Revisiting the impact of serial therapeutic phlebotomy in polycythaemia on laboratory and clinical parameters using a fixed interval and fixed volume protocol.

OBJECTIVES: Therapeutic phlebotomy allows for a controlled and gradual decrease in red cell mass leading to improved blood flow and symptomatic relief in polycythaemia. The present study was aimed to determine the impact of serial fixed volume and fixed interval therapeutic phlebotomy protocol on the laboratory and clinical parameters in patients of polycythaemia. MATERIAL AND METHODS: This prospective longitudinal study was conducted over 18 months. The desired haematocrit for polycythemia vera and secondary polycythemia was 45% and 52% respectively. A fixed volume of 350 ml phlebotomy was performed every-three days till the achievement of desired haematocrit. Complete blood count was performed before and after each procedure and iron studies were done at the time of enrolment and after the achievement of desired haematocrit. Post-procedure symptomatic relief was assessed by a 10-point visual analogue scale (VAS). RESULTS: Of the 29 patients enrolled in the study, 3 patients were lost to follow up and data of 26 patients was analyzed. Mean Hb declined from 17.84 ± 1.88 gdL-1 to 14.67 ± 1.14 gdL-1 (p < 0.001) and mean haematocrit decreased from a baseline of 57.11 ± 5.47% to 46.27 ± 3.763% (p < 0.001) upon achievement of desired haematocrit. There was a significant decline in serum iron from the baseline of 132.85 ± 94.136 µg dL-1 to 69.41 ± 58.643 µg dL-1 at desired haematocrit. A significant change in VAS score of almost all clinical parameters was observed. Post phlebotomy hematocrit correlated negatively with the number of procedures (p = 0.015). CONCLUSION: Our protocol yielded rapid and marked improvement in patients of primary and secondary polycythemia with minimal adverse events and significant amelioration of clinical parameters.

Pharmacokinetics, Safety and Efficacy of Intravenous Vedolizumab in Paediatric Patients with Ulcerative Colitis or Crohn's Disease: Results from the Phase 2 HUBBLE Study.

BACKGROUND AND AIMS: To date, there are no systematic pharmacokinetic [PK] data on vedolizumab in paediatric inflammatory bowel disease [IBD]. We report results from HUBBLE, a dose-ranging, phase 2 trial evaluating the PK, safety and efficacy of intravenous vedolizumab for paediatric IBD. METHODS: Enrolled patients [aged 2-17 years] with moderate to severe ulcerative colitis [UC] or Crohn's disease [CD] and body weight ≥10 kg were randomized by weight to receive low- or high-dose vedolizumab [≥30 kg, 150 or 300 mg; <30 kg, 100 or 200 mg] on Day 1 and Weeks 2, 6 and 14. Week 14 assessments included PK, clinical response and exposure-response relationship. Safety and immunogenicity were assessed. RESULTS: Randomized patients weighing ≥30 kg [UC, n = 25; CD, n = 24] and <30 kg [UC, n = 19; CD, n = 21] had a baseline mean [standard deviation] age of 13.5 [2.5] and 7.6 [3.2] years, respectively. In almost all indication and weight groups, area under the concentration curve and average concentration increased ~2-fold from low to high dose; the trough concentration was higher in each high-dose arm compared with the low-dose arms. At Week 14, clinical response occurred in 40.0-69.2% of patients with UC and 33.3-63.6% with CD in both weight groups. Clinical responders with UC generally had higher trough concentration vs non-responders, while this trend was not observed in CD. Fourteen per cent [12/88] of patients had treatment-related adverse events and 6.8% [6/88] had anti-drug antibodies. CONCLUSIONS: Vedolizumab exposure increased in an approximate dose-proportional manner. No clear dose-response relationship was observed in this limited cohort. No new safety signals were identified.

Efficacy and Safety of Subcutaneous Vedolizumab in Patients With Moderately to Severely Active Crohn's Disease: Results From the VISIBLE 2 Randomised Trial.

BACKGROUND AND AIMS: To report results from VISIBLE 2, a randomised, double-blind, placebo-controlled, phase 3 trial evaluating a new subcutaneous [SC] vedolizumab formulation as maintenance treatment in adults with moderately to severely active Crohn's disease [CD]. METHODS: Following open-label vedolizumab 300 mg intravenous induction therapy at Weeks 0 and 2, Week 6 clinical responders (≥70-point decrease in CD Activity Index [CDAI] score from baseline) were randomised 2:1 to receive double-blind maintenance vedolizumab 108 mg SC or placebo every 2 weeks until Week 50. Assessments at Week 52 included clinical remission [primary endpoint; CDAI ≤150], enhanced clinical response [≥100-point decrease in CDAI from baseline], corticosteroid-free clinical remission among patients using a corticosteroid at baseline, clinical remission in anti-tumour necrosis factor [anti-TNF]-naïve patients, and safety. RESULTS: Following vedolizumab intravenous induction, 275 patients were randomised to vedolizumab SC and 135 to placebo maintenance. At Week 52, 48.0% of patients receiving vedolizumab SC versus 34.3% receiving placebo were in clinical remission [p = 0.008]. Enhanced clinical response at Week 52 was achieved by 52.0% versus 44.8% of patients receiving vedolizumab SC versus placebo, respectively [p = 0.167]. At Week 52, 45.3% and 18.2% of patients receiving vedolizumab SC and placebo, respectively, were in corticosteroid-free clinical remission, and 48.6% of anti-TNF-naïve patients receiving vedolizumab SC and 42.9% receiving placebo were in clinical remission. Injection site reaction was the only new safety finding observed for vedolizumab SC [2.9%]. CONCLUSIONS: Vedolizumab SC is an effective and safe maintenance therapy in patients with CD who responded to two infusions of vedolizumab intravenous induction therapy.

Comparative proteomics of geographically distinct saw-scaled viper (Echis carinatus) venoms from India.

Snakebite is a socio-economic problem in tropical countries and it is exacerbated by geographical venom variation of snakes. We investigated on venom variation in geographically distinct populations of Echis carinatus from three ecologically distinct regions: Tamil Nadu (ECVTN), Goa (ECVGO), and Rajasthan (ECVRAJ). Venom was fractionated by RP-HPLC, combined with SDS-PAGE, and subjected to tandem mass spectrometry. Toxins were identified, and their relative abundance was estimated. Using NCBI database of Echis genus, we queried the MS/MS spectra, and found 69, 38 and 38 proteins in ECVTN, ECVGO and ECVRAJ respectively, belonging to 8-10 different toxin families. The differences in the venom profiles were due to change in the relative composition of the toxin families. Snake venom metalloproteinase (svMP), Snaclecs and Phospholipase A2 (PLA2) were the major venom components in all the venoms. Heteromeric Disintegrins were found in ECVTN and absent in other venoms. ECVRAJ showed higher abundance of low-molecular-weight (>30 kDa) proteins than ECVTN and ECVGO. Cysteine-rich venom protein (CRISP) was highest in ECVRAJ (7.34%), followed by ECVTN (0.01%) and in ECVGO, it was not detected. These findings highlight the need for evaluating the efficacy of the polyvalent anti-venom to neutralize the toxins from geographically distinct venoms of E. carinatus.

Efficacy and Safety of Vedolizumab Subcutaneous Formulation in a Randomized Trial of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Maintenance treatment with vedolizumab, a monoclonal antibody that inhibits the gut-selective α4ß7 integrin, is administered intravenously. Some patients might prefer a subcutaneous formulation of vedolizumab for maintenance treatment. Subcutaneous vedolizumab was investigated as maintenance treatment in patients with moderately to severely active ulcerative colitis. METHODS: We performed a phase 3, double-blind, double-dummy trial at 141 sites in 29 countries from December 18, 2015 through August 21, 2018. Patients with moderately to severely active ulcerative colitis received open-label treatment with intravenous vedolizumab 300 mg at weeks 0 and 2. At week 6, patients with clinical response were randomly assigned maintenance treatment with subcutaneous vedolizumab 108 mg every 2 weeks, intravenous vedolizumab 300 mg every 8 weeks, or placebo. The primary end point was clinical remission at week 52, which was defined as a total Mayo score of ≤2 and no subscore >1. RESULTS: Among the randomized 216 patients, clinical remission at week 52 was achieved by 46.2%, 42.6%, and 14.3% of patients in the subcutaneous vedolizumab, intravenous vedolizumab, and placebo groups, respectively (subcutaneous vedolizumab vs placebo: Δ32.3%; 95% confidence interval, 19.7%-45.0%; P < .001). The subcutaneous vedolizumab group also had greater endoscopic improvement and durable clinical response at week 52 compared with placebo (both P < .001). The incidence of injection-site reactions was more frequent in patients given subcutaneous vedolizumab (10.4%) than intravenous vedolizumab (1.9%) or placebo (0%); these were not treatment limiting, most were mild, and none resulted in discontinuation. Subcutaneous and intravenous vedolizumab safety profiles were otherwise similar. CONCLUSIONS: Subcutaneous vedolizumab is effective as maintenance therapy in patients with moderately to severely active ulcerative colitis who had a clinical response to intravenous vedolizumab induction therapy. It has a favorable safety and tolerability profile. ClinicalTrials.gov ID: NCT02611830; EudraCT 2015-000480-14.