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Lengthening adalimumab dosing interval in quiescent Crohn's disease patients: protocol for the pragmatic randomised non-inferiority LADI study.

ABSTRACT: INTRODUCTION:Adalimumab is effective for maintenance of remission in patients with Crohn's disease (CD) at a dose of 40?mg subcutaneously every 2 weeks. However, adalimumab is associated with (long-term) adverse events and is costly. The aim of this study is to demonstrate non-inferiority and cost-effectiveness of disease activity guided adalimumab interval lengthening compared to standard dosing of every other week (EOW). METHODS AND ANALYSIS:The Lengthening Adalimumab Dosing Interval (LADI) study is a pragmatic, multicentre, open label, randomised controlled non-inferiority trial. Non-inferiority is reached if the difference in cumulative incidence of persistent (>8 weeks) flares does not exceed the non-inferiority margin of 15%. 174?CD patients on adalimumab maintenance therapy in long-term (>9 months) clinical and biochemical remission will be included (C-reactive protein (CRP) <10?mg/L, faecal calprotectin (FC) <150?µg/g, Harvey-Bradshaw Index (HBI) <5). Patients will be randomised 2:1 into the intervention (adalimumab interval lengthening) or control group (adalimumab EOW). The intervention group will lengthen the adalimumab administration interval to every 3 weeks, and after 24 weeks to every 4 weeks. Clinical and biochemical disease activity will be monitored every 12 weeks by physician global assessment, HBI, CRP and FC. In case of disease flare, dosing will be increased. A flare is defined as two of three of the following criteria; FC>250 µg/g, CRP?10 mg/l, HBI?5. Secondary outcomes include cumulative incidence of transient flares, adverse events, predictors for successful dose reduction and cost-effectiveness. ETHICS AND DISSEMINATION:The study is approved by the Medical Ethics Committee Arnhem-Nijmegen, the Netherlands (registration number NL58948.091.16). Results will be published in peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBERS:EudraCT registry (2016-003321-42); Clinicaltrials.gov registry (NCT03172377); Dutch trial registry (NTRID6417).

SUBMITTER: Smits LJT

PROVIDER: S-EPMC7259868 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Lengthening adalimumab dosing interval in quiescent Crohn's disease patients: protocol for the pragmatic randomised non-inferiority LADI study.

Smits L J T LJT Pauwels R W M RWM Kievit W W de Jong D J DJ de Vries A C AC Hoentjen F F van der Woude C J CJ

BMJ open 20200526 5

<h4>Introduction</h4>Adalimumab is effective for maintenance of remission in patients with Crohn's disease (CD) at a dose of 40 mg subcutaneously every 2 weeks. However, adalimumab is associated with (long-term) adverse events and is costly. The aim of this study is to demonstrate non-inferiority and cost-effectiveness of disease activity guided adalimumab interval lengthening compared to standard dosing of every other week (EOW).<h4>Methods and analysis</h4>The Lengthening Adalimumab Dosing Int ...[more]

PMID: 32461297

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Project description:Introduction Anti-tumour necrosis factor (TNF) therapy has greatly improved treatment outcomes in patients with inflammatory bowel disease (IBD), but long-term use is associated with cutaneous reactions, susceptibility to infections and frequent injections or hospital visits. Several non-controlled studies have demonstrated that dose reduction is feasible for a subset of patients, provided that early detection of a disease flare is possible. Here, we aim to compare the effectiveness of interval lengthening with standard dosing in maintaining remission in young patients with IBD. Methods and analysis In this international, prospective, non-inferiority, partially randomised patient preference trial, we aim to recruit 148 patients aged 12–25 years with luminal Crohn’s disease or ulcerative colitis in sustained remission (ie, three consecutive in-range faecal calprotectin (FC) results or recently confirmed endoscopic remission). In the interventional arm, the dosing interval will be lengthened from 8 to 12 weeks for infliximab users and from 2 to 3 weeks for adalimumab users. In the control group, standard dosing will be continued. Rapid tests will be performed for FC every 4 weeks and for anti-TNF trough levels every 12 weeks. The primary outcome is the cumulative incidence of out-of-range FC results at 48-week follow-up. Secondary endpoints include time to get out-of-range FC results, cumulative incidence of adverse effects, proportion of patients progressing to loss of response and identification of predictors of successful interval lengthening. Ethics and dissemination The protocol has been approved by the Medical Ethics Review Committee of the University Medical Centre Groningen and is pending at the other participating centres. Results will be disseminated in peer-reviewed journals and presented at scientific meetings. Trial registration number EudraCT number: 2020-001811-26; ClinicalTrials.gov Identifier: NCT04646187. Protocol version 4, date 17 September 2021.

Project description:BackgroundDupuytren's contracture is a fibro-proliferative disease of the hands affecting over 2 million UK adults, particularly the white, male population. Surgery is the traditional treatment; however, recent studies have indicated that an alternative to surgery-collagenase clostridium histolyticum (collagenase)-is better than a placebo in the treatment of Dupuytren's contracture. There is however no robust randomised controlled trial that provides a definitive answer on the clinical effectiveness of collagenase compared with limited fasciectomy surgery. Dupuytren's intervention surgery vs collagenase trial (DISC) trial was therefore designed to fill this evidence gap.Methods/designThe DISC trial is a multi-centre pragmatic two-arm parallel-group, randomised controlled trial. Participants will be assigned 1:1 to receive either collagenase injection or surgery (limited fasciectomy). We aim to recruit 710 adult participants with Dupuytren's contracture. Potential participants will be identified in primary and secondary care, screened by a delegated clinician and if eligible and consenting, baseline data will be collected and randomisation completed. The primary outcome will be the self-reported patient evaluation measure assessed 1 year after treatment. Secondary outcome measures include the Unité Rhumatologique des Affections de la Main Scale, the Michigan Hand Questionnaire, EQ-5D-5L, resource use, further procedures, complications, recurrence, total active movement and extension deficit, and time to return to function. Given the limited evidence comparing recurrence rates following collagenase injection and limited fasciectomy, and the importance of a return to function as soon as possible for patients, the associated measures for each will be prioritised to allow treatment effectiveness in the context of these key elements to be assessed. An economic evaluation will assess the cost-effectiveness of treatments, and a qualitative sub-study will assess participants' experiences and preferences of the treatments.DiscussionThe DISC trial is the first randomised controlled trial, to our knowledge, to investigate the clinical and cost-effectiveness of collagenase compared to limited fasciectomy surgery for patients with Dupuytren's contracture.Trial registrationClinical.Trials.gov ISRCTN18254597 . Registered on April 11, 2017.

Project description:BACKGROUND:At least half of all adult women will experience infective cystitis (urinary tract infection: UTI) at least once in their life and many suffer from repeated episodes. Recurrent urinary tract infection (rUTI) in adult women is usually treated with long-term, low-dose antibiotics and current national and international guidelines recommend this as the 'gold standard' preventative treatment. Although they are reasonably effective, long-term antibiotics can result in bacteria becoming resistant not only to the prescribed antibiotic but to other antimicrobial agents. The problem of antimicrobial resistance is recognised as a global threat and the recent drive for antibiotic stewardship has emphasised the need for careful consideration prior to prescribing antibiotics. This has led clinicians and patients alike to explore potential non-antibiotic options for recurrent UTI prevention. DESIGN /METHODS:This is a multicentre, pragmatic, patient-randomised, non-inferiority trial comparing a non-antibiotic preventative treatment for rUTI in women, methenamine hippurate, against the current standard of daily low-dose antibiotics. Women who require preventative treatment for rUTI are the target population. This group is comprised of those with a diagnosis of rUTI, defined as three episodes in 1 year or two episodes in 6 months, and those with a single severe infection requiring hospitalisation. Participants will be recruited from secondary care urology / urogynaecology departments in the UK following referral with rUTI. Participants will be followed up during a 12-month period of treatment and in the subsequent 6 months following completion of the prophylactic medication. Outcomes will be assessed from patient recorded symptoms, quality of life questionnaires and microbiological examination of urine and perineal swabs. The primary outcome is the incidence of symptomatic antibiotic-treated UTI self-reported by participants during the 12-month period of preventative treatment. Health economic outcomes will also be assessed to define the cost-effectiveness of both treatments. A qualitative study will be conducted in the first 8 months of the trial to explore with participants/non-participants' and recruiting clinicians' views on trial processes and identify potential barriers to recruitment, reasons for participating and non-participation and for dropping out of the study. DISCUSSION:The study was commissioned and funded by the National Institute for Health Research (NIHR) and approved under the Medicines and Healthcare products Regulatory Agency (MHRA) notification scheme as a 'Type A' study. TRIAL REGISTRATION:International Standard Randomised Controlled Trial Number (ISRCTN), registry number: ISRCTN70219762 . Registered on 31 May 2016.

Project description:The traditional system of routine outpatient follow-up of chronic disease in secondary care may involve a waste of resources if patients are well. The use of patient-reported outcomes (PRO) could support more flexible, cost-saving follow-up activities. AmbuFlex is a PRO system used in outpatient follow-up in the Central Denmark Region. PRO questionnaires are sent to patients at fixed intervals. The clinicians use the PRO data to decide whether a patient needs a visit or not (standard telePRO). PRO may make patients become more involved in their own care pathway, which may improve their self-management. Better self-management may also be achieved by letting patients initiate contact. The aim of this study is to obtain data on the effects of patient-initiated follow-up (open access telePRO) on resource utilisation, quality of care, and the patient perspective.The study is a pragmatic, randomised, controlled trial in outpatients with epilepsy. Participants are randomly assigned to one of two follow-up activities: a) standard telePRO or b) open access telePRO. Inclusion criteria are age???15 years and previous referral to standard telePRO follow-up at Aarhus University Hospital, Denmark. Furthermore, patients must have answered the last questionnaire via the Internet. The number of contacts will be used as the primary outcome measure. Secondary outcome measures include well-being (WHO-5 Well-Being Index), general health, number of seizures, treatment side effects, mortality, health literacy (Health Literacy Questionnaire), self-efficacy (General Self-Efficacy scale), patient activation, confidence, safety, and satisfaction. In addition, the patient perspective will be explored by qualitative methods. Data will be collected at baseline and 18 month after randomisation. Inclusion of patients in the study started in January 2016. Statistical analysis will be performed on an intention-to-treat and per-protocol basis. For qualitative data, the interpretive description strategy will be used.The benefits and possible drawbacks of the PRO-based open access approach will be evaluated. The present study will provide important knowledge to guide future telePRO interventions in relation to effect on resource utilisation, quality of care, and the patient perspective.ClinicalTrials.gov: NCT02673580 (Registration date January 28, 2016).

Project description:To compare adalimumab versus etanercept in patients with active rheumatoid arthritis (RA) to test the hypothesis that adalimumab was not inferior to etanercept in terms of drug continuation by a margin of 15% after 52 weeks of treatment.Pragmatic, randomised, parallel group, multicentre, unblinded and non-inferiority trial. Randomisation stratified by baseline use of methotrexate.125 adults with active RA despite treatment with two disease-modifying drugs (DMARDs), including methotrexate randomised (1?:?1) to adalimumab 40 mg alternate weeks or etanercept 50 mg weekly, added to existing medication.The primary outcome was proportion of patients continuing treatment after 52 weeks. Secondary outcomes included: disease activity score using 28 joints (DAS28), treatment satisfaction (TSQM V.2), health status (Euroqol-5D), drug toxicity and persistence with therapy after 2 years.Persistence with therapy was 65% for adalimumab versus 56.7% for etanercept (one-sided 95% CI for proportion still taking adalimumab minus proportion on etanercept ?-7.9%); demonstrating non-inferiority at the 15% margin. After 2 years these figures were: adalimumab 58.3% and etanecept 43.3% (CI ?-1.7%). The proportion of good, moderate and non-responders based on DAS28-C reactive protein, after 52 weeks, were 26.3%, 33.3% and 40.4%, respectively, for adalimumab versus 16.7%, 31.7% and 51.7%, respectively, for etanercept (p=0.158). Baseline median EQ-5D scores improved from 0.52 to 0.69 for adalimumab and from 0.52 to 0.64 for etanercept (p=0.046) after 52 weeks. Global satisfaction, effectiveness, side effects and convenience scores based on the TSQM were similar for both drugs. Fourteen serious adverse events occurred including two deaths from myocardial infarction, one patient with ovarian cancer and one with acute myeloid leukaemia.Clinicians choosing a first tumour necrosis factor inhibitor for active RA, despite trying two DMARDs including methotrexate, may choose either adalimumab or etanercept in the knowledge that these drugs are similarly effective.EU Clinical Trials Register 2006-006275-21/GB.

Project description:BackgroundAvailable research on the contribution of traditional midwifery to safe motherhood focuses on retraining and redefining traditional midwives, assuming cultural prominence of Western ways. Our objective was to test if supporting traditional midwives on their own terms increases cultural safety (respect of Indigenous traditions) without worsening maternal health outcomes.MethodsPragmatic parallel-group cluster-randomised controlled non-inferiority trial in four municipalities in Guerrero State, southern Mexico, with Nahua, Na savi, Me'phaa and Nancue ñomndaa Indigenous groups. The study included all pregnant women in 80 communities and 30 traditional midwives in 40 intervention communities. Between July 2015 and April 2017, traditional midwives and their apprentices received a monthly stipend and support from a trained intercultural broker, and local official health personnel attended a workshop for improving attitudes towards traditional midwifery. Forty communities in two control municipalities continued with usual health services. Trained Indigenous female interviewers administered a baseline and follow-up household survey, interviewing all women who reported pregnancy or childbirth in all involved municipalities since January 2016. Primary outcomes included childbirth and neonatal complications, perinatal deaths, and postnatal complications, and secondary outcomes were traditional childbirth (at home, in vertical position, with traditional midwife and family), access and experience in Western healthcare, food intake, reduction of heavy work, and cost of health care.ResultsAmong 872 completed pregnancies, women in intervention communities had lower rates of primary outcomes (perinatal deaths or childbirth or neonatal complications) (RD -0.06 95%CI - 0.09 to - 0.02) and reported more traditional childbirths (RD 0.10 95%CI 0.02 to 0.18). Among institutional childbirths, women from intervention communities reported more traditional management of placenta (RD 0.34 95%CI 0.21 to 0.48) but also more non-traditional cold-water baths (RD 0.10 95%CI 0.02 to 0.19). Among home-based childbirths, women from intervention communities had fewer postpartum complications (RD -0.12 95%CI - 0.27 to 0.01).ConclusionsSupporting traditional midwifery increased culturally safe childbirth without worsening health outcomes. The fixed population size restricted our confidence for inference of non-inferiority for mortality outcomes. Traditional midwifery could contribute to safer birth among Indigenous communities if, instead of attempting to replace traditional practices, health authorities promoted intercultural dialogue.Trial registrationRetrospectively registered ISRCTN12397283 . Trial status: concluded.

Dataset Information

Lengthening adalimumab dosing interval in quiescent Crohn's disease patients: protocol for the pragmatic randomised non-inferiority LADI study.

Publications

Lengthening adalimumab dosing interval in quiescent Crohn's disease patients: protocol for the pragmatic randomised non-inferiority LADI study.

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