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Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial.

ABSTRACT: INTRODUCTION:Atacicept is a soluble, fully human, recombinant fusion protein that inhibits B cell-stimulating factors APRIL (a proliferation-inducing ligand) and BLyS (B-lymphocyte stimulator). The APRIL- LN study aimed to evaluate the efficacy and safety of atacicept in patients with active lupus nephritis (LN), receiving newly initiated corticosteroids (CS) and mycophenolate mofetil (MMF). METHODS:This was a randomized, double-blind, placebo-controlled Phase II/III, 52-week study. At screening (Day -14), patients initiated high-dose CS (the lesser of 0.8 mg/kg/day or 60 mg/day prednisone) and MMF (1 g daily, increased by 1 g/day each week to 3 g daily). From Day 1, atacicept (150 mg, subcutaneously, twice weekly for 4 weeks, then weekly) was initiated with MMF along with a tapered dose of CS. RESULTS:The trial was terminated after the enrollment of six patients, due to an unexpected decline in serum immunoglobulin G (IgG) and the occurrence of serious infections. Efficacy was thus not evaluated. By Day 1, serum IgG levels had declined substantially in patients then randomized to atacicept (n = 4) compared with placebo (n = 2). Patients receiving atacicept also had more severe proteinuria on Day -14 than those on placebo. Lymphocyte counts were low at screening in all patients. IgG decline continued following initiation (Day 1) of atacicept. Three atacicept-treated patients developed serum IgG below the protocol-defined discontinuation threshold of 3 g/l, two of whom developed serious pneumonia. CONCLUSIONS:Future studies are needed to characterize the safety, efficacy, and pharmacodynamic response of atacicept in LN patients. TRIAL REGISTRATION:ClinicalTrials.gov: NCT00573157.

SUBMITTER: Ginzler EM

PROVIDER: S-EPMC3392829 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial.

Ginzler Ellen M EM Wax Stephen S Rajeswaran Anand A Copt Samuel S Hillson Jan J Ramos Eleanor E Singer Nora G NG

Arthritis research & therapy 20120207 1

<h4>Introduction</h4>Atacicept is a soluble, fully human, recombinant fusion protein that inhibits B cell-stimulating factors APRIL (a proliferation-inducing ligand) and BLyS (B-lymphocyte stimulator). The APRIL- LN study aimed to evaluate the efficacy and safety of atacicept in patients with active lupus nephritis (LN), receiving newly initiated corticosteroids (CS) and mycophenolate mofetil (MMF).<h4>Methods</h4>This was a randomized, double-blind, placebo-controlled Phase II/III, 52-week stud ...[more]

PMID: 22325903

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Project description:Background and purposeIntravenous alteplase (rtPA) remains the only approved treatment for acute ischemic stroke, but its use remains limited. In a previous pilot dose-escalation study, intravenous tenecteplase showed promise as a potentially safer alternative. Therefore, a Phase IIB clinical trial was begun to (1) choose a best dose of tenecteplase to carry forward; and (2) to provide evidence for either promise or futility of further testing of tenecteplase versus rtPA. If promise was established, then the trial would continue as a Phase III efficacy trial comparing the selected tenecteplase dose to standard rtPA.MethodsThe trial began as a small, multicenter, randomized, double-blind, controlled clinical trial comparing 0.1, 0.25, and 0.4 mg/kg tenecteplase with standard 0.9 mg/kg rtPA in patients with acute stroke within 3 hours of onset. An adaptive sequential design used an early (24-hour) assessment of major neurological improvement balanced against occurrence of symptomatic intracranial hemorrhage to choose a "best" dose of tenecteplase to carry forward. Once a "best" dose was established, the trial was to continue until at least 100 pairs of the selected tenecteplase dose versus standard rtPA could be compared by 3-month outcome using the modified Rankin Scale in an interim analysis. Decision rules were devised to yield a clear recommendation to either stop for futility or to continue into Phase III.ResultsThe trial was prematurely terminated for slow enrollment after only 112 patients had been randomized at 8 clinical centers between 2006 and 2008. The 0.4-mg/kg dose was discarded as inferior after only 73 patients were randomized, but the selection procedure was still unable to distinguish between 0.1 mg/kg and 0.25 mg/kg as a propitious dose at the time the trial was stopped. There were no statistically persuasive differences in 3-month outcomes between the remaining tenecteplase groups and rtPA. Symptomatic intracranial hemorrhage rates were highest in the discarded 0.4-mg/kg tenecteplase group and lowest (0 of 31) in the 0.1-mg/kg tenecteplase group. Neither promise nor futility could be established.ConclusionThis prematurely terminated trial has demonstrated the potential efficiency of a novel design in selecting a propitious dose for future study of a new thrombolytic agent for acute stroke. Given the truncation of the trial, no convincing conclusions can be made about the promise of future study of tenecteplase in acute stroke.

Project description:Background: Although there have been many trials and interventions for reducing upper-extremity impairment in stroke survivors, it remains a challenge. A novel intervention is needed to provide high-repetition task-specific training early after stroke. Objective: This study aimed to investigate the effect of smart glove training (SGT) for upper-extremity rehabilitation in patients with subacute stroke. Methods: A prospective, multicenter, randomized, controlled study was conducted in patients with upper-extremity hemiparesis with Brunnstrom stage for arm 2-5 in the subacute phase after stroke. Eligible participants were randomly allocated to the SGT group or the control group. The SGT group underwent 30 min of standard occupational therapy plus 30 min of upper-extremity training with smart glove. The control group underwent standard occupational therapy for 30 min plus upper-extremity self-training (homework tasks at bedside) for 30 min. All participants underwent each intervention 5 days/week for 2 consecutive weeks. They were evaluated before, immediately after, and 4 weeks after the intervention. The primary outcome measure was the change in the score of the Fugl-Meyer assessment of the upper extremity (FMA-UE). Results: Twenty-three patients were enrolled. Repeated-measures analysis of covariance after controlling for age and disease duration showed significant time × group interaction effects in the FMA-UE, FMA-distal, and FMA-coordination/speed (p = 0.018, p = 0.002, p = 0.006). Repeated-measures analysis of variance showed significant time × group interaction effects in the FMA-UE, FMA-distal, and Box and Block Test (p = 0.034, p = 0.010, p = 0.046). Mann-Whitney U-test showed a statistically higher increase in the FMA-UE and FMA-distal in the SGT group than in the control group (p = 0.023, p = 0.032). Conclusion: Upper-extremity rehabilitation with a smart glove may reduce upper-extremity impairment in patients with subacute stroke. Clinical Trial Registration: ClinicalTrials.gov (NCT02592759).

Project description:ObjectiveTo characterise the safety and efficacy of anifrolumab in active lupus nephritis (LN) through year 2 of the phase II randomised, double-blind Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP)-LN trial (NCT02547922) of 2 anifrolumab dosing regimens versus placebo.MethodsPatients received intravenous anifrolumab 900 mg for the first 3 doses followed by 300 mg anifrolumab (intensified regimen (IR)), 300 mg anifrolumab (basic regimen (BR)) or placebo every 4 weeks throughout. To continue into Year 2, patients must have achieved at least partial renal response and a glucocorticoid tapering target.ResultsOf 147 randomised patients, 101 completed Year 1 study treatment; of these, 75 (74%) continued into Year 2 (anifrolumab IR: n=29, BR: n=23 and placebo: n=23). During Year 2, 72% of patients reported ≥1 adverse event (AE); serious AEs were reported in 6.9%, 8.7% and 8.7% of patients (anifrolumab IR, BR and placebo, respectively); 3 patients discontinued treatment due to an AE (anifrolumab IR: n=2 and placebo: n=1) and herpes zoster was reported in 2 patients (anifrolumab IR: n=1 and BR: n=1). The study was ongoing at the start of the pandemic, but no COVID-19 cases were reported. Of the 145 patients receiving treatment, more patients on the IR attained complete renal response at Week 104 compared with those on BR or placebo (27.3% vs 18.6% and 17.8%) and simultaneously achieved sustained glucocorticoid tapering (IR: 25.0%; BR: 18.6% and placebo: 17.8%). The improvements in estimated glomerular filtration rate were numerically larger in both anifrolumab groups versus placebo.ConclusionsThe safety and tolerability profile through Year 2 of TULIP-LN was generally consistent with Year 1, with promising efficacy results for the anifrolumab IR regimen. Collectively, the results support further investigation of an anifrolumab intensified dosing regimen in larger populations of patients with active proliferative LN.Trial registration numberNCT02547922.

Project description:BackgroundAlthough smoking is the leading cause of chronic obstructive pulmonary disease (COPD), many patients with COPD smoke, highlighting the need for effective smoking cessation interventions in this population. This study examined the efficacy and safety of varenicline in increasing smoking cessation rates through "gradual" versus "abrupt" cessation in COPD patients with low motivation to quit smoking.MethodsA randomized, open label, 30-week, controlled trial (ClinicalTrials.gov identifier: NCT02894957) was conducted between January 2019 and October 2020 at a center in Israel. Smokers with COPD, poorly motivated to quit, were randomized to 6 weeks of varenicline for smoking reduction and a target quit day (TQD) at the end of week 6 (gradual cessation group) or ad libitum smoking for 5 weeks, 1 week of varenicline, and a TQD at the end of week 6 (abrupt cessation group). After the pre-quit phase, both groups received 12-week regular varenicline treatment and 12-week follow-up. Primary outcome was biochemically-validated continuous abstinence for weeks 6-30. Secondary outcomes were: (1) biochemically-confirmed7-day point prevalence abstinence for weeks 4-30, (2) efficient smoking reduction (≥50% in number of cigarettes/day) in the pre-quit phase; and (3) number of cigarettes/day, motivation to quit, and changes in respiratory symptoms and spirometry from baseline through week 30.ResultsA drug recall issued by the study sponsor stopped the study after 70/242 (28.9%) patients had been enrolled. The gradual cessation group (n=29) had significantly higher continuous abstinence rates from TQD through week 30 versus the abrupt cessation group (n=41): 20.7% versus 4.9% (odds ratio [OR]=5.09; 95% confidence interval [CI] 0.89-29.17; p=0.048) and higher 7-day point prevalence abstinence levels at all time points but week 18 (p=0.027 at week 6, 0.056 at week 7, and 0.096 at week 9). Motivation to quit increased (p=0.002) and the number of cigarettes/day decreased (p=0.002) over time in both groups. Respiratory symptoms, but not spirometry, improved in both groups at week 30. Treatment was safe and well tolerated.ConclusionIn poorly motivated smokers with COPD, using varenicline for a 6-week gradual smoking cessation before TQD, compared with abrupt cessation, significantly increased quit rates up to 6 months. Results were not affected by the smaller-than-expected sample size. Further studies are needed to confirm these data.

Project description:BackgroundNicotine replacement therapy (NRT) bought over the counter (OTC) appears to be largely ineffective for smoking cessation, which may be partially explained by poor adherence. We developed and evaluated the NRT2Quit smartphone app (for iOS) designed to improve quit attempts with OTC NRT by improving adherence to the medications.MethodsThis study was a pragmatic double-blind randomised controlled trial with remote recruitment through leaflets distributed to over 300 UK-based community pharmacies. The study recruited adult daily smokers (≥10 cigarettes per day) who bought NRT, wanted to quit smoking, downloaded NTR2Quit and completed the registration process within the app. Participants were automatically randomly assigned within the app to the intervention (full) version of NRT2Quit or to its control (minimal) versions. The primary outcome was biochemically verified 4-week abstinence assessed at 8-week follow-up using Russell Standard criteria and intention to treat. Bayes factors were calculated for the cessation outcome. Secondary outcomes were self-reported abstinence, NRT use, app use and satisfaction with the app.ResultsThe study under-recruited. Only 41 participants (3.5% of the target sample) were randomly assigned to NRT2Quit (n = 16) or the control (n = 25) app versions between March 2015 and September 2016. The follow-up rate was 51.2%. The intervention participants had numerically higher biochemically verified quit rates (25.0% versus 8.0%, P = 0.19, odds ratio = 3.83, 0.61-24.02). The calculated Bayes factor, 1.92, showed that the data were insensitive to test for the hypothesis that the intervention app version aided cessation. The intervention participants had higher median logins (2.5 versus 0, P = 0.01) and were more likely to use NRT at follow-up (100.0% versus 28.6%, P = 0.03) and recommend NRT2Quit to others (100.0% versus 28.6%, P = 0.01).ConclusionsDespite very low recruitment, there was preliminary but inconclusive evidence that NRT2Quit may improve short-term abstinence and adherence among smokers using NRT. Well-powered studies on NRT2Quit are needed, but different recruitment methods will be required to engage smokers through community pharmacies or other channels.Trial registrationISRCTN ISRCTN33423896 , prospectively registered on 22 March 2015.

Dataset Information

Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial.

Publications

Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial.

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