Placebo-controlled Non-inferiority Trial Research Articles

Predicting Gout Flares in People Starting Allopurinol Using the Start-Low Go-Slow Dose Escalation Strategy.

The study objective was to determine predictors of gout flare when commencing allopurinol using the "start-low go-slow" dose escalation strategy. A post hoc analysis of a 12-month double-blind placebo-controlled noninferiority trial with participants randomized 1:1 to colchicine 0.5 mg daily or placebo for the first six months was undertaken. Multivariate logistic regression models were used to identify independent predictors of gout flares in the first and last six months of the trial. Multivariable analysis revealed a significant association between risk of a gout flare in the first six months and flare in the month before starting allopurinol (odds ratio [OR] 2.65, 95% confidence interval [CI] 1.36-5.17) and allopurinol 100 mg starting dose (OR 3.21, 95% CI 1.41-7.27). The predictors of any gout flares in the last six months of the trial, after stopping colchicine or placebo, were having received colchicine (OR 2.95, 95% CI 1.48-5.86), at least one flare in the month before stopping study drug (OR 5.39, 95% CI 2.21-13.15), and serum urate ≥0.36 mmol/L at month 6 (OR 2.85, 95% CI 1.14-7.12). Anti-inflammatory prophylaxis when starting allopurinol using the "start-low go-slow" dose escalation strategy may be best targeted at those who have had a gout flare in the month before starting allopurinol and are commencing allopurinol 100 mg daily. For those with ongoing gout flares during the first six months of starting allopurinol who have not yet achieved serum urate target, a longer period of prophylaxis may be required.

What Is the Role of a Periarticular Injection for Knee Arthroplasty Patients Receiving a Multimodal Analgesia Regimen Incorporating Adductor Canal and Infiltration Between the Popliteal Artery and Capsule of the Knee Blocks? A Randomized Blinded Placebo-Controlled Noninferiority Trial.

Optimal analgesic protocols for total knee arthroplasty (TKA) patients remain controversial. Multimodal analgesia is advocated, often including peripheral nerve blocks and/or periarticular injections (PAIs). If 2 blocks (adductor canal block [ACB] plus infiltration between the popliteal artery and capsule of the knee [IPACK]) are used, also performing PAI may not be necessary. This noninferiority trial hypothesized that TKA patients with ACB + IPACK + saline PAI (sham infiltration) would have pain scores that were no worse than those of patients with ACB + IPACK + active PAI with local anesthetic. A multimodal analgesic protocol of spinal anesthesia, ACB and IPACK blocks, intraoperative ketamine and ketorolac, postoperative ketorolac followed by meloxicam, acetaminophen, duloxetine, and oral opioids was used. Patients undergoing primary unilateral TKA were randomized to receive either active PAI or control PAI. The active PAI included a deep injection, performed before cementation, of bupivacaine 0.25% with epinephrine, 30 mL; morphine; methylprednisolone; cefazolin; with normal saline to bring total volume to 64 mL. A superficial injection of 20 mL bupivacaine, 0.25%, was administered before closure. Control injections were normal saline injected with the same injection technique and volumes. The primary outcome was numeric rating scale pain with ambulation on postoperative day 1. A noninferiority margin of 1.0 was used. Ninety-four patients were randomized. NRS pain with ambulation at POD1 in the ACB + IPACK + saline PAI group was not found to be noninferior to that of the ACB + IPACK + active PAI group (difference = 0.3, 95% confidence interval [CI], [-0.9 to 1.5], P = .120). Pain scores at rest did not differ significantly among groups. No significant difference was observed in opioid consumption between groups. Cumulative oral morphine equivalents through postoperative day 2 were 89 ± 40 mg (mean ± standard deviation), saline PAI, vs 73 ± 52, active PAI, P = .1. No significant differences were observed for worst pain, fraction of time in severe pain, pain interference, side-effects (nausea, drowsiness, itching, dizziness), quality of recovery, satisfaction, length of stay, chronic pain, and orthopedic outcomes. For TKA patients given a comprehensive analgesic protocol, use of saline PAI did not demonstrate noninferiority compared to active PAI. Neither the primary nor any secondary outcomes demonstrated superiority for active PAI, however. As we cannot claim either technique to be better or worse, there remains flexibility for use of either technique.

Is colchicine prophylaxis required with start-low go-slow allopurinol dose escalation in gout? A non-inferiority randomised double-blind placebo-controlled trial

ObjectivesTo determine whether placebo is non-inferior to low-dose colchicine for reducing gout flares during the first 6 months of allopurinol using the ‘start-low go-slow’ dose approach.MethodsA 12-month double-blind, placebo-controlled non-inferiority...

A double-blinded randomized placebo-controlled non-inferiority trial protocol for postoperative infections associated with canine pyometra

BackgroundPyometra is a common infectious condition, especially in elderly bitches. In addition to an infected uterus, dogs may have concurrent urinary tract infection (UTI). The preferred treatment is surgical removal of the ovaries and uterus, whereupon the general prognosis is excellent. In addition, antimicrobial therapy is frequently prescribed for postoperative treatment. However, no research exists on the benefit of postoperative antimicrobial treatment in uncomplicated canine pyometra. Antimicrobial resistance has become a major challenge in treatment of bacterial infections. Diminishing overuse of antimicrobial agents is essential for controlling the development of antimicrobial resistance in both animals and humans.MethodsThis double-blinded, randomized, placebo-controlled two-arm clinical trial is designed to compare the incidence of postoperative infections associated with surgical treatment of uncomplicated pyometra followed by two different treatment protocols. For the study, 150 dogs presenting with an uncomplicated pyometra and that are to undergo surgical treatment will be recruited. Dogs with body weight < 3 or > 93 kg, complicated pyometra, primary disease increasing the risk of infection, or immunosuppressive medication will be excluded. All dogs will receive one dose of sulfadoxine-trimethoprim intravenously as an antimicrobial prophylaxis. Postoperatively, dogs will be randomized to receive either a five-day course of placebo or an active drug, sulfadiazine-trimethoprim orally. During the surgery microbiological samples will be taken from urine and uterine content. The follow-up includes a control visit in 12 days and an interview of the owner 30 days after surgery. If bacteriuria is detected at the time of surgery, a urinary sample will be cultured for bacterial growth at the control visit. The primary outcome is the incidence of a postoperative surgical site infection (SSI), and the secondary outcome is the occurrence of clinical UTI with bacteriuria. Intention-to-treat and per-protocol analyses will be performed to compare outcome incidences between the treatment groups.DiscussionResearch-based evidence is necessary to create treatment guidelines for judicious use of antimicrobials. The goals of this study are to provide evidence for reducing the use of antimicrobials and targeting the treatment to patients proven to benefit from it. Publishing the trial protocol will increase transparency and promote open science practices.

Is a Lower Dose of More Bioavailable Iron (18-mg Ferrous Bisglycinate) Noninferior to 60-mg Ferrous Sulfate in Increasing Ferritin Concentrations While Reducing Gut Inflammation and Enteropathogen Detection in Cambodian Women? A Randomized Controlled Noninferiority Trial

BackgroundGlobal guidelines recommend untargeted iron supplementation for women in regions of anemia prevalence ≥40%, such as Cambodia. However, the potential harms of untargeted iron on the gut have not been rigorously studied in women and likely vary depending on iron dose and form. ObjectivesWe investigated if a lower dose of a highly bioavailable iron amino acid chelate was as effective as the standard dose of iron salts in increasing ferritin concentrations and whether any differences were observed in gut inflammation or enteropathogen detection. MethodsA double-blind, randomized placebo-controlled noninferiority trial was conducted in Cambodia. Nonpregnant women (n = 480, 18–45 y) were randomly assigned to 60-mg ferrous sulfate, 18-mg ferrous bisglycinate, or placebo for 12 wk. Nonfasting blood and stool specimens were collected at baseline and 12 wk. Ferritin and fecal calprotectin were measured with an ELISA. A molecular assay was used to detect 11 enteropathogens in a random subset of n = 100 women. Generalized linear mixed-effects models were used to estimate the adjusted mean difference in ferritin concentrations at 12 wk (primary outcome), as compared with our ‘a priori’ noninferiority margin of 20 μg/L. ResultsBaseline anemia and iron deficiency prevalence was low (17% and 6%, respectively). The adjusted mean difference in ferritin concentrations between the iron groups was 14.6 (95% confidence interval [CI]: 7.6, 21.6) μg/L. Mean ferritin concentration at 12 wk was higher in the ferrous sulfate (99 [95% CI: 95, 103] μg/L, P < 0.001) than in ferrous bisglycinate (84 [95% CI: 80, 88] μg/L) and placebo groups (78 [95% CI: 74, 82] μg/L). No differences in fecal calprotectin concentrations or enteropathogen detection were observed across groups at 12 wk. ConclusionsFerrous bisglycinate (18-mg) was not as effective as ferrous sulfate (60-mg) in increasing ferritin concentrations and did not differentially influence biomarkers of gut health in this predominantly iron-replete population of Cambodian women.This trial was registered at clinicaltrials.gov registry as NCT04017598.

Effect of 7 vs 14 Days of Antibiotic Therapy on Resolution of Symptoms Among Afebrile Men With Urinary Tract Infection

Determination of optimal treatment durations for common infectious diseases is an important strategy to preserve antibiotic effectiveness. To determine whether 7 days of treatment is noninferior to 14 days when using ciprofloxacin or trimethoprim/sulfamethoxazole to treat urinary tract infection (UTI) in afebrile men. Randomized, double-blind, placebo-controlled noninferiority trial of afebrile men with presumed symptomatic UTI treated with ciprofloxacin or trimethoprim/sulfamethoxazole at 2 US Veterans Affairs medical centers (enrollment, April 2014 through December 2019; final follow-up, January 28, 2020). Of 1058 eligible men, 272 were randomized. Participants continued the antibiotic prescribed by their treating clinician for 7 days of treatment and were randomized to receive continued antibiotic therapy (n = 136) or placebo (n = 136) for days 8 to 14 of treatment. The prespecified primary outcome was resolution of UTI symptoms by 14 days after completion of active antibiotic treatment. A noninferiority margin of 10% was selected. The as-treated population (participants who took ≥26 of 28 doses and missed no more than 2 consecutive doses) was used for the primary analysis, and a secondary analysis included all patients as randomized, regardless of treatment adherence. Secondary outcomes included recurrence of UTI symptoms and/or adverse events within 28 days of stopping study medication. Among 272 patients (median [interquartile range] age, 69 [62-73] years) who were randomized, 100% completed the trial and 254 (93.4%) were included in the primary as-treated analysis. Symptom resolution occurred in 122/131 (93.1%) participants in the 7-day group vs 111/123 (90.2%) in the 14-day group (difference, 2.9% [1-sided 97.5% CI, -5.2% to ∞]), meeting the noninferiority criterion. In the secondary as-randomized analysis, symptom resolution occurred in 125/136 (91.9%) participants in the 7-day group vs 123/136 (90.4%) in the 14-day group (difference, 1.5% [1-sided 97.5% CI, -5.8% to ∞]) Recurrence of UTI symptoms occurred in 13/131 (9.9%) participants in the 7-day group vs 15/123 (12.9%) in the 14-day group (difference, -3.0% [95% CI, -10.8% to 6.2%]; P = .70). Adverse events occurred in 28/136 (20.6%) participants in the 7-day group vs 33/136 (24.3%) in the 14-day group. Among afebrile men with suspected UTI, treatment with ciprofloxacin or trimethoprim/sulfamethoxazole for 7 days was noninferior to 14 days of treatment with regard to resolution of UTI symptoms by 14 days after antibiotic therapy. The findings support the use of a 7-day course of ciprofloxacin or trimethoprim/sulfamethoxazole as an alternative to a 14-day course for treatment of afebrile men with UTI. ClinicalTrials.gov identifier: NCT01994538.

A Novel Nano-Iron Supplement Versus Standard Treatment for Iron Deficiency Anaemia in Children 6-35 Months (IHAT-GUT Trial): A Double-Blind, Randomised, Placebo-Controlled Non-Inferiority Trial in the Gambia

Background: Iron deficiency anaemia (IDA) is the leading cause of years lost to disability in most sub-Saharan African countries and is especially common in young children. The IHAT-GUT trial assessed the efficacy and safety of a novel nano iron supplement, which is a dietary ferritin analogue termed iron hydroxide adipate tartrate (IHAT), for the treatment of IDA in children under 3 years of age. Methods: In this single-centre, randomised, double-blind, parallel, placebo-controlled, non-inferiority study in The Gambia, children 6-35 months with IDA (7£Hb<11g/dL and ferritin<30mg/L) were randomly assigned (1:1:1) to receive either IHAT, ferrous sulphate (FeSO4) or placebo daily for 3 months (85 days). The daily iron dose was 12.5mg Fe equivalent for FeSO4 and the estimated bioequivalent dose for IHAT (20mg Fe). The primary efficacy endpoint was the composite of haemoglobin response at day 85 and correction of iron deficiency. The non-inferiority margin was 10%. The primary safety endpoint was moderate-severe diarrhoea analysed as incidence density and prevalence over the 3 months intervention. Secondary endpoints reported herein include hospitalisation, acute respiratory infection, malaria, treatment failures, iron handling markers, inflammatory markers, longitudinal prevalence of diarrhoea and incidence density of bloody diarrhoea. Main analyses were per-protocol (PP) and intention-to-treat (ITT) analyses. Findings: Between Nov 2017 and Nov 2018, 642 children were randomised into the study (214 per study group). A total of 50 children (26.5%) in the IHAT group achieved the primary efficacy endpoint, as compared with 42 (21.2%) in the FeSO4 group (OR 1.39, 80% CI 1.01-1.91, P=0.0002 for non-inferiority) and with 2 (1%) in the placebo group. Diarrhoea prevalence was similar between groups, with 40 children (21.2%) in the IHAT group developing at least one episode of moderate-severe diarrhoea over the 85 days intervention, compared with 47 (23.7%) in the FeSO4 group (OR 1.18, 80% CI 0.86-1.62,P=0.25 for superiority) and 40 (20.5%) in the placebo group (OR 0.96, 80% CI 0.7-1.33, P=0.001 for noninferiority). Incidence density of moderate-severe diarrhoea was 2.74 in the IHAT group, 3.51 in the FeSO4 group and 2.96 in the placebo group (RR 0.77, 80% CI 0.59-1.01, P=0.11 for superiority). There were 143 children with adverse events (AEs) in the IHAT group, 146 in the FeSO4 group and 143 in the placebo group. There were overall 35 cases of diarrhoea reported as AEs in the IHAT group compared with 51 cases in the FeSO4 group and 37 cases in the placebo group. Interpretation: In young children with IDA, IHAT was non-inferior to standard-of-care FeSO4 in terms of ID correction and haemoglobin response and was not associated with increased adverse events or cases of diarrhoea in comparison with placebo. Clinical Trial Registration Details: This trial is registered with clinicaltrials.gov (NCT02941081). Funding Information: Bill & Melinda Gates Foundation (OPP1140952). Declaration of Interests: D.I.A.P., N.F. and J.J.P. are inventors of the IHAT iron supplementation technology, for which they could receive future awards to inventors through the MRC Awards to Inventor scheme. They are also scientific advisors to Nemysis Ltd, who now hold the license for IHAT. They have received honoraria or consultancy fees from some or all of: Vifor Pharma UK, Shield Therapeutics, Entia Ltd, Danone Nutricia, UN Food and Agriculture Organisation (FAO) and Nemysis Ltd, for work concerning iron in health. D.I.A.P. has since moved to full employment in the iron and health industry with Vifor Pharma UK but all work pertaining to this publication was conducted whilst at the University of Cambridge and MRC Unit The Gambia at LSHTM. Notwithstanding, the authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Ethics Approval Statement: The trial was conducted in accordance with the ethical principles of the Declaration of Helsinki, and that are consistent with the International Conference on Harmonisation (ICH) requirements for Good Clinical Practice (GCP), and the applicable regulatory requirements. The study sponsor was the London School of Hygiene and Tropical Medicine (LSHTM) and the study was conducted at the Medical Research Council (MRC) Unit The Gambia at LSHTM (MRCG). Scientific advice on the study protocol was given by the UK Medicines and Healthcare products Regulatory Agency (MHRA 1400, 21/12/2016). The study protocol and any subsequent amendments were reviewed and approved by The Gambia Government/MRC Joint Ethics Committee(reference SCC1489). Clinical Trials Authorisation was granted by the Medicines Control Agency, The Gambia (HP373/347/16/MJK(80)). Informed consent given by parent or guardian.

639. Short Course Therapy for Urinary Tract Infections (SCOUT) in Children

BackgroundThe AAP recommends 7 to 14-days of antimicrobials for the treatment of urinary tract infections (UTIs), one of the most common bacterial infections of childhood. However, most physicians routinely prescribe at least 10 days of therapy. Prior observational studies suggest that courses shorter than 10 days might be effective.MethodsThe primary objective was to determine if halting antimicrobial therapy in children who improved clinically after 5 days of therapy (short course therapy) results in a similar failure rate as children who continue antimicrobials for an additional 5 days (standard course therapy).This was a multi-center, randomized, double-blind, placebo-controlled non-inferiority clinical trial of children ages 2 to 10 years with UTI. Subjects treated with 1 of 5 antibiotics (trimethoprim-sulfamethoxazole, amoxicillin-clavulanate, cefixime, cefdinir or cephalexin) were eligible. Children were stratified by presence or absence of fever and were enrolled if they had clinical improvement before Day 5 of treatment. The a priori equivalence interval was set at 0.05 for a one-sided analysis. The primary outcome was development of a symptomatic UTI defined as the presence of symptoms, pyuria, and a positive urine culture. The Intent-to-Treat population included children who took at least one dose of study medication.ResultsA total of 693 children were randomized, 345 to short course and 348 to standard course. Median age was 4 years old (IQR; 2-6), 652 (96.3%) were female and 255 were febrile (37%). Treatment success rate was 322/336 (96%) for short course and 326/328 (99%) for standard course. The 95% upper CI limit for the difference was 0.054. Treatment failure was not related to age group, fever at presentation, antibiotic type, or study site. There were no significant differences between groups the in the rates of adverse events, recurrent infection, clinical symptoms that may have been related to UTI, or emergent antibiotic resistance.ConclusionIn children aged 2 months to 10 years with UTI, halting antimicrobial therapy in children who had exhibited clinical improvement after 5 days and continuing for an additional 5 days both resulted in high success rates. However, short course was inferior to treatment for 10 days.Disclosures Kevin J. Downes, MD, Merck, Inc. (Grant/Research Support) Brian T. Fisher, DO, MPH, MSCE, Astellas (Advisor or Review Panel member)Merck (Grant/Research Support)Pfizer (Grant/Research Support)

The IDEAL trial - a study protocol for a phase III randomized, double-blinded clinical trial assessing the ultra-short antibiotic prophylaxis of Isoniazid and Rifapentine in non-immunosuppressed patients with newly diagnosed latent tuberculosis

Introduction Tuberculosis (TB) is a global infectious disease that has plagued human beings for centuries. It currently ranks as one of the primary causes of death by a single agent. Treatment of latent TB (LTBI) is one of the cornerstones used to prevent the activation of TB. The current regimens are lengthy, associated with poor treatment adherence and several side effects. The need for shorter regimens is essential to control TB infection and accomplish the “End TB Strategy,” which has been proclaimed by the World Health Organization (WHO). Our study aims to provide a study design that assesses the efficacy of one month of Isoniazid (IHN) and Rifapentine (RFT) in non-immunosuppressed patients. Methods The proposed study will be a phase III, single-center, randomized, two-arms (1:1 ratio), double-blinded, placebo-controlled non-inferiority trial. We will include immunocompetent patients above the age of 18 with a new diagnosis of LTBI. Participants will be randomized, either receiving one month of INH with RFT or 6 months of INH alone with respective placebo to maintain blinding. The primary study outcome is the cumulative incidence of active TB in the studied treatment arms. The secondary outcome is the cumulative incidence and severity of adverse effects of the studied regimens. Discussion Given the scope and spread of LTBI around the globe, shorter and safer treatment options are of the utmost importance to eradicate TB. The proposed trial can contribute to this objective by improving the current standard of care. Potential disadvantages of the trial design include the need for many participants, trial duration, and costs.

Clinical Surveillance vs. Anticoagulation For low-risk patiEnts with isolated SubSegmental Pulmonary Embolism: protocol for a multicentre randomised placebo-controlled non-inferiority trial (SAFE-SSPE)

IntroductionThe clinical significance of subsegmental pulmonary embolism (SSPE) is currently unclear. Although growing evidence from observational studies suggests that withholding anticoagulant treatment may be a safe option in selected patients...

Randomized Trial of Amoxicillin for Pneumonia in Pakistan

BackgroundThe World Health Organization (WHO) recommends oral amoxicillin for patients who have pneumonia with tachypnea, yet trial data indicate that not using amoxicillin to treat this condition may be noninferior to using amoxicillin.MethodsWe conducted a double-blind, randomized, placebo-controlled noninferiority trial involving children at primary health care centers in low-income communities in Karachi, Pakistan. Children who were 2 to 59 months of age and who met WHO criteria for nonsevere pneumonia with tachypnea were randomly assigned to a 3-day course of a suspension of amoxicillin (the active control) of 50 mg per milliliter or matched volume of placebo (the test regimen), according to WHO weight bands (500 mg every 12 hours for a weight of 4 to <10 kg, 1000 mg every 12 hours for a weight of 10 to <14 kg, or 1500 mg every 12 hours for a weight of 14 to <20 kg). The primary outcome was treatment failure during the 3-day course of amoxicillin or placebo. The prespecified noninferiority margin was 1.75 percentage points.ResultsFrom November 9, 2014, through November 30, 2017, a total of 4002 children underwent randomization (1999 in the placebo group and 2003 in the amoxicillin group). In the per-protocol analysis, the incidence of treatment failure was 4.9% among placebo recipients (95 of 1927 children) and 2.6% among amoxicillin recipients (51 of 1929 children) (between-group difference, 2.3 percentage points; 95% confidence interval [CI], 0.9 to 3.7). Results were similar in the intention-to-treat analysis. The presence of fever and wheeze predicted treatment failure. The number needed to treat to prevent one treatment failure was 44 (95% CI, 31 to 80). One patient (<0.1%) in each group died. Relapse occurred in 40 children (2.2%) in the placebo group and in 58 children (3.1%) in the amoxicillin group.ConclusionsAmong children younger than 5 years of age with nonsevere pneumonia, the frequency of treatment failure was higher in the placebo group than in the amoxicillin group, a difference that did not meet the noninferiority margin for placebo. (Funded by the Joint Global Health Trials Scheme [of the Department for International Development, Medical Research Council, and Wellcome] and others; RETAPP ClinicalTrials.gov number, NCT02372461.)

Herbal Treatment with Uva Ursi Extract &lt;i&gt;versus&lt;/i&gt; Fosfomycin for Women with Uncomplicated Urinary Tract Infection: A Double-Blind, Randomised, Controlled Comparative Effectiveness Phase 4 Trial (REGATTA)

Background: Antimicrobial resistance threatens the treatment success in patients with uncomplicated urinary tract infection (UTI). Uva Ursi (UU) is a widely used herbal remedy, which is approved in Germany as Arbutin to treat symptoms of UTIs. We aimed to explore whether initial treatment with UU reduces antibiotic use in women with uncomplicated UTI without increasing symptom burden and rate of complications. Methods: We did a pragmatic double-blind, randomised, placebo-controlled non-inferiority trial in 42 German general practices. Women aged 18–75 years with suspected uncomplicated UTI and at least two of the symptoms dysuria, urgency, frequency or low abdominal pain were randomly assigned (1:1) to either UU (dry extract) 105 mg 3 × 2 tablets for 5 days (intervention) or fosfomycin 3g single dose (control) and respective placebo dummies. Both participants and investigators were blinded. The two co-primary outcomes were 1) number of all antibiotic courses regardless of indication from day 0–28, and 2) symptom burden, defined as weighted sum of daily total symptom scores from day 0–7, both assessed by intention to treat. The predefined non-inferiority margin for symptom burden was 125%. Findings: Between May 3, 2017, and May 23, 2019, 917 women were screened, of whom 398 were randomly allocated to either UU (207) or fosfomycin (191). For the co-primary outcome 1) 385 women were analysed (UU 196, fosfomycin 189) and for 2) 398 (UU 207 and fosfomycin 191). Five women did not receive the intervention (UU 3, fosfomycin 2), and for 13 patients no information on antibiotic intake was available (UU 11, fosfomycin 2). The number of antibiotic courses from day 0–28 was 63∙6% lower (95% confidence interval (CI) 53∙6%–71.4%, p<0.0001) in the UU group, with 92 courses as compared to 233 in the fosfomycin group. The ratio of the total symptom burden in the UU group compared to control was 136.5% (95% CI 122∙7–151∙9). In the UU group, eight women developed pyelonephritis and three fever as compared to two women with pyelonephritis and none with fever in the fosfomycin group. Otherwise there was no difference in the occurrence of adverse events. Interpretation: Initial treatment with UU reduced antibiotic use but lead to higher symptom burden in women with uncomplicated UTI. Higher occurrence of pyelonephritis and fever argue against UU as initial treatment in general. Our findings suggest that UU might provide a further non-antibiotic treatment approach for women who wish to avoid immediate antibiotics and as long as fast switch to antibiotic treatment is warranted. Trial Registration: The trial is registered with Clinical trials.gov, NCT03151603. Funding Statement: The study was funded by the German Federal Ministry of Education and Research (BMBF) No. 01KG1601. Declaration of Interests: All authors declare that they have no competing interest and no financial relationships with any organisations that might have an interest in the submitted work. All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/coi_disclosure.pdf. Ethics Approval Statement: The trial was done in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki and in cooperation with the Clinical Trials Unit of the University Medical Centre Gottingen. The trial protocol was developed following SPIRIT guidelines (standard protocol items: recommendations for interventional trials)19 and was approved by the Ethics Committee of the University Medical Center Gottingen in November 2016 (Ref. Nr. 16/11/16).

Re: Treatment Duration of Febrile Urinary Tract Infection: A Pragmatic Randomized, Double-blind, Placebo-controlled Non-inferiority Trial in Men and Women

Re: Treatment Duration of Febrile Urinary Tract Infection: A Pragmatic Randomized, Double-blind, Placebo-controlled Non-inferiority Trial in Men and Women

Comparison of home fortification with two iron formulations among Kenyan children: Rationale and design of a placebo-controlled non-inferiority trial.

IntroductionHome fortification powders containing iron and other micronutrients have been recommended by World Health Organisation to prevent iron deficiency anaemia in areas of high prevalence. There is evidence, however, that home fortification at this iron dose may cause gastrointestinal adverse events including diarrhoea. Providing a low dose of highly absorbable iron (3 mg iron as NaFeEDTA) may be safer because the decreased amount of iron in the gut lumen can possibly reduce the burden of these adverse effects whilst resulting in similar or higher amounts of absorbed iron.ObjectiveTo show non-inferiority of home fortification with 3 mg iron as NaFeEDTA compared with 12.5 mg iron as encapsulated ferrous fumarate, with haemoglobin response as the primary outcome.Design338 Kenyan children aged 12–36 months will be randomly allocated to daily home fortification with either: a) 3 mg iron as NaFeEDTA (experimental treatment), b) 12.5 mg iron as encapsulated ferrous fumarate (reference), or c) placebo. At baseline, after 30 days of intervention and within 100 days post-intervention, blood samples will be assessed for primary outcome (haemoglobin concentration), iron status markers, Plasmodium parasitaemia and inflammation markers. Urine and stool samples will be assessed for hepcidin concentrations and inflammation, respectively. Adherence will be assessed by self-reporting, sachet counts and by an electronic monitoring device.ConclusionIf daily home fortification with a low dose of iron (3 mg NaFeEDTA) has similar or superior efficacy to a high dose (12.5 mg ferrous fumarate) then it would be the preferred choice for treatment of iron deficiency anaemia in children.

Treatment duration of febrile urinary tract infection: a pragmatic randomized, double-blind, placebo-controlled non-inferiority trial in men and women

BackgroundIn adults with febrile urinary tract infection (fUTI), data on optimal treatment duration in patients other than non-pregnant women without comorbidities are lacking.MethodsA randomized placebo-controlled, double-blind, non-inferiority trial among 35 primary care centers and 7 emergency departments of regional hospitals in the Netherlands. Women and men aged ≥ 18 years with a diagnosis of fUTI were randomly assigned to receive antibiotic treatment for 7 or 14 days (the second week being ciprofloxacin 500 mg or placebo orally twice daily). Patients indicated to receive antimicrobial treatment for at least 14 days were excluded from randomization.The primary endpoint was the clinical cure rate through the 10- to 18-day post-treatment visit with preset subgroup analysis including sex. Secondary endpoints were bacteriologic cure rate at 10–18 days post-treatment and clinical cure at 70–84 days post-treatment.ResultsOf 357 patients included, 200 were eligible for randomization; 97 patients were randomly assigned to 7 days and 103 patients to 14 days of treatment. Overall, short-term clinical cure occurred in 85 (90%) patients treated for 7 days and in 94 (95%) of those treated for 14 days (difference –4.5%; 90% CI, –10.7 to 1.7; Pnon-inferiority = 0.072, non-inferiority not confirmed). In women, clinical cure was 94% and 93% in those treated for 7 and 14 days, respectively (difference 0.9; 90% CI, –6.9 to 8.7, Pnon-inferiority = 0.011, non-inferiority confirmed) and, in men, this was 86% versus 98% (difference –11.2; 90% CI –20.6 to –1.8, Psuperiority = 0.025, inferiority confirmed).The bacteriologic cure rate was 93% versus 97% (difference –4.3%; 90% CI, –9.7 to 1.2, Pnon-inferiority = 0.041) and the long-term clinical cure rate was 92% versus 91% (difference 1.6%; 90% CI, –5.3 to 8.4; Pnon-inferiority = 0.005) for 7 days versus 14 days of treatment, respectively. In the subgroups of men and women, long-term clinical cure rates met the criteria for non-inferiority, indicating there was no difference in the need for antibiotic retreatment for UTI during 70–84 days follow-up post-treatment.ConclusionsWomen with fUTI can be treated successfully with antibiotics for 7 days. In men, 7 days of antibiotic treatment for fUTI is inferior to 14 days during short-term follow-up but it is non-inferior when looking at longer follow-up.Trial registrationThe study was registered at ClinicalTrials.gov [NCT00809913; December 16, 2008] and trialregister.nl [NTR1583; December 19, 2008].

A double blind community-based randomized trial of amoxicillin versus placebo for fast breathing pneumonia in children aged 2-59 months in Karachi, Pakistan (RETAPP).

BackgroundFast breathing pneumonia is characterized by tachypnoea in the absence of danger signs and is mostly viral in etiology. Current guidelines recommend antibiotic therapy for all children with fast breathing pneumonia in resource limited settings, presuming that most pneumonia is bacterial. High quality clinical trial evidence to challenge or support the continued use of antibiotics, as recommended by the World Health Organization is lacking.Methods/designThis is a randomized double blinded placebo-controlled non-inferiority trial using parallel assignment with 1:1 allocation ratio, to be conducted in low income squatter settlements of urban Karachi, Pakistan. Children 2–59 months old with fast breathing, without any WHO-defined danger signs and seeking care at the primary health care center are randomized to receive either three days of placebo or amoxicillin. From prior studies, a sample size of 2430 children is required over a period of 28 months. Primary outcome is the difference in cumulative treatment failure between the two groups, defined as a new clinical sign based on preset definitions indicating illness progression or mortality and confirmed by two independent primary health care physicians on day 0, 1, 2 or 3 of therapy. Secondary outcomes include relapse measured between days 5–14. Modified per protocol analysis comparing hazards of treatment failure with 95 % confidence intervals in the placebo arm with hazards in the amoxicillin arm will be done.DiscussionThis study will provide evidence to support or refute the use of antibiotics for fast breathing pneumonia paving a way for guideline change.Trial registrationClinical Trials (NIH) Register NCT02372461

How soon to start: aspirin resumption after upper gastrointestinal bleed?

Background It is uncertain whether aspirin therapy should be continued after endoscopic hemostatic therapy in patients who develop peptic ulcer bleeding while receiving lowdose aspirin. Objective To test that continuing aspirin therapy with protonpump inhibitors after endoscopic control of ulcer bleeding was not inferior to stopping aspirin therapy, in terms of recurrent ulcer bleeding in adults with cardiovascular or cerebrovascular diseases. Design A parallel randomized, placebo-controlled noninferiority trial, in which both patients and clinicians were blinded to treatment assignment, was conducted from 2003 to 2006 by using computer-generated numbers in concealed envelopes. (ClinicalTrials.gov registration number: NCT00153725) Setting A tertiary endoscopy center. Patients Low-dose aspirin recipients with peptic ulcer bleeding. Intervention 78 patients received aspirin, 80 mg/d, and 78 received placebo for 8 weeks immediately after endoscopic therapy. All patients received a 72-hour infusion of pantoprazole followed by oral pantoprazole. All patients completed follow-up. Measurements The primary end point was recurrent ulcer bleeding within 30 days confirmed by endoscopy. Secondary end points were all-cause and cause-specific mortality in 8 weeks. Results 156 patients were included in an intention-to-treat analysis. Three patients withdrew from the trial before finishing follow-up. Recurrent ulcer bleeding within 30 days was 10.3% in the aspirin group and 5.4% in the placebo group (difference, 4.9 percentage points [95% CI, -3.6 to 13.4 percentage points]). Patients who received aspirin had lower all-cause mortality rates than patients who received placebo (1.3% vs. 12.9%; difference, 11.6 percentage points [CI, 3.7 to 19.5 percentage points]). Patients in the aspirin group had lower mortality rates attributable to cardiovascular, cerebrovascular, or gastrointestinal complications than patients in the placebo group (1.3% vs. 10.3%; difference, 9 percentage points [CI, 1.7 to 16.3 percentage points]). Limitations The sample size is relatively small, and only low-dose aspirin, 80 mg, was used. Two patients with recurrent bleeding in the placebo group did not have further endoscopy. Conclusion Among low-dose aspirin recipients who had peptic ulcer bleeding, continuous aspirin therapy may increase the risk for recurrent bleeding but potentially reduces mortality rates. Larger trials are needed to confirm these findings.

Continuation of Low-Dose Aspirin Therapy in Peptic Ulcer Bleeding

It is uncertain whether aspirin therapy should be continued after endoscopic hemostatic therapy in patients who develop peptic ulcer bleeding while receiving low-dose aspirin. To test that continuing aspirin therapy with proton-pump inhibitors after endoscopic control of ulcer bleeding was not inferior to stopping aspirin therapy, in terms of recurrent ulcer bleeding in adults with cardiovascular or cerebrovascular diseases. A parallel randomized, placebo-controlled noninferiority trial, in which both patients and clinicians were blinded to treatment assignment, was conducted from 2003 to 2006 by using computer-generated numbers in concealed envelopes. (ClinicalTrials.gov registration number: NCT00153725) A tertiary endoscopy center. Low-dose aspirin recipients with peptic ulcer bleeding. 78 patients received aspirin, 80 mg/d, and 78 received placebo for 8 weeks immediately after endoscopic therapy. All patients received a 72-hour infusion of pantoprazole followed by oral pantoprazole. All patients completed follow-up. The primary end point was recurrent ulcer bleeding within 30 days confirmed by endoscopy. Secondary end points were all-cause and specific-cause mortality in 8 weeks. 156 patients were included in an intention-to-treat analysis. Three patients withdrew from the trial before finishing follow-up. Recurrent ulcer bleeding within 30 days was 10.3% in the aspirin group and 5.4% in the placebo group (difference, 4.9 percentage points [95% CI, -3.6 to 13.4 percentage points]). Patients who received aspirin had lower all-cause mortality rates than patients who received placebo (1.3% vs. 12.9%; difference, 11.6 percentage points [CI, 3.7 to 19.5 percentage points]). Patients in the aspirin group had lower mortality rates attributable to cardiovascular, cerebrovascular, or gastrointestinal complications than patients in the placebo group (1.3% vs. 10.3%; difference, 9 percentage points [CI, 1.7 to 16.3 percentage points]). The sample size is relatively small, and only low-dose aspirin, 80 mg, was used. Two patients with recurrent bleeding in the placebo group did not have further endoscopy. Among low-dose aspirin recipients who had peptic ulcer bleeding, continuous aspirin therapy may increase the risk for recurrent bleeding but potentially reduces mortality rates. Larger trials are needed to confirm these findings.

One-Day Compared With 7-Day Nitrofurantoin for Asymptomatic Bacteriuria in Pregnancy: A Randomized Controlled Trial

OBJECTIVE: To evaluate whether a 1-day nitrofurantoin regimen is as effective as a 7-day regimen in eradicating asymptomatic bacteriuria during pregnancy. METHODS: A multicenter, double-blind, randomized, placebo controlled noninferiority trial was conducted in antenatal clinics in Thailand, the Philippines, Vietnam, and Argentina. Pregnant women seeking antenatal care between March 2004 and March 2007 who met the inclusion and exclusion criteria were invited to participate in the study. Those who consented were randomly allocated to receive either a 1-day or a 7-day course of 100 mg capsules of nitrofurantoin, which was taken twice daily. The primary outcome was bacteriologic cure on day 14 of treatment. RESULTS: : A total of 1,248 of 24,430 eligible women had asymptomatic bacteriuria, making the overall prevalence of 5.1%. Of these 1,248 women, 778 women were successfully recruited, and 386 and 392 women were randomly allocated to 1-day and 7-day regimens, respectively. Escherichia coli was the most common potentially pathogenic bacteria detected, its prevalence approaching 50%. Bacteriologic cure rates at treatment day 14 were 75.7% and 86.2% for 1-day and 7-day regimens, respectively. The cure rate difference was -10.5% (95% confidence interval -16.1% to -4.9%). Mean birth weight and mean gestational age at delivery were significantly lower in the 1-day regimen group. There were fewer adverse effects in the 1-day regimen group, but the differences were not statistically significant. CONCLUSION: A 1-day regimen of nitrofurantoin is significantly less effective than a 7-day regimen. Women with asymptomatic bacteriuria in pregnancy should receive the standard 7-day regimen. CLINICAL TRIAL REGISTRATION: ISRCTN, isrctn.org, ISRCTN11966080 LEVEL OF EVIDENCE: I.

One-Day Compared With 7-Day Nitrofurantoin for Asymptomatic Bacteriuria in Pregnancy

To evaluate whether a 1-day nitrofurantoin regimen is as effective as a 7-day regimen in eradicating asymptomatic bacteriuria during pregnancy. A multicenter, double-blind, randomized, placebo controlled noninferiority trial was conducted in antenatal clinics in Thailand, the Philippines, Vietnam, and Argentina. Pregnant women seeking antenatal care between March 2004 and March 2007 who met the inclusion and exclusion criteria were invited to participate in the study. Those who consented were randomly allocated to receive either a 1-day or a 7-day course of 100 mg capsules of nitrofurantoin, which was taken twice daily. The primary outcome was bacteriologic cure on day 14 of treatment. : A total of 1,248 of 24,430 eligible women had asymptomatic bacteriuria, making the overall prevalence of 5.1%. Of these 1,248 women, 778 women were successfully recruited, and 386 and 392 women were randomly allocated to 1-day and 7-day regimens, respectively. Escherichia coli was the most common potentially pathogenic bacteria detected, its prevalence approaching 50%. Bacteriologic cure rates at treatment day 14 were 75.7% and 86.2% for 1-day and 7-day regimens, respectively. The cure rate difference was -10.5% (95% confidence interval -16.1% to -4.9%). Mean birth weight and mean gestational age at delivery were significantly lower in the 1-day regimen group. There were fewer adverse effects in the 1-day regimen group, but the differences were not statistically significant. A 1-day regimen of nitrofurantoin is significantly less effective than a 7-day regimen. Women with asymptomatic bacteriuria in pregnancy should receive the standard 7-day regimen. ISRCTN, isrctn.org, ISRCTN11966080 I.