Subcutaneous Infliximab (CT-P13 SC) as Maintenance Therapy for Inflammatory Bowel Disease: Two Randomized Phase 3 Trials.

BACKGROUND AND AIMS: CT-P13 subcutaneous (SC), an SC formulation of the intravenous (IV) infliximab biosimilar CT-P13 IV, creates a unique exposure profile. We aimed to demonstrate superiority of CT-P13 SC versus placebo as maintenance therapy in patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Two randomized, placebo-controlled, double-blind studies were conducted in patients with moderately-to-severely active CD or UC and inadequate response/intolerance to corticosteroids and immunomodulators. All patients received open-label CT-P13 IV 5 mg/kg at weeks (W) 0, 2, and 6. At W10, clinical responders were randomized (2:1) to CT-P13 SC 120 mg or placebo every 2 weeks until W54 (maintenance phase) using pre-filled syringes. (Co-)primary endpoints were clinical remission and endoscopic response (CD) and clinical remission (UC) at W54 (all-randomized population). RESULTS: Overall, 396 patients with CD and 548 patients with UC received induction treatment. At W54 in the CD study, statistically significant higher proportions of CT-P13 SC- versus placebo-treated patients achieved clinical remission (62.3% versus 32.1%; P < 0.0001) and endoscopic response (51.1% versus 17.9%; P < 0.0001). In the UC study, clinical remission rates at W54 were statistically significantly higher with CT-P13 SC versus placebo (43.2% versus 20.8%; P < 0.0001). Achievement of key secondary endpoints was significantly higher with CT-P13 SC versus placebo across both studies. CT-P13 SC was well tolerated, with no new safety signals identified. CONCLUSION: CT-P13 SC was more effective than placebo as maintenance therapy and well tolerated in patients with moderately-to-severely active CD or UC who responded to CT-P13 IV induction. CLINICALTRIALS: gov, NCT03945019 (CD) and NCT04205643 (UC).

Physicochemical methods for biofilm removal allow for control of biofilm retention time in a high rate MBBR.

Controlling biofilm retention time in moving bed biofilm reactor (MBBR) and maintaining its performance for A-stage carbon redirection requires a reliable method to use as side stream biocarriers treatment. This paper investigates biofilm detachment and residual biofilm activity under multiple physicochemical treatment scenarios aiming to provide an applicable technique for control of biofilm retention time. Different mixing intensities (i.e. 30-120 rpm), filling fractions (i.e. 20%-100%), and pH (i.e. 2-12) were evaluated. Two continuously operating MBBRs were subjected to pH shocks of 2 and 12 to evaluate the impact of residual acidic or alkaline compounds on performance. The highest solids detachment (i.e. 70 ± 5%) was found in alkaline conditions and independent of mixing intensity and filling fraction. Biofilm detachment test revealed that alkaline shock produced higher detachment levels in a longer exposure time when compared to acidic conditions. The kinetic tests revealed 60% and 90% of the residual biofilm activity was lost at pH 12 and 2. The continuously operating MBBRs subjected to pH shocks of 2 and 12 demonstrated a 50% loss of soluble COD removal capability within one hydraulic retention time. Extracellular polymeric substances changes in its structure and surface properties influencing the degree of biofilm detachment and its solubilization properties leading to differences in biofilm resilience. The findings have shown that by applying a side stream alkali treatment it could be possible to control biofilm retention time ensuring its detachment up to 70% and a reduced impact on the residual biofilm activity returning to the reactor.

Performance and recovery of nitrifying biofilm after exposure to prolonged starvation.

Achieving consistent ammonia removal in post-lagoon processes faces two major challenges impacting nitrifiers due to the unique seasonal variation of lagoon-based systems: summer to winter temperature drop and summer to fall ammonia starvation period while lagoon is removing ammonia. The objective of this study was to follow microbial diversity and define conditions that could overcome these challenges in a post-lagoon moving bed biofilm reactor (MBBR) operated at an initial surface area loading rate (SALR) of 0.3 g-NH4-N m-2d-1 from mesophilic (20 °C) to psychrophilic (4 °C). Initially the temperature was maintained at 20 °C and decreased to 10 °C until steady state was achieved. During starvation conditions (i.e., continuous, intermittent and no aeration without inflow; decanted media; and intermittent and continuous ammonia supplement) the temperature was decreased by 2 °C per week until 4 °C. The results indicated that operational procedures, such as intermittent ammonia supplement with SALR of 0.15 g-NH4-N m-2d-1 could improve performance with 80% ammonia removal achieved immediately after starvation period. Intermittent ammonia supplement had produced the greatest biofilm preservation comparable to the initial load with the highest specific and surface area removal rates. In the recovery phase (initial load restoration) 10 days were required to reestablish performance above 95% ammonia removal. When temperature was decreased from mesophilic to psychrophilic, the microbial diversity was found higher when starving biofilm compared to the control operated at the initial load while it converged to a similar population over recovery. The main actors associated to nitrification enriched at psychrophilic conditions were Proteobacteria and Bacteriodotes at phyla level. Ammonia oxidation to nitrite was mainly driven by the order Burkholderiales and nitrite oxidation to nitrate by Pseudomonadales. This procedure should be considered in the implementation of full-scale post-lagoon MBBR technologies to ensure reliable, robust, and consistent performance despite the inherent seasonal variability of lagoon-based processes.

Randomized Controlled Trial: Subcutaneous vs Intravenous Infliximab CT-P13 Maintenance in Inflammatory Bowel Disease.

BACKGROUND & AIMS: This study compared pharmacokinetics, symptomatic and endoscopic efficacy, safety, and immunogenicity of a subcutaneous formulation of the infliximab biosimilar CT-P13 (CT-P13 SC) vs intravenous CT-P13 (CT-P13 IV) in patients with inflammatory bowel disease (IBD). METHODS: This randomized, multicenter, open-label, parallel-group, phase 1 study enrolled tumor necrosis factor inhibitor-naïve patients with active ulcerative colitis (total Mayo score 6-12 points with endoscopic subscore ≥2) or Crohn's disease (Crohn's Disease Activity Index 220-450 points) at 50 centers. After CT-P13 IV induction at Week (W) 0/W2, patients were randomized (1:1) to receive CT-P13 SC every 2 weeks (q2w) from W6 to W54 or CT-P13 IV every 8 weeks from W6 to W22. At W30, all patients receiving CT-P13 IV switched to CT-P13 SC q2w until W54. The primary endpoint was noninferiority of CT-P13 SC to CT-P13 IV for observed predose CT-P13 concentration at W22 (Ctrough,W22), concluded if the lower bound of the 2-sided 90% confidence interval (CI) for the ratio of geometric least-squares means exceeded 80%. RESULTS: Overall, 66 and 65 patients were randomized to CT-P13 SC and CT-P13 IV, respectively. The primary endpoint of noninferiority was met with a geometric least-squares means ratio for Ctrough,W22 of 1154.17% (90% CI 786.37-1694.00; n = 59 [CT-P13 SC]; n = 57 [CT-P13 IV]). W30/W54 clinical remission rates were comparable between arms. Other efficacy, safety, and immunogenicity assessments were also broadly comparable between arms, including after switching. CONCLUSIONS: The pharmacokinetic noninferiority of CT-P13 SC to CT-P13 IV, and the comparable efficacy, safety, and immunogenicity profiles, support the potential suitability of CT-P13 SC treatment in IBD. ClinicalTrials.gov ID: NCT02883452.

Modeling of the attached and suspended biomass fractions in a moving bed biofilm reactor.

The performance, kinetics, and stoichiometry of three high-rate moving bed biofilm reactors (MBBRs) were evaluated. A constant surface area loading rate (SALR) and three different hydraulic retention times (HRTs) were utilized to create scenarios where the attached and suspended biomass fractions would differentiate, despite the main design parameter remaining constant. Performance was simulated using BioWin™ 6.0 software. The objective was to evaluate whether a calibrated/validated model could accurately predict experimental results. Initially, a sensitivity analysis was performed to determine influential parameters. The calibration/validation of influential parameters was then conducted via steady-state simulations for two base cases: 1) highest HRT; and 2) lowest HRT. Both sets of calibrated/validated parameters were substantiated using: 1) steady-state simulations at the other HRTs; and 2) dynamic simulations to evaluate the kinetic rates of attached and suspended biomass fractions at all HRTs. Results demonstrated that the model could be calibrated/validated for a single HRT, but could not accurately predict the performance, kinetics, or stoichiometry at other HRTs.

Controlling biofilm retention time in an A-stage high-rate moving bed biofilm reactor for organic carbon redirection.

The A-stage of the AB process can minimize carbon oxidation by redirecting carbon to side-stream processes for harvesting carbon as energy and/or bioproduct. The redirection/harvesting of carbon has been studied in systems which utilize suspended biomass cultures. The potential of high-rate moving bed biofilm reactors, however, has not been explored. This study sought to control the biofilm solids retention time in a high-rate moving bed biofilm reactor operated at 17 ± 4 g-bCOD m-2d-1. Biofilm solids retention time was controlled by one of two strategies (i.e., 100% and 60% effective biofilm removal) that targeted several nominal biofilm solids retention times (i.e., 8, 6, 4, and 2 days) by employing different biocarrier replacement times. The results demonstrated that the suspended solids activity could be reduced by decreasing the nominal biofilm solids retention time. Using the 60% biofilm removal strategy, the actual biofilm solids retention time with a nominal biofilm solids retention time of 2 days was 12 h. When utilizing the 100% biofilm removal strategy, an actual biofilm solids retention time of less than 3 h was achieved with a nominal biofilm solids retention time of 2 days. The control reactor, which was a conventional moving bed biofilm reactor with no biocarrier replacement, was estimated to have a biofilm solids retention time of 2 days. Overall, the biofilm removal strategies favored carbon redirection and maximized the biomass yield at 1.1 ± 0.3 g-TSS g-COD-1 removed.

Kinetics of aerobic granular sludge treating low-strength synthetic wastewater at high dissolved oxygen.

Three parallel reactors (i.e. R1-R3) were operated with 340 mg-COD L-1, 42 mg-TN L-1, and 7 mg-TP L-1 at 20 ± 1°C. A mature granular sludge developed in 40 d and was stable for the 120 d experimentation period at an average food to microorganism ratio of 0.25 ± 0.08 g-COD g-VSS-1 d-1. Reactor biomass had higher inorganic content (i.e. 0.78-0.80 g-VSS g-TSS-1) than effluent biomass (i.e. 0.88-0.92 g-VSS g-TSS-1). Average granule diameter was 0.7-1.0 mm. Maximum phosphorus uptake and release rates averaged 4 ± 3 and 4 ± 2 mg-P g-VSS-1 h-1, respectively. Maximum observed nitrification rates averaged 1.9 ± 0.6 mg-N g-VSS-1 h-1. Phosphorus kinetics were similar between R1-R3 (i.e. P = 0.5309-0.6870) while nitrification kinetics varied significantly (i.e. P = 0.0002) even though conditions were the same. Effluent phosphate was on average 0.2 ± 0.4 mg-P L-1 while total inorganic nitrogen removal averaged 60 ± 10% resulting in an average effluent of 17 mg-N L-1. Aerobic granular sludge was capable of reliable nutrient removal from low-strength wastewater without volatile fatty acid source and at high dissolved oxygen concentrations.

Ammonia, thiocyanate, and cyanate removal in an aerobic up-flow submerged attached growth reactor treating gold mine wastewater.

The objective of the study was to investigate the nitrification process, as well as the bio-chemical removal of cyanate and thiocyanate, while treating gold mining wastewater using an aerobic up-flow SAGR. A total of six SAGRs, each packed with locally sourced pea gravel (estimated specific surface area of 297 m-2 m-3), were operated at various HRTs and tested on both low- and high-strength gold mining wastewaters. The two sets of three SAGRs were operated at HRTs of 0.45 days, 1.20 days, and 2.40 days. Nitrification was successfully achieved in all six SAGRs regardless of the wastewater strength or HRT examined. The steady-state, 20 °C surface area loading rate was determined to be 1.2 g-TAN m-2 d-1 in order to comply with an effluent discharge limit at 10 mg-TAN L-1 (i.e., with the wastewater sources examined). At all ammonia loading rates, thiocyanate was successfully removed, and residual concentrations were below 2 mg-SCN-N L-1. Cyanate appeared to be hydrolyzed and subsequently nitrified. Acute toxicity tests conducted on both daphnia and trout revealed the effluent to be safe for direct discharge.

Effective nitrogen removal in a two-stage partial nitritation-anammox reactor treating municipal wastewater - Piloting PN-MBBR/AMX-IFAS configuration.

A novel partial nitritation-anammox (PNA) reactor configuration was piloted for 250 days. Primary effluent from full-scale municipal wastewater treatment plant was treated in a two-stage biofilm system incorporating innovative process control for cold partial nitritation. Partial nitritation was combined with carbon removal in a moving bed biofilm reactor (MBBR) to achieve high-rate treatment and nitritation was obtained with dissolved oxygen to total ammonium nitrogen (DO/TAN) ratio control and free ammonia (FA) for inhibition of nitratation. Effluent from MBBR was directed to an integrated fixed-film activated sludge (IFAS) reactor where nitrogen was removed via anammox. MBBR achieved partial nitritation at 2.0 ±â€¯0.3 g-N m-2 d-1 and nitrogen removal in the IFAS reactor reached 0.45 ±â€¯0.1 g-N m-2 d-1 (55 g-N m-3 d-1). The process performed well at 19 ±â€¯3 °C with an average effluent total inorganic nitrogen (TIN) concentration of 11 ±â€¯4 mg L-1.

Moving bed biofilm reactor technology in municipal wastewater treatment: A review.

The review encompasses the development of municipal wastewater treatment process using MBBR from early stages, established application, and recent advancements. An overview of main drivers leading to the MBBR technology development over its early stage is discussed. Biocarriers types and features together with biofilm development and role of extracellular polymeric substances (EPS) are presented, ultimately, addressing the challenge in decreasing startup time required for full operation. Furthermore, the review investigates the state of the art of MBBR technology for nutrient removal (i.e., COD and BOD, nitrogen and phosphorus) through process functionality and configuration of established (e.g., IFAS) and under development (e.g. PN/A) applications. Reactor operational characteristics such as filling fractions, mixing properties, dissolved oxygen requirements, and loading rates are presented and related to full scale examples. Current literature discussing the most recent studies on MBBR capability in reduction and removal of chemicals of emerging concern (CEC) released is presented. Ultimately, high rate carbon and nitrogen removal through A/B stage process are examined in its main operational parameters and its application towards energy neutrality suggesting novel MBBR application to further reduce energy requirements and plant footprint.

Controlling cold temperature partial nitritation in moving bed biofilm reactor.

Mainstream partial nitritation was studied at 10 °C in a moving bed biofilm reactor treating synthetic wastewater containing both nitrogen (≈40 mg L-1) and organic carbon at COD/N ratio ranging from 1.3 to 2.2. Three different control strategies were investigated to achieve partial nitritation. Initially, biofilm age was controlled by incorporating a media replacement strategy. Next, separately from the media replacement, oxygen limited conditions were investigated and finally pH control was incorporated together with oxygen limitation. Successful partial nitritation was achieved only by combining oxygen limitation with pH control. The average NH4-N concentration was equal to 16.0 ±â€¯1.6 mg L-1 and average NO2-N concentration was equal to 15.7 ±â€¯2.4 mg L-1 during steady state partial nitritation. The average residual NO3-N concentration was equal to 2.6 ±â€¯2.2 mg L-1. The results obtained from this study prove for the first time that partial nitritation can be successfully controlled in a biofilm reactor treating wastewater with low nitrogen concentration, relatively high COD/N ratio and at low temperature. An algorithm for dynamic process control of partial nitritation has been also developed.

Attachment of anaerobic ammonium-oxidizing bacteria to augmented carrier material.

The formation of stable and highly active anammox biofilm is a lengthy process leading to long start-up times of deammonifying reactors of several months or more. This study aims to provide a quick solution to the problem of long start-up periods by pretreating the surface of carrier material. Two different techniques were investigated. The first one focused on growing a layer of heterotrophic biofilm on the surface of the plastic carriers prior to inoculation with anammox biomass. Specific anammox activity increased by almost 400% as compared to seed values and was equal to 250 mg NH4-N/gVSS/L•d. In the second technique, the carrier material was coated with a layer of granular-activated carbon to provide a higher surface area. The anammox activity increased by approximately 50%. In comparison, the control reactor did not develop any biofilm and no anammox activity was detected. Rapid attachment of the anammox biomass was achieved in a reactor with media that had a predeveloped layer of a biofilm. In a way, this approach is analogous to a primer or an undercoat that is put on materials before painting to ensure better adhesion of paint to the surface, hence the suggested name - bioprimer.

Electrocoagulation of wastewater using aluminum, iron, and magnesium electrodes.

Primary influent from a municipal wastewater treatment plant was electrochemically treated with sacrificial aluminum, iron, and magnesium electrodes. The influence of sacrificial anodes on the removal of chemical oxygen demand, total nitrogen, total phosphorus, and orthophosphate during sedimentation was investigated. Nitrification kinetics were assessed on treated supernatant and biogas production was monitored on settled solids. Changes in alkalinity, conductivity, and pH were also recorded. Aluminum and iron electrodes provided high rates of orthophosphate removal (i.e., 6.8 mg-P/mmol-e). Aluminum and iron electrodes also provided similar treatment to equivalent doses of alum and ferric salts (i.e., 38-68% chemical oxygen demand, 10-13% total nitrogen, and 67-93% total phosphorus). The estimated stochiometric ratio of aluminum and iron dosed to orthophosphate removed was approximately 1.3:1 and 4.1:1, respectively. Magnesium electrodes, on the other hand, removed orthophosphate at rates 8-9 times slower than aluminum and iron (i.e., 0.9 mg-P/mmol-e). Magnesium had to be dosed at a ratio of 13.5:1 orthophosphate for phosphorus removal. Orthophosphate removal by magnesium electrodes was most likely limited by electrolysis reactions responsible for increases in pH (i.e., 0.52 pH units/mmol-e). Magnesium electrodes removed 49% chemical oxygen demand and 21% total nitrogen at the high molar ratios required for orthophosphate removal.

Start-up and long-term performance of anammox moving bed biofilm reactor seeded with granular biomass.

Availability of granular anammox sludge is much higher than biofilm seed carriers and the sludge is easier to transport. This paper describes and investigates a formation of mature anammox biofilm originated from granular sludge and proves that an anammox moving bed biofilm reactors (MBBR) can be easily and quickly started-up by seeding with granular sludge. The reactor was fed with synthetic wastewater containing ammonium and nitrite. Successful start-up was completed in as little as 50 days when TN removal increased to more than 80%. Surface nitrogen loading rate during start-up was equal to 0.75 g m-2 d and was stepwise increased up to 5.3 g m-2 d. Biofilm thickness reached 1269 ±â€¯444 µm at the end of the study with specific anammox activity of 22.0 ±â€¯2.1 mg N g-1 VSS h. This study shows that granular biomass can be transitioned to a biofilm relatively easily which opens a new window of opportunity for starting-up anammox MBBRs.

The effect of substrate roughness on the surface structure of TiO(2), SiO(2), and doped thin films prepared by the sol-gel method.

Pure and calcium-doped silica and titanium dioxide thin films were prepared by the sol-gel method. Two different metallic substrates, i.e. stainless steel (316L) and titanium alloy (Ti6Al4V), were used for thin film deposition. Physicochemical properties and roughness of the thin films derived were investigated using the Raman spectroscopy, X-ray diffraction analysis, scanning electron microscopy and Taylor-Hobson's surface analyser. It is suggested that the synthesized coatings display physicochemical and surface properties suitable for materials used for implant.