Certolizumab pegol, a monthly subcutaneously administered Fc-free anti-TNFalpha, improves health-related quality of life in patients with moderate to severe Crohn's disease.
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ABSTRACT:
SUBMITTER: Rutgeerts P
PROVIDER: S-EPMC2225995 | biostudies-other | 2008 Mar
REPOSITORIES: biostudies-other
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Project description:Adherence to antipsychotic medications is a major challenge in schizophrenia. Long-acting injectable antipsychotics have been shown to offer advantages over oral formulations. A new extended release formulation of risperidone for subcutaneous injection was developed to address issues of non-adherence. The aim of this manuscript was to compare the new subcutaneous formulation to currently available formulations of injectable risperidone and paliperidone to determine whether the novel delivery by subcutaneous injection may provide substantial benefits. A literature search was conducted using PubMed, OVID, and Cochrane Library electronic databases to assess the advantages and disadvantages of long-acting formulations of risperidone. Potential advantages of risperidone for subcutaneous injection include a simplified dosing and ease of administration. Potential disadvantages include injection site pain and medication cost.
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Project description:Therapeutic options in development for the treatment of Crohn's disease represent a broad range of approaches to this complex disease. This active pipeline contains a combination of both small-molecule entities and targeted monoclonal antibodies.
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Project description:IntroductionIn patients with moderate to severe Crohn's disease (CD), intravenous induction and subcutaneous maintenance dosing with risankizumab was efficacious and well tolerated. Long-term management of CD via self-administration of risankizumab using an on-body injector (OBI) may improve treatment adherence through convenience and ease of use.MethodsWithin the FORTIFY maintenance study, 46 patients from the United States (US) sites participated in an open-label extension Substudy and received 180 mg or 360 mg risankizumab delivered subcutaneously via OBI [360 mg (2.4 mL, 150 mg/mL) or 180 mg (1.2 mL, 150 mg/mL)]. At the Week 0 visit, patients were trained (pre-injection) by site staff, using Instructions for Use (IFU) and a training video, to self-administer risankizumab at Weeks 0 (on site), 8 (at home), and 16 (on site). Key objectives of the Substudy 4 were to assess OBI usability (observer rating of successful self-administration), hazard-free self-injection at Weeks 0 and 16, and patient rating of acceptability using the Self-Injection Assessment Questionnaire (SIAQ) at Weeks 0, 8, and 16. Additionally, the proportion of patients in clinical remission (CD Activity Index < 150) was collected at Weeks 0 and 16.ResultsAll patients successfully self-administered risankizumab via OBI, including two patients who successfully self-administered with a second OBI (i.e., required two injection attempts). Acceptability of self-injection was high. Two patients (n = 2) experienced a use-related hazard. Stable clinical remission was observed with both risankizumab doses. Two patients experienced injection site reactions; neither was related to the OBI per investigator's assessment. Two device-related adverse events related to topical adhesive reactions were reported, both mild and resolved. No new safety risks were observed.ConclusionThe efficacy and safety of maintenance risankizumab delivered via OBI and OBI usability support the use of this device in patients with moderate to severe CD.Trial registrationClinicalTrials.gov identifiers NCT03105102 (FORTIFY).
| S-EPMC10011765 | biostudies-literature
Project description:IntroductionIn the phase 2 CELEST study, positive efficacy results were obtained with the Janus kinase 1 inhibitor upadacitinib for adult patients with moderate to severe Crohn's disease. We present the health-related quality of life and work productivity improvement results with upadacitinib from CELEST.MethodsCELEST (NCT02365649) was a double-blind study where patients were randomized 1:1:1:1:1:1 in the 16-week induction period to placebo or upadacitinib 3 mg twice daily (BID), 6 mg BID, 12 mg BID, 24 mg BID, or 24 mg once daily (QD). Patients completing the induction period were re-randomized 1:1:1 to receive upadacitinib 3 mg BID, 12 mg BID, or 24 mg QD for 36 weeks or 3 mg BID, 6 mg BID, or 12 mg BID (after amendment). Inflammatory Bowel Disease Questionnaire (IBDQ), European Quality of Life-5 Dimensions visual analog scale (EQ-5D VAS), and Work Productivity and Activity Impairment (WPAI) questionnaire outcomes were assessed at baseline and Weeks 8, 16, and 52.ResultsAt Week 16, a significant percentage (P ≤ 0.05) of patients receiving upadacitinib 6-mg BID dose or higher achieved IBDQ response (IBDQ score change ≥ 16 points; 49%-57% for upadacitinib vs. 24% for placebo) and IBDQ remission, except 24 mg QD (IBDQ score ≥ 170; 26%-39% for upadacitinib vs. 11% for placebo). Greater improvements in IBDQ total score, EQ-5D VAS, and activity impairment from baseline (P ≤ 0.1) versus placebo were also observed. Larger improvements (P ≤ 0.1) in IBDQ response and total score and EQ-5D VAS were observed at Week 8 with 6 and 24 mg BID versus placebo, with improvements for all dosages maintained or greater at Week 52 for IBDQ, EQ-5D VAS, and WPAI endpoints, in particular for the 12-mg BID group.ConclusionImprovements in health-related quality of life and work productivity were achieved and sustained with upadacitinib in patients with moderate to severe Crohn's disease.Trial registrationClinicalTrials.gov identifier, NCT02365649.
| S-EPMC8107073 | biostudies-literature
Project description:OBJECTIVE:To evaluate open-label adalimumab therapy for clinical effectiveness, fistula healing, patient-reported outcomes and safety in Canadian patients with moderate to severe Crohn's disease (CD) who were either naive to or previously exposed to antitumour necrosis factor (anti-TNF) therapy. METHODS:Patients with moderate to severe CD (CD activity index [CDAI] score of greater than 220, or Harvey-Bradshaw index [HBI] of 7 or greater) were eligible. Patients received open-label adalimumab as induction (160 mg and 80 mg subcutaneously [sc]) at weeks 0 and 2, respectively and maintenance (40 mg sc every other week) therapy. At or after eight weeks, patients with flare or nonresponse could have their dosage increased to 40 mg sc weekly. Patients were followed for a minimum of six months or until adalimumab was commercially available in Canada. RESULTS:Of the 304 patients enrolled, 160 were infliximab experienced, while 144 were anti-TNF naive. HBI remission (HBI score of 4 or lower) at week 24 was achieved by 53% of anti-TNF-naive and 36% of infliximab-experienced patients (P<0.01; P<0.001 for both groups for all visits versus baseline). Fistula healing rates at week 12 were 48% for anti-TNF-naive patients, and 26% for infliximab-experienced patients. At week 24, fistula healing rates were significantly greater for the anti-TNF-naive group (60% versus 28%; P<0.01). Improvements in quality of life and work productivity were sustained from week 4 to week 24 for all patients. Serious infections occurred in 2% of patients. CONCLUSIONS:Adalimumab therapy induced and sustained steroidfree remission in both infliximab-experienced and anti-TNF-naive patients with moderate to severe CD. Clinically meaningful rates of fistula healing were also observed. Improvements in patient-reported outcomes were sustained throughout the 24-week study period.
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Project description:Background and objectivesA multi-centre, non-comparative study examining the efficacy and safety of Subgam, a normal immunoglobulin (IgG) given weekly as a rapid subcutaneous infusion to patients with primary immune deficiency (PID), is reported. Also included is a summary of adverse drug reactions associated with the use of marketed Subgam in the UK.Materials and methods50 patients with stable PID on IgG therapy were enrolled: Stage 1 included three infusions with prior IgG product followed by 6 months with Subgam, Stage 2 involved long-term Subgam therapy up to 4 years.ResultsStage 1, 85% of the subjects aged >12 years and 93% of the subjects aged <12 years achieved IgG levels ≥6 and ≥4 g/L, respectively at all observations. There were 3.62 infections/patient/year during Subgam treatment. The most common product-related events were infusion site reactions (50% of patients). Recent post-hoc pharmacokinetics analysis of the post-infusion serum total IgG concentration indicated that the mean dose-normalised incremental IgG AUCτ following intravenous dosing (120.5 g.day/L) was 1.64-fold that of the dose-normalised mean incremental IgG AUCτ following subcutaneous dosing (73.6 g.day/L), corresponding to an estimated IgG bioavailability for subcutaneous dosing of 61%. Only 34 post-licensing adverse reactions have been received in 30 patients over a period of 10 years; fourteen were classed as serious as defined by the ICH guidelines on good clinical practice. The most common post-licensing adverse reaction was infusion site reaction (7 reports). There were 7 reports of flu-like symptoms (pyrexia/shivering/rigors/feeling hot or cold), 2 other reports of combined flu-like symptoms and infusion site reactions, 5 reports of generalised skin reactions, and 3 reports of combined infusion site and skin reactions. There were also reports of anaphylaxis (2 reports) and 8 other adverse events (including headache). In conclusion, Subgam is effective and well tolerated in the treatment of PID.Trial registrationClinicalTrials.gov NCT02247141.
| S-EPMC4519338 | biostudies-literature
Project description:The development of nanomaterials to induce antigen-specific immune tolerance has shown promise for treating autoimmune diseases. While PEGylation has been widely used to reduce host immune responses to nanomaterials, its tolerogenic potential has not been reported. Here, we report for the first time that a subcutaneous injection of PEGylated poly(lactide-co-glycolide) (PLGA) nanoparticles containing auto-antigen peptide MOG35-55 without any tolerogenic drugs is sufficient to dramatically ameliorate symptoms after disease onset in an antigen-specific manner in a mouse model of multiple sclerosis. Neither free MOG35-55 nor particles without PEG exhibit this efficacy. Interestingly, mechanistic studies indicate that PEGylation of nanoparticles does not reduce dendritic cell activation through direct nanoparticle-cell interactions. Instead, PEGylated nanoparticles induce lower complement activation, neutrophil recruitment, and co-stimulatory molecule expression on dendritic cells around the injection sitecompared to non-PEGylated PLGA nanoparticles, creating a more tolerogenic microenvironment in vivo. We further demonstrate that the locally recruited dendritic cells traffic to lymphoid organs to induce T cell tolerance. These results highlight the critical role of surface properties of nanomaterials in inducing immune tolerance via subcutaneous administration.
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Project description:The advent of anti-tumor necrosis factor (TNF)-? therapy has been a major advance in the medical management of Crohn's disease (CD). However, a significant proportion of patients with CD do not respond adequately to treatment with these agents. Primary and secondary nonresponse to anti-TNF? therapy represents a common clinical challenge, and highlights the need for the development of additional medication options for CD. The proinflammatory cytokines interleukin (IL)-12 and IL-23 are thought to play a key role in the pathogenesis of CD, and serve as a potential target for additional biologic therapies. Monoclonal antibodies targeting IL-12/23 have shown efficacy in animal models of colitis, and are currently being studied in Phase III clinical trials of CD. This review focuses on ustekinumab, a fully human immunoglobulin G1 monoclonal antibody, which blocks activity of IL-12 and IL-23 through binding the p40 subunit, and describes the current efficacy and safety data for ustekinumab in patients with CD.
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Project description:Plasma pharmacokinetic profiles and the anti-inflammatory efficacy of meloxicam were determined when administered subcutaneously (SC) or intramuscularly (IM) to sheep. Merino ewes were initially injected with 0.1 mL of oil of turpentine into a forelimb to induce inflammation, followed by either 1.0 mg/kg or 2.0 mg/kg of meloxicam administered either SC or IM (n = 6 per treatment group) or followed by no meloxicam administration (control) (n = 4). Ewes were examined to determine skin temperature, limb circumference, limb sensitivity and signs of lameness at 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 24 and 48 h following treatment, with blood collected at these time-points to quantify meloxicam plasma concentrations. Skin temperature of ewes dosed with meloxicam at 1.0 mg/kg SC and 2.0 mg/kg IM at 12 h and 1.0 mg/kg SC at 24 were significantly different to the controls (P < 0.05). Limb circumferences of ewes dosed with 1.0 mg/kg IM were significantly different to controls at 10 h and 12 h (P < 0.05). All meloxicam treatment groups resulted in reduced limb sensitivity compared to controls at 6 h, with the 1.0 and 2.0 mg/kg IM treatments significantly different at 12 h (P < 0.05) and 1.0 and 2.0 mg/kg SC groups, significantly different to controls at 48 h (P < 0.05). No significant difference in lameness scores were detected over 48 h. The 1.0 mg/kg IM treatment had a significantly greater plasma meloxicam concentration than the 1.0 mg/kg SC treatment over 0.5 to 4 h (P < 0.001). Both 1.0 mg/kg SC and IM treatments demonstrated elimination half-lives (mean ± SD) of 10.82 ± 2.46 and 12.63 ± 2.37 h, respectively. Meloxicam at all doses provided some anti-inflammatory and analgesic effects from 6 to 48 h; however no route could be distinguished as more efficacious than the others.
| S-EPMC6481916 | biostudies-literature
Project description:IntroductionThe rapid clearance of factor IX necessitates frequent intravenous administrations to achieve effective prophylaxis for patients with hemophilia B. Subcutaneous administration has historically been limited by low bioavailability and potency. Dalcinonacog alfa was developed using a rational design approach to be a subcutaneously administered, next-generation coagulation prophylactic factor IX therapy.AimThis study aimed to investigate the pharmacokinetic, pharmacodynamic, and safety profile of dalcinonacog alfa administered subcutaneously in hemophilia B dogs.MethodsTwo hemophilia B dogs received single-dose daily subcutaneous dalcinonacog alfa injections for six days. Factor IX antigen and activity, whole blood clotting time, and activated partial thromboplastin time were measured at various time points. Additionally, safety assessments for clinical adverse events and evaluations of laboratory test results were conducted.ResultsThere was an increase in plasma factor IX antigen with daily subcutaneous dalcinonacog alfa. Bioavailability of subcutaneous dalcinonacog alfa was 10.3% in hemophilia B dogs. Daily subcutaneous dosing of dalcinonacog alfa demonstrated the effects of bioavailability, time to maximal concentration, and half-life by reaching a steady-state activity sufficient to correct severe hemophilia to normal, after four days.ConclusionThe increased potency of dalcinonacog alfa facilitated the initiation and completion of the Phase 1/2 subcutaneous dosing study in individuals with hemophilia B.
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