primary angle-closure glaucoma (PACG) over 5 years. RESULTS: Of the 480 randomized participants, most were Chinese (92.7%) and were women (75.8%) with mean age of 62.8 ± 6.9 years. Eyes treated with LPI reached the end point less frequently after 5 years (n = 24 [5.0%]; incidence rate [IR], 11.65 per 1000 eye-years) compared with control eyes (n = 45 [9.4%]; IR, 21.84 per 1000 eye-years; P = 0.001). The adjusted hazard ratio (HR) for progression to PAC was 0.55 (95% confidence interval [CI], 0.37-0.83; P = 0.004) in LPI-treated eyes compared with control eyes. Older participants (per year; HR, 1.06; 95% CI, 1.03-1.10; P < 0.001) and eyes with higher baseline IOP (per millimeter of mercury; HR, 1.35; 95% CI, 1.22-1.50; P < 0.0001) were more likely to reach an end point. The number needed to treat to prevent an end point was 22 (95% CI, 12.8-57.5). CONCLUSIONS: In patients with bilateral asymptomatic PACS, eyes that underwent prophylactic LPI reached significantly fewer end points compared with control eyes over 5 years. However, the overall incidence of PAC or PACG was low.

Frequency and Clinical Impact of Serious Adverse Events on Post-Stroke Recovery with NeuroAiD (MLC601) versus Placebo: The CHInese Medicine Neuroaid Efficacy on Stroke Recovery Study.

BACKGROUND: Most comparative clinical trials are designed to assess the treatment effect for efficacy endpoints, with less emphasis on the analysis of safety outcomes. However, an extensive analysis of safety data could demonstrate beneficial results in terms of effectiveness by reducing serious adverse events (SAEs), and their unfavourable clinical impact on the study population. We aimed to conduct an exploratory analysis of the CHInese Medicine Neuroaid Efficacy on Stroke recovery (CHIMES) study safety database comparing the frequency of SAEs and their clinical impacts among subjects having received MLC601 or placebo during the first 3 months post-stroke. METHODS: Analyses were performed by using the safety database of the multicentre, randomised, double-blind, placebo-controlled CHIMES study of 3 months of NeuroAiD versus placebo in subjects with acute ischaemic stroke of intermediate severity in the preceding 72 h. SAEs as reported by investigators at any time-point during the 3-month study were analysed on their frequency and that of any of their outcomes (death, and life threatening, new and/or prolonged hospitalisation, disability, and medical importance, in surviving subjects), as well as their time to onset and resolution. RESULTS: Of the 1,099 subjects in the CHIMES study, 1,087 were included in the safety analysis (MLC601 = 542) and (placebo = 545); the 12 who did not receive study treatment were excluded. There was a total of 135 subjects with SAEs (MLC601 = 60, placebo = 75). At baseline, overall, subjects with SAEs were older and had lower MMSE score. In the MLC601 group, they had higher NIHSS score, and more frequently a history of ischaemic heart disease and hyperlipidaemia. The number of SAEs per subjects was statistically significantly lower in the MLC601 group than placebo one, especially for subjects with ≥2 SAEs (6.7 vs. 29.3%; p < 0.001). This benefit was seen throughout the study period and during the initial hospitalisation. The main clinical impact of SAEs was an increase in hospitalisation time, reduced in the MLC601 arm with the rate of subjects hospitalised for a prolonged period being significantly threefold lower in surviving subjects (1.1 vs. 3.7%; p < 0.01). CONCLUSIONS: This post hoc analysis of SAEs from the CHIMES study database shows that subjects receiving a 3-month course of MLC601 experienced fewer SAEs, with lower rates of harmful clinical impacts, especially in terms of hospitalisation duration. These findings could translate to a benefit in terms of reduction of both healthcare burden and additional medical costs.

Coadministration of Allopurinol To Increase Antimycobacterial Efficacy of Pyrazinamide as Evaluated in a Whole-Blood Bactericidal Activity Model.

Coadministering pyrazinamide (PZA) with the xanthine oxidase inhibitor allopurinol increases systemic levels of the active metabolite, pyrazinoic acid (POA), but the effects on bactericidal activity against tuberculosis are unknown. We randomized healthy volunteers to take a single dose of PZA (either 10 or 25 mg/kg of body weight) at the first visit and the same dose 7 days later, coadministered with allopurinol (100 mg daily; 2 days before to 1 day after the PZA dose). Blood was drawn at intervals until 48 h after each PZA dose, and drug levels were measured using liquid chromatography-tandem mass spectrometry. Whole-blood bactericidal activity (WBA) was measured by inoculating blood samples with Mycobacterium tuberculosis and estimating the change in bacterial CFU after 72 h of incubation. Allopurinol increased the POA area under the concentration-time curve from 0 to 8 h (AUC0-8) (18.32 h · µg/ml versus 24.63 h · µg/ml for PZA alone versus PZA plus allopurinol) (P < 0.001) and its peak plasma concentration (Cmax) (2.81 µg/ml versus 4.00 µg/ml) (P < 0.001). There was no effect of allopurinol on mean cumulative WBA (0.01 ± 0.02 ΔlogCFU versus 0.00 ± 0.02 ΔlogCFU for PZA alone versus PZA plus allopurinol) (P = 0.49). Higher systemic POA levels were associated with greater WBA levels (P < 0.001), but the relationship was evident only at low POA concentrations. The lack of an effect of allopurinol on WBA despite a significant increase in blood POA levels suggests that host-generated POA may be less effective than POA generated inside bacteria. Coadministration of allopurinol does not appear to be a useful strategy for increasing the efficacy of PZA in clinical practice. (This study has been registered at ClinicalTrials.gov under registration no. NCT02700347.).

Activity of faropenem with and without rifampicin against Mycobacterium tuberculosis: evaluation in a whole-blood bactericidal activity trial.

Background: Faropenem has in vitro activity against Mycobacterium tuberculosis (Mtb) and shows synergy with rifampicin. We tested this in a whole-blood bactericidal activity (WBA) trial. Methods: We randomized healthy volunteers to receive a single oral dose of faropenem (600 mg) with amoxicillin/clavulanic acid (500/125 mg) ( n = 8), rifampicin (10 mg/kg) ( n = 14) or the combination rifampicin + faropenem + amoxicillin/clavulanic acid ( n = 14). Blood was drawn at intervals to 8 h post-dose. Drug levels were measured using LC-tandem MS. WBA was measured by inoculating blood samples with Mtb and estimating the change in bacterial cfu after 72 h. Trial registration: ClinicalTrials.gov (NCT02393586). Results: There was no activity in the faropenem + amoxicillin/clavulanic acid group (cumulative WBA 0.02 Δlog cfu; P = 0.99 versus zero change). There was a suggestion of a trend favouring the rifampicin + faropenem + amoxicillin/clavulanic acid group at 8 h (cumulative WBA -0.19 ±âŸ0.03 and -0.26 ±âŸ0.03 Δlog cfu in the rifampicin and rifampicin + faropenem + amoxicillin/clavulanic acid groups, respectively; P = 0.180), which was significant in the first hour post-dose ( P = 0.032). Faropenem C max and AUC were 5.4 mg/L and 16.2 mg·h/L, respectively, and MIC for Mtb H37Rv was 5-10 mg/L. Conclusions: Faropenem is not active when used alone, possibly due to inadequate plasma levels relative to MIC. However, there was a suggestion of modest synergy with rifampicin that may merit further testing in clinical trials.

Five-Year Clinical Trial on Atropine for the Treatment of Myopia 2: Myopia Control with Atropine 0.01% Eyedrops.

PURPOSE: To compare the safety and efficacy of different concentrations of atropine eyedrops in controlling myopia progression over 5 years. DESIGN: Randomized, double-masked clinical trial. PARTICIPANTS: A total of 400 children originally randomized to receive atropine 0.5%, 0.1%, or 0.01% once daily in both eyes in a 2:2:1 ratio. METHODS: Children received atropine for 24 months (phase 1), after which medication was stopped for 12 months (phase 2). Children who had myopia progression (≥-0.50 diopters [D] in at least 1 eye) during phase 2 were restarted on atropine 0.01% for a further 24 months (phase 3). MAIN OUTCOME MEASURES: Change in spherical equivalent and axial length over 5 years. RESULTS: There was a dose-related response in phase 1 with a greater effect in higher doses, but an inverse dose-related increase in myopia during phase 2 (washout), resulting in atropine 0.01% being most effective in reducing myopia progression at 3 years. Some 24%, 59%, and 68% of children originally in the atropine 0.01%, 0.1%, and 0.5% groups, respectively, who progressed in phase 2 were restarted on atropine 0.01%. Younger children and those with greater myopic progression in year 1 were more likely to require re-treatment. The lower myopia progression in the 0.01% group persisted during phase 3, with overall myopia progression and change in axial elongation at the end of 5 years being lowest in this group (-1.38±0.98 D; 0.75±0.48 mm) compared with the 0.1% (-1.83±1.16 D, P = 0.003; 0.85±0.53 mm, P = 0.144) and 0.5% (-1.98±1.10 D, P < 0.001; 0.87±0.49 mm, P = 0.075) groups. Atropine 0.01% also caused minimal pupil dilation (0.8 mm), minimal loss of accommodation (2-3 D), and no near visual loss compared with higher doses. CONCLUSIONS: Over 5 years, atropine 0.01% eyedrops were more effective in slowing myopia progression with less visual side effects compared with higher doses of atropine.

Emergency Department Management of Sepsis Patients: A Randomized, Goal-Oriented, Noninvasive Sepsis Trial.

STUDY OBJECTIVE: The noninvasive cardiac output monitor and passive leg-raising maneuver has been shown to be reasonably accurate in predicting fluid responsiveness in critically ill patients. We examine whether using a noninvasive protocol would result in more rapid lactate clearance after 3 hours in patients with severe sepsis and septic shock in the emergency department. METHODS: In this open-label randomized controlled trial, 122 adult patients with sepsis and serum lactate concentration of greater than or equal to 3.0 mmol/L were randomized to receive usual care or intravenous fluid bolus administration guided by measurements of change of stroke volume index, using the noninvasive cardiac output monitor after passive leg-raising maneuver. The primary outcome was lactate clearance of more than 20% at 3 hours. Secondary outcomes included mortality, length of hospital and ICU stay, and total hospital cost. Analysis was intention to treat. RESULTS: Similar proportions of patients in the randomized intervention group (70.5%; N=61) versus control group (73.8%; N=61) achieved the primary outcome, with a relative risk of 0.96 (95% confidence interval [CI] 0.77 to 1.19). Secondary outcomes were similar in both groups (P>.05 for all comparisons). Hospital mortality occurred in 6 patients (9.8%) each in the intervention and control groups on or before 28 days (relative risk=1.00; 95% CI 0.34 to 2.93). Among a subgroup of patients with underlying fluid overload states, those in the intervention group tended to receive clinically significantly more intravenous fluids at 3 hours (difference=975 mL; 95% CI -450 to 1,725 mL) and attained better lactate clearance (difference=19.7%; 95% CI -34.6% to 60.2%) compared with the control group, with shorter hospital lengths of stay (difference=-4.5 days; 95% CI -9.5 to 2.5 days). CONCLUSION: Protocol-based fluid resuscitation of patients with severe sepsis and septic shock with the noninvasive cardiac output monitor and passive leg-raising maneuver did not result in better outcomes compared with usual care. Future studies to demonstrate the use of the noninvasive protocol-based care in patients with preexisting fluid overload states may be warranted.

Supplementation with probiotics in the first 6 months of life did not protect against eczema and allergy in at-risk Asian infants: a 5-year follow-up.

BACKGROUND: Healthy gut microflora is essential for oral tolerance and immunity. A promising approach to preventing allergic diseases in genetically at-risk infants is to introduce administration of probiotics early in life when their immune system is still relatively immature. OBJECTIVE: In this follow-up study, we aim to determine if early-life supplementation with strains of probiotics has any long-term effect on allergic outcomes. METHODS: We analyzed the charts and electronic databases of the PROMPT (Probiotics in Milk for the Prevention of Atopy Trial) study cohort. This cohort consisted of 253 infants at risk for allergy who were administered cow's milk supplemented with or without probiotics from the first day of life to the age of 6 months. The cohort was then followed up until the children were 5 years old and clinical outcomes were assessed. RESULTS: Of the 253 children recruited into the study, 220 (87%) completed the follow-up. At the age of 5 years, there were no significant differences between the groups in the proportion of children who had developed any asthma, allergic rhinitis, eczema, food allergy and sensitization to inhalant allergens. Similar growth rates were observed in both groups. CONCLUSIONS: The supplementation of probiotics in early childhood did not play a role in the prevention of allergic diseases. Clinical/Key Message: Early-life supplementation with probiotics did not change allergic outcomes at 5 years of age.

Rosuvastatin adjunctive therapy for rifampicin-susceptible pulmonary tuberculosis: a phase 2b, randomised, open-label, multicentre trial.

BACKGROUND: Shorter treatments are needed for drug-susceptible tuberculosis. Adjunctive statins increase bactericidal activity in preclinical tuberculosis models. We investigated the safety and efficacy of adjunctive rosuvastatin in people with tuberculosis. We tested the hypothesis that adjunctive rosuvastatin accelerates sputum culture conversion within the first 8 weeks of treatment of rifampicin-susceptible tuberculosis. METHODS: This phase 2b, randomised, open-label, multicentre trial conducted in five hospitals or clinics in three countries with high tuberculosis burden (ie, the Philippines, Viet Nam, and Uganda) enrolled adult participants aged 18-75 years with sputum smear or Xpert MTB/RIF positive, rifampicin-susceptible tuberculosis who had received less than 7 days of previous tuberculosis treatment. Participants were randomly assigned via a web-based system to receive either 10 mg rosuvastatin once per day for 8 weeks plus standard tuberculosis therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol; rosuvastatin group) or standard tuberculosis therapy alone (control group). Randomisation was stratified by trial site, history of diabetes, and HIV co-infection. Laboratory staff and central investigators involved in data cleaning and analysis were masked to treatment allocation, but study participants and site investigators were not. Both groups continued standard treatment to week 24. Sputum samples were collected once per week for the first 8 weeks after randomisation, and then at weeks 10, 12, and 24. The primary efficacy outcome was time to culture conversion (TTCC; days) in liquid culture by week 8, assessed in randomised participants who had microbiological confirmation of tuberculosis, took at least one dose of rosuvastatin, and who did not show resistance to rifampicin (modified intention-to-treat population), for which groups were compared with the Cox proportional hazards model. The main safety outcome was grade 3-5 adverse events by week 24, assessed in the intention-to-treat population, for which groups were compared with Fisher's exact test. All participants completed 24 weeks of follow-up. This trial is registered with ClinicalTrials.gov (NCT04504851). FINDINGS: Between Sept 2, 2020, and Jan 14, 2021, 174 participants were screened and 137 were randomly assigned to the rosuvastatin group (70 participants) or control group (67 participants). In the modified intention-to-treat population of 135 participants, 102 (76%) were men and 33 (24%) were women. Median TTCC in liquid media was 42 days (95% CI 35-49) in the rosuvastatin group (68 participants) and 42 days (36-53) in the control group (67 participants; hazard ratio 1·30 [0·88-1·91], p=0·19). Grade 3-5 adverse events occurred in six (9%) of 70 in the rosuvastatin group (none were considered related to rosuvastatin) and four (6%) of 67 in the control group (p=0·75). There were no serious adverse events that were considered to be related to rosuvastatin. INTERPRETATION: Adjunctive rosuvastatin at 10 mg once per day was safe but did not produce substantive benefits on culture conversion in the overall study population. Future trials could explore the safety and efficacy of higher doses of adjunctive rosuvastatin. FUNDING: National Medical Research Council, Singapore.

Analysis of time-to-event data with nonuniform patient entry and loss to follow-up under a two-stage seamless adaptive design with weibull distribution.

In the pharmaceutical industry, a two-stage seamless adaptive design that combines two separate independent clinical trials into a single clinical study is commonly employed in clinical research and development. In practice, in the interest of shortening the development process, it is not uncommon to consider study endpoints with different treatment durations at different stages (Chow and Chang, 2006 ; Maca et al., 2006 ). In this study, our attention is placed on the case where the study endpoints of interest are time-to-event data where the durations at the two stages are different with nonuniform patient entry and losses to follow-up or dropouts. Test statistics for the final analysis based on the combined data are developed under various hypotheses for testing equality, superiority, noninferiority, and equivalence. In addition, formulas for sample size calculation and allocation between the two stages based on the proposed test statistic are derived.

Alzheimer's Disease THErapy With NEuroaid (ATHENE): A Randomized Double-Blind Delayed-Start Trial.

OBJECTIVES: Preclinical and clinical studies indicate a role for MLC901 (NeuroAiD II) in Alzheimer's disease (AD). The primary aim was to investigate its safety as add-on therapy to standard treatment and the secondary aims its effect on cognition and slowing disease progression. DESIGN: Randomized double-blind placebo-controlled delayed-start study. SETTING AND PARTICIPANT: Patients with mild to moderate probable AD by NINCDS-ADRDA criteria, stable on acetylcholinesterase inhibitors or memantine (n = 125), were randomized to receive MLC901 (early starters) or placebo (delayed starters) for 6 months, followed by a further 6 months when all patients received MLC901, in a delayed-start design (clinical trial registration: ClinicalTrials.gov, NCT03038035). METHODS: The primary outcome measure was occurrence of serious adverse events (SAEs) at 6 months. Secondary outcomes included the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and other assessment scales. RESULTS: There was no significant difference in the risk of SAEs between early and delayed starters at month (M) 6 (22.6% vs 27.0%, risk difference -4.4%, 90% CI -16.9% to 8.3%). Similarly, there was no significant difference in the risk of adverse events and the occurrence of stroke or vascular events between early and delayed starters throughout the 12-month study period. Early starters did not differ significantly on ADAS-Cog from delayed starters at M6 [mean difference (MD) -1.0, 95% CI -3.3 to 1.3] and M12 (MD -2.35, 95% CI -5.45 to 0.74) on intention-to-treat analysis. Other cognitive assessment scales did not show significant differences. CONCLUSIONS AND IMPLICATIONS: This study of 125 persons with dementia found no evidence of a significant increase in adverse events between MLC901 and placebo, thus providing support for further studies on both efficacy and safety. Analyses suggest the potential of MLC901 in slowing down AD progression, but this requires further confirmation in larger and longer studies using biomarkers for AD.

Pre- and apnoeic high-flow oxygenation for rapid sequence intubation in the emergency department (the Pre-AeRATE trial): A multicentre randomised controlled trial.

INTRODUCTION: Evidence regarding the efficacy of high-flow nasal cannula (HFNC) oxygenation for preoxygenation and apnoeic oxygenation is conflicting. Our objective is to evaluate whether HFNC oxygenation for preoxygenation and apnoeic oxygenation maintains higher oxygen saturation (SpO2) during rapid sequence intubation (RSI) in ED patients compared to usual care. METHODS: This was a multicentre, open-label, randomised controlled trial in adult ED patients requiring RSI. Patients were randomly assigned 1:1 to either intervention (HFNC oxygenation at 60L/min) group or control (non-rebreather mask for preoxygenation and nasal prongs of at least 15L/min oxygen flow for apnoeic oxygenation) group. Primary outcome was lowest SpO2 during the first intubation attempt. Secondary outcomes included incidence of SpO2 falling below 90% and safe apnoea time. RESULTS: One hundred and ninety patients were included, with 97 in the intervention and 93 in the control group. Median lowest SpO2 during the first intubation attempt was 100% in both groups. Incidence of SpO2 falling below 90% was lower in the intervention group (15.5%) compared to the control group (22.6%) (adjusted relative risk=0.68, 95% confidence interval [CI] 0.37-1.25). Post hoc quantile regression analysis showed that the first quartile of lowest SpO2 during the first intubation attempt was greater by 5.46% (95% CI 1.48-9.45%, P=0.007) in the intervention group. CONCLUSION: Use of HFNC for preoxygenation and apnoeic oxygenation, when compared to usual care, did not improve lowest SpO2 during the first intubation attempt but may prolong safe apnoea time.

NEURoaid II (MLC901) in cognitively Impaired not demenTEd patientS (NEURITES): A pilot double blind, placebo-controlled randomized trial.

OBJECTIVE: To investigate the efficacy and safety of MLC901 in vascular cognitive impairment no dementia (VCIND) patients. DESIGN: This was a multi-center, double-blind, randomized, placebo-controlled pilot study. SETTING AND PARTICIPANT: VCIND patients from hospitals in Singapore (67), Vietnam (19), and the Philippines (17) were recruited and followed-up from March 2013 to April 2018. METHODS: The primary outcome was executive function as measured by the Verbal Fluency (VF) and 2-part Color Trails Test (CTT). The mean difference in the scores between baseline and week 12, and baseline and week 24, was compared between MLC901 and placebo using a two-sample t-test. RESULTS: The trial randomized 103 subjects: MLC901 (n = 57) and placebo (n = 46). The mean age of participants was 68.3 ± 8.4 years and 38.8% were female. Improvement in executive function with MLC901 was not significantly better than placebo at week 12 (CTT1 mean difference [md] 3.8 seconds, 95% confidence interval [CI]: -9.0 to 16.5, CTT2 md 10.9 seconds, 95% CI: -0.2 to 22.0), and at week 24 (CTT1 md 2.8 seconds, 95% CI: -8.4 to 14.0, CTT2 md = 4.4 seconds, 95% CI: -8.2 to 16.9). Improvement in VF from baseline was not significantly different between MLC901 and placebo at weeks 12 and 24. There were no significant differences in adverse events (43.5% vs. 56.1%) or serious adverse events (13% vs. 22.8%) in placebo versus MLC901 groups. In post hoc exploratory analysis, the treatment effect of MLC901 on cognitive function appears more apparent in subjects with existing impairment in executive function: CTT2 (md 14.4 seconds [P = .05] and 9.9 seconds [P = .3] at week 12 and week 24, respectively). CONCLUSIONS: Whilst MLC901 appears to be safe, there was no significant cognitive benefit from MLC901 in the study population. Post hoc hypotheses generating analyses suggest that VCIND patients with existing impairment in executive function may show benefit.

Analysis of time-to-event data under a two-stage survival adaptive design in clinical trials.

In recent years, the use of a two-stage seamless design in clinical trials has attracted much attention. A two-stage seamless trial design is referred to as a study design that combines two separate clinical studies that are normally conducted to achieve separate objectives, such as a phase II study for treatment selection and a phase III study for efficacy confirmation. Furthermore, it is not uncommon to consider study endpoints with different treatment durations at different stages (see, e.g., Chow and Chang, 2006; Maca et al., 2006). Chow et al. (2007) and Lu et al. (2009) considered the cases where the study endpoints are continuous variables and binary responses, respectively. In this article, our attention is placed on the case where the study endpoints are time-to-event data with different treatment durations. For testing equality, superiority, and noninferiority/equivalence of two treatments, test statistics for the analysis of the combined data collected from the two stages are developed for Weibull distributed data. In addition, formulas for sample size calculation and sample size allocation between the two stages for each of the hypotheses are derived. Corresponding results are also derived under Cox's proportional hazards model.

Statistical methods for assessment of biosimilarity using biomarker data.

The problem for assessing biosimilarity between biologic products is studied. For approval of follow-on biologic products, the U.S. Food and Drug Administration (FDA) indicated that the follow-on biologic products can be approved under an abbreviated new drug application (ANDA) if the innovator products are approved under a new drug application (NDA). However, for biologic products that are licensed under a BLA, there exists no abbreviated BLA in current Codes of Federal Regulations (CFR). In this case, draft guidance for assessment of biosimilarity is being prepared. As indicated in Chow and Liu (2008), the assessment of bioequivalence for drug products is performed under a so-called fundamental bioequivalence assumption, which uses pharmacokinetic responses as the surrogate endpoint for clinical endpoint for evaluation of the safety and efficacy of the drug products. Following a similar idea, in this article, statistical methods for assessment of biosimilarity between a follow-on biologic product and an innovator product are derived under a fundamental biosimilar assumption and a probability-based criterion for biosimilarity using biomarker data, assuming that the biomarker is predictive of the clinical outcome of the biologic product.

On assessing bioequivalence using genomic data with model misspecification.

This study considers the effect of a nonlinear relationship between pharmacokinetic (PK) and genomic data on bioequivalence assessment using genomic data. A true relationship between PK and genomic data is assumed to be quadratic, but a linear relationship is used instead to assess bioequivalence. Based on this misspecified model, we compare the corresponding power function and sample size for testing average bioequivalence (ABE) to those based on the true model. A numerical study is performed to explore the effect of the misspecification.

Sample size estimation based on event data for a two-stage survival adaptive trial with different durations.

In clinical development, an adaptive design combining results from two separate studies (e.g., a seamless adaptive design with a dose finding study phase and a confirmatory study phase) is commonly considered. The purpose of an adaptive design is not only to reduce lead time between the two studies, but also to evaluate the treatment effect in a more efficient way. In this paper, the focus is on the case where the study objectives are the same but the time durations of the study periods are different in the two stages. In particular, event data are collected in both stages. Statistical procedure for combining data observed from the two different stages is discussed. Furthermore, results on hypotheses testing and sample size calculation are derived for the comparison of two treatments.