Noninferiority Randomized Clinical Trial Research Articles

Rotation of a toric intraocular lens with and without capsular tension ring: data from a multicenter non-inferiority randomized clinical trial (RCT)

BackgroundEvaluation of clinical outcome in cohorts with versus without simultaneous implantation of a capsular tension ring (CTR) and a toric lens (Tecnis Toric). Main parameter was rotation referring - in contrast to misalignment - to the IOL axis change from immediately after implantation to the final postoperative position.MethodsLens position was measured at baseline with the patient still in recumbent position, postoperative rotation was calculated by software. Postoperative evaluation included measurement three months after surgery or prior to an indicated revision surgery. Explorative re-evaluation of the underlying RCT’s intent-to-treat population was performed for the entire sample and stratified for cohorts by 95% confidence intervals for binary endpoints’ incidences (primary endpoint: absolute postoperative rotation ≤5 degrees; secondary endpoints: absolute deviation between achieved cylinder and target cylinder ≤0.5 dpt, postoperative corrected distance visual acuity (CDVA) ≥ 0.8). Data exploration was based on medians and quartiles.SettingOutpatient study sites.DesignRe-evaluation based on data from a multicenter non-inferiority randomized clinical trial (RCT).ResultsSub cohorts (without CTR 89, with CTR 90 patients) did not present clinically relevant differences in preoperative characteristics: revision surgery was performed in 7 cases (3 without and 4 with CTR). Primary endpoint incidences for the total sample, without and with CTR were 90%/89%/90%; cylinder endpoint incidences were 46%/45%/46% and CDVA endpoint incidences 90%/92%/88%. Median absolute rotations were 1.74°/1.79°/1.72°, median absolute cylinder deviations 0.55/0.52/0.55 dpt and median visual acuity 1.0/1.0/1.0.ConclusionNo clinically relevant differences between CTR subgroups were found; a satisfying three months rotational stability was achieved.Trial registrationThe trial was registered retrospectively in the trial registry DRKS, trial registration number DRKS00015316, date of registration 27. August 2018.

Assessment of gastric emptying of maltodextrin, coffee with milk and orange juice during labour at term using point of care ultrasound: a non-inferiority randomised clinical trial.

Labouring women have been shown to have slower gastric emptying than non-pregnant subjects, and this argument is sometimes used to recommend fasting guidelines such as nil-by-mouth during labour. We performed a parallel group, randomised non-inferiority trial, comparing gastric emptying of 450ml isocalorically-adjusted maltodextrin, coffee with milk or pulp-free orange juice, with 18 women in each group. The women were initially fasted for 2h for clear fluids, 6h for a light meal and 8h for a high fat or high protein meal. We performed gastric ultrasound in the semirecumbent-right lateral decubitus position. Gastric antral area was measured at baseline and at 5min, 30min, 60min, 90min and 120min. Gastric emptying of maltodextrin was significantly faster than coffee with milk (p<0.001) and orange juice (p<0.001). There was no statistically significant difference between pulp-free orange juice and coffee with milk (p=0.97). The estimated gastric residual volume was lower than baseline from 90min after drinking maltodextrin. In labouring women, maltodextrin is cleared from the stomach faster than coffee with milk and orange juice. Gastric emptying depends on other factors besides the caloric load and volume of the drink.

Randomized controlled trial of lobaplatin plus etoposide vs. cisplatin plus etoposide as first-line therapy in patients with extensive-stage small cell lung cancer.

The majority of previous studies of lobaplatin in small cell lung cancer (SCLC) are small phase I-II studies. The present study aimed to verify the non-inferiority (in terms of efficacy) of lobaplatin plus etoposide (EL) vs. cisplatin plus etoposide (EP) in patients with previously untreated extensive-stage SCLC (ES-SCLC). This phase III non-inferiority randomized clinical trial enrolled patients at 17 sites between September 2010 and May 2013. Patients were randomized to EL (30 mg/m2 lobaplatin on day 1 and 100 mg/m2 etoposide on days 1-3, for 21-day cycles) or EP (80 mg/m2 cisplatin on day 1 and 100 mg/m2 etoposide on days 1-3, for 21-day cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, disease control rate (DCR), toxicity and quality of life (QoL). A total of 234 patients were randomized to the EL (n=122) and EP (n=112) treatment groups. The median PFS, median OS and DCR were 5.1 vs. 5.3 months (P=0.786), 10.6 vs. 9.7 months (P=0.701) and 85.5 vs. 86.7% (P=0.848) in the EL vs. EP groups, respectively. Patients in the EL group had significantly lower frequencies of nephrotoxicity (2.5 vs. 11.7%; P=0.008), nausea (22.3 vs. 40.5%; P=0.003) and vomiting (14.1 vs. 35.1%; P<0.001) than those in the EP group. Overall, EL was not inferior to EP in terms of PFS and OS. The tolerance and QoL of the EL regimen were better than those of the EP regimen. EL is thus an alternative choice for the first-line treatment of ES-SCLC.

Randomized Trial of Silver Nitrate with Sodium Fluoride for Caries Arrest.

The aim of this noninferiority double-blind randomized clinical trial was to compare the effectiveness of the topical semiannual application of a 25% silver nitrate (AgNO3) solution followed by a 5% sodium fluoride (NaF) varnish with that of a 38% silver diamine fluoride (SDF) solution in arresting caries among preschool children. Healthy 3-y-old children with active dentine carious lesions were randomly allocated to 2 groups via computer-generated random numbers. Lesions in group A received applications of a 25% AgNO3 solution followed by a 5% NaF varnish semiannually (every 6 mo). Lesions in group B received semiannual applications of a 38% SDF solution followed by a placebo varnish. A trained examiner recorded the status of caries and oral hygiene at baseline and during follow-up examinations. The examiner, children, and their caretakers were blinded to the intervention allocation. This study adopted an intention-to-treat analysis. A noninferiority test was conducted for the data analysis. Group A's noninferiority was accepted if the lower limit of the 95% CI for the difference in the mean number of arrested surfaces was >-0.5. A total of 1,070 children were recruited at baseline, with 535 children in each group. After 18 mo, the mean ± SD number of arrested surfaces was 3.3 ± 3.4 in group A (n = 484) and 3.2 ± 3.5 in group B (n = 476; P = 0.664). The difference in the mean number of arrested surfaces between the groups was 0.092 (95% CI, -0.322 to 0.505). Apart from black staining on the arrested lesions, no other significant side effect was observed. A semiannual application of 25% AgNO3 followed by 5% NaF is no worse than a 38% SDF in arresting dentine caries among preschool children over 18 mo. The Hong Kong Research Grants Council (GRF 17107315) funded this trial, which was registered at ClinicalTrials.gov (NCT02019160). This randomized clinical trial found that silver nitrate solution followed by sodium fluoride varnish is effective in arresting dentine caries among preschool children. As silver nitrate followed by sodium fluoride is a noninvasive and simple protocol, it can be an alternative strategy to manage dental caries among young children, especially in countries where silver diamine fluoride is not available.

Economic Benefit of a Novel Dual Mode Ambulatory Compression Device for Treatment of Chronic Venous Leg Ulcers

Compression is critical to heal chronic venous leg ulcers (VLUs). A novel dual mode ambulatory pneumatic compression (APC) device was tested in comparison to multilayered compression bandaging systems for the treatment of nonhealing VLUs in a prospective randomized clinical trial (RCT). Patients with VLUs measuring between 2 and 50 cm2 present for 1 to 12 months were randomized to treatment with the APC device (ACT group; Actitouch; Tactile Medical, Minneapolis, Minn] or multilayered compression bandaging (MLB) with either Profore (Smith & Nephew, Memphis, Tenn) or Coban 2 (3M Health Care, St. Paul, Minn) compression systems. Patients in the ACT group were asked to wear the device for sustained or intermittent compression throughout the day and to wear a light compression stocking at night. The ACT group patients were seen every 2 to 3 weeks for follow-up to 16 weeks, allowing more in-home care. The MLB group was seen in the outpatient clinic weekly. Other aspects of VLU care were standardized between the two groups. The primary study objective was to compare wound size reduction at 16 weeks between the two groups in a noninferiority RCT. Secondary objectives assessed the effect of each therapy on medical resource utilization and the direct cost of care. There were 58 patients who were randomized to treatment with either MLB (n = 30) or ACT (n=28). Both groups experienced similar rates of wound healing during the 16-week follow-up period, with ACT group patients decreasing from 4.01 ± 2.4 cm2 to 1.21 ± 2.5 cm2 and MLB-treated wounds decreasing from 7.6 ± 7.9 cm2 to 2.5 ± 6.1 cm2. There was no significant difference between groups in percentage of wound closure, incidence of complete wound healing, or improvement in Venous Clinical Severity Score. ACT-treated wounds had lower utilization of non-study-related clinic visits compared with the MLB cohort (50.0% vs 63.3%, respectively). In addition, there were fewer ACT-scheduled patient visits without any associated complications, resulting in lower direct medical costs compared with the MLB cohort (− difference [−$2733; P = .06]). The trial was halted before full randomization to make improvements to the ACT device to increase the patient’s comfort and usability, as suggested by both participating physicians and patients. In this preliminary RCT, a novel APC device achieved similar VLU wound healing results in comparison to MLB but with lower direct costs. The study has led to important changes in device design that will allow confirmation of these findings in a larger RCT.

Self-compression Technique vs Standard Compression in Mammography

Many women dread undergoing mammography, and some may not attend or reattend breast cancer screening because of the discomfort or pain induced by breast compression. To evaluate the noninferiority of the self-compression mammography technique for reducing breast thickness compared with standard compression. This prospective, parallel-group, noninferiority randomized clinical trial was conducted from May 7, 2013, to October 26, 2015, at 6 cancer care centers in France. Participants were women aged 50 to 75 years, without a history of recent breast surgical procedure or treatment, and who could perform self-compression. Analyses were performed on intention-to-treat basis from January 27, 2017, to March 30, 2018. Patients were randomized 1:1 to the self-compression group or the standard compression group. Primary end point was breast thickness expressed as the mean of 4 views: right and left craniocaudal and right and left mediolateral oblique. The predefined noninferiority margin was a difference of 3 mm, with a 1-sided 95% CI. Secondary end points included compression force, image quality, requirement for additional views, pain, and patient satisfaction and radiographer assessment questionnaires. Among the 549 women randomized, 548 (97.3%) completed the trial. Of these, 275 (48.8%) (mean [SD] age, 61.35 [6.34] years) were randomized to the self-compression arm and 273 (48.5%) (mean [SD] age, 60.84 [6.41] years) to the standard compression arm. The difference in the mean thickness between the 2 arms was lower than the noninferiority margin, with an upper 1-sided 95% CI less than 3 mm (-0.17; 95% CI,-∞ to 1.89 mm; P < .05). Compression force was higher in the self-compression group compared with the standard compression arm for the 4 mammographic views. Pain was statistically significantly lower in the self-compression group (n = 274) compared with the standard compression group (n = 269) (median [interquartile range (IQR)] score, 2 [1-5] vs 3 [1-5]; P = .009). No difference was reported in the image quality scores of the 2 groups or in the number of additional views performed (median [IQR] extra views, 2 [2-2] vs 2 [2-3] extra views; P = .64), whatever the indication, including insufficient image quality (29 [16.8%] vs 27 [15.0%] insufficient quality views; P = .65). No adverse effects or pain were reported by the participants after the self-compression mammography. Self-compression does not appear to be inferior to standard compression mammography in achieving minimal breast thickness without increasing pain or compromising image quality; this technique may be an effective option for women who want to be involved in their breast examination. ClinicalTrials.gov identifier: NCT02866591.

Predictors of Spectacle Wear and Reasons for Nonwear in Students Randomized to Ready-made or Custom-made Spectacles

Visual impairment from uncorrected refractive errors affects 12.8 million children globally. Spectacle correction is simple and cost-effective; however, low adherence to spectacle wear, which can occur in all income settings, limits visual potential. To investigate predictors of spectacle wear and reasons for nonwear in students randomized to ready-made or custom-made spectacles. In planned secondary objectives of a noninferiority randomized clinical trial, students aged 11 to 15 years who fulfilled eligibility criteria, which included improvement in vision with correction by at least 2 lines in the better eye, were recruited from government schools in Bangalore, India. Recruitment took place between January 12 and July 15, 2015, and analysis for the primary outcome occurred in August 2016. Data analysis for the secondary outcome was conducted in August 2018. Spectacle wear was assessed by masked observers at unannounced visits to schools 3 to 4 months after spectacles were distributed. Students not wearing their spectacles were asked an open-ended question to elicit reasons for nonwear. Predictors of spectacle wear and reasons for nonwear. Of 460 students recruited and randomized (52.2% male; 46 students aged 11 to 12 years and 13 to 15 years in each trial arm), 78.7% (362 of 460) were traced at follow-up, and 25.4% (92 of 362) were not wearing their spectacles (no difference between trial arms). Poorer presenting visual acuity (VA) and improvement in VA with correction predicted spectacle wear. Students initially seen with an uncorrected VA less than 6/18 in the better eye were almost 3 times more likely to be wearing their spectacles than those with less than 6/9 to 6/12 (adjusted odds ratio, 2.84; 95% CI, 1.52-5.27). Improvement of VA with correction of 3 to 6 lines or more than 6 lines had adjusted odds ratios of 2.31 (95% CI, 1.19-4.50) and 2.57 (95% CI, 1.32-5.01), respectively, compared with an improvement of less than 3 lines. The main reason students gave for nonwear was teasing or bullying by peers (48.9% [45 of 92]). Girls reported parental disapproval as a reason more frequently than boys (difference, 7.2%). Three-quarters of students receiving spectacles were wearing them at follow-up, which supports the use of the prescribing guidelines applied in this trial. Predictors of spectacle wear, poorer presenting VA, and greater improvement in VA with correction are similar to other studies. Interventions to reduce teasing and bullying are required, and health education of parents is particularly needed for girls in this setting. isrctn.org Identifier: ISRCTN14715120.

P630 A non-inferiority randomised clinical trial of the use of the smartphone-based health applications IBDsmart and IBDoc® in the care of inflammatory bowel disease patients

P630 A non-inferiority randomised clinical trial of the use of the smartphone-based health applications IBDsmart and IBDoc® in the care of inflammatory bowel disease patients

Impact of different restorative treatments for deep caries lesion in primary teeth (CEPECO 1) \u2013 study protocol for a noninferiority randomized clinical trial

BackgroundDue to the lack of evidence to determine the best treatment for deep cavitated caries lesions in primary molars, the search for an effective restorative technique, which results in a minimal discomfort to patients, and reduce the time needed for the treatment, becomes relevant. The objective of this randomized clinical trial was to evaluate if high-viscosity glass ionomer cement (HVGIC) restorations is noninferior to restoration with calcium hydroxide cement associated with HVGIC for treatment of deep lesions in primary molars, as well as the impact of the treatments on cost and discomfort of the patient.MethodsA non-inferiority randomized clinical trial with two parallels arms (1:1) will be conducted. Children with 4 to 8 years will be selected at Clinic of Pediatric Dentistry at Ibirapuera University. 108 teeth will be randomized into two groups: (1) Calcium hydroxide cement associated with HVGIC and (2) HVGIC restoration. Primary outcome will be considered the pulp vitality and to be evaluated after 6, 12, 18 and 24 months by two calibrated examiners. Survival of restorations will also be evaluated in the equal intervals. The duration of dentals treatment and the cost of all materials used will be considered for estimating of cost-efficacy of each treatment. Individual discomfort will be measured after each dental procedure using the Wong-Baker’s Facial Scale. For the primary outcome, Kaplan-Meier survival and the long-rank test will be used to comparison between the groups. Cox regression will be performed to assess the influence of variables on the outcome. For all analyzes, the significance level is set at 5%.DiscussionBased on the philosophy of ART, our hypothesis is that the HVGIC restoration is a possible approach to restore the deep caries lesion with pulp vitality without the use of rubber dam and anesthesia.Trial registrationClinicaltrials.gov registration NCT02903979. Registered on June 9th 2016.

Accuracy of a 3-Dimensionally Printed Navigational Template for Localizing Small Pulmonary Nodules

Localization of small lung nodules are challenging because of the difficulty of nodule recognition during video-assisted thoracoscopic surgery. Using 3-dimensional (3-D) printing technology, a navigational template was recently created to assist percutaneous lung nodule localization; however, the efficacy and safety of this template have not yet been evaluated. To assess the noninferiority of the efficacy and safety of a 3-D-printed navigational template guide for localizing small peripheral lung nodules. This noninferiority randomized clinical trial conducted between October 2016 and October 2017 at Shanghai Pulmonary Hospital, Shanghai, China, compared the safety and precision of lung nodule localization using a template-guided approach vs the conventional computed tomography (CT)-guided approach. In total, 213 surgical candidates with small peripheral lung nodules (<2 cm) were recruited to undergo either CT- or template-guided lung nodule localization. An intention-to-treat analysis was conducted. Percutaneous lung nodule localization. The primary outcome was the accuracy of lung nodule localization (localizer deviation), and secondary outcomes were procedural duration, radiation dosage, and complication rate. Of the 200 patients randomized at a ratio of 1:1 to the template- and CT-guided groups, most were women (147 vs 53), body mass index ranged from 15.4 to 37.3, the mean (SD) nodule size was 9.7 (2.9) mm, and the mean distance between the outer edge of target nodule and the pleura was 7.8 (range, 0.0-43.9) mm. In total, 190 patients underwent either CT- or template-guided lung nodule localization and subsequent surgery. Among these patients, localizer deviation did not significantly differ between the template- and CT-guided groups (mean [SD], 8.7 [6.9] vs 9.6 [5.8] mm; P = .36). The mean (SD) procedural durations were 7.4 (3.2) minutes for the template-guided group and 9.5 (3.6) minutes for the CT-guided group (P < .001). The mean (SD) radiation dose was 229 (65) mGy × cm in the template-guided group and 313 (84) mGy × cm in CT-guided group (P < .001). The use of the 3-D-printed navigational template for localization of small peripheral lung nodules showed efficacy and safety that were not substantially worse than those for the CT-guided approach while significantly simplifying the localization procedure and decreasing patient radiation exposure. ClinicalTrials.gov identifier: NCT02952261.

Assessment of biomarkers in women with endometriosis-associated pain using the ENG contraceptive implant or the 52 mg LNG-IUS: a non-inferiority randomised clinical trial

Objective: The aim of the study was to assess the serum levels of the following biomarkers in women with endometriosis-associated pelvic pain before and after six months of using the etonogestrel (ENG) contraceptive implant or the 52 mg levonorgestrel-releasing intrauterine system (LNG-IUS): cancer antigen (CA)-125, cluster of differentiation (CD) 23 and endometrial nerve fibre density. Methods: The study was conducted at the Department of Obstetrics and Gynaecology, University of Campinas Medical School, Brazil. A total of 103 women with endometriosis-associated pain diagnosed by surgery, transvaginal ultrasound and/or magnetic resonance imaging were included. Endometrial nerve fibre density and serum levels of CA-125 and soluble CD23 were assessed before and after six months of using the allocated method and were correlated to 10 cm visual analogue scale (VAS) scores for non-cyclical pelvic pain and dysmenorrhoea. Results: Both contraceptive methods significantly reduced concentrations of serum soluble CD23 and endometrial nerve fibre density (p < .001); however, CA-125 was significantly reduced only among users of the ENG implant (p < .05). No correlation was observed between reduction of biomarkers and improvement of VAS pain and dysmenorrhoea scores. No differences were observed between the ENG implant and the LNG-IUS. Conclusion: Both progestin-only contraceptives significantly reduced two out of the three biomarkers evaluated. These two biomarkers could, therefore, be used as surrogate markers to follow up medical treatment of endometriosis-associated pain.

Defining Non-inferiority Margins for Quality of Surgical Resection for Rectal Cancer: A Delphi Consensus Study.

Quality of surgical resection metrics (QSRMs) have been used as surrogates for long-term oncologic outcomes in non-inferiority randomized clinical trials (RCTs) comparing laparoscopic and open surgery for rectal cancer. However, non-inferiority margins (ΔNI) for QSRMs have not been previously defined. A two-round, web-based Delphi was used to define ΔNI for four QSRMs: positive circumferential resection margin (CRM), incomplete plane of mesorectal excision (PME), positive distal resection margin (DRM), and a composite of these outcomes. Overall, 130 international experts in rectal cancer (68 surgeons, 20 medical oncologists, 16 radiation oncologists, and 26 pathologists) were invited to participate. Experts were presented with evidence syntheses summarizing the association between QSRMs and long-term outcomes, and pooled quality of surgical resection outcomes for open surgery, and were asked to provide ΔNI for all outcomes balancing the risks and benefits of minimally invasive surgery. Seventy-two experts participated: 57 completed the initial questionnaire and 58 completed the revised questionnaire, with 43 participating in both rounds. Consensus was reached for all individual QSRM ΔNI but not for the composite. The mean (standard deviation) ΔNI was an absolute difference of 2.33% (1.59%) for the proportion of positive CRMs when comparing surgical interventions for the treatment of rectal cancer: 2.85% (1.83%) for incomplete PME; 1.28% (1.13%) for positive DRMs; and 2.71% (2.28%) for the composite. However, opinions varied widely for the composite outcome. Web-based Delphi processes are a feasible approach to generate ΔNI to evaluate novel surgical interventions. The generated ΔNI for QSRMs for rectal cancer can be used for future RCTs and non-inferiority meta-analyses.

Procalcitonin-guided antibiotic therapy in patients with fever in a general emergency department population: a multicentre non-inferiority randomized clinical trial (HiTEMP study)

ObjectivesOveruse of broad-spectrum antibiotics in emergency departments (EDs) results in antibiotic resistance. We determined whether procalcitonin (PCT) -guided therapy can be used to reduce antibiotic regimens in EDs by investigating efficacy, safety and accuracy. MethodsThis was a non-inferiority multicentre randomized clinical trial, performed in two Dutch hospitals. Adult patients with fever ≥38.2°C (100.8°F) in triage were randomized between standard diagnostic workup (control group) and PCT-guided therapy, defined as standard workup with the addition of one single PCT measurement. The treatment algorithm encouraged withholding antibiotic regimens with PCT <0.5 μg/L, and starting antibiotic regimens at PCT ≥0.5 μg/L. Exclusion criteria were immunocompromised conditions, pregnancy, moribund patients, patients <72 h after surgery or requiring primary surgical intervention. Primary outcomes were efficacy, defined as number of prescribed antibiotic regimens; safety, defined as combined safety end point consisting of 30 days mortality, intensive-care unit admission, ED return visit within 2 weeks; accuracy, defined as sensitivity, specificity and area-under-the-curve (AUC) of PCT for bacterial infections. Non-inferiority margin for safety outcome was 7.5%. ResultsBetween August 2014 and January 2017, 551 individuals were included. In the PCT-guided group (n = 275) 200 (73%) patients were prescribed antibiotic regimens, in the control group (n = 276) 212 (77%) patients were prescribed antibiotics (p 0.28). There was no significant difference in combined safety end point between the PCT-guided group, 29 (11%), and control group, 46 (16%) (p 0.16), with a non-inferiority margin of 0.46% (n = 526). AUC for confirmed bacterial infections for PCT was 0.681 (95% CI 0.633–0.730), and for CRP was 0.619 (95% CI 0.569–0.669). ConclusionsPCT-guided therapy was non-inferior in terms of safety, but did not reduce prescription of antibiotic regimens in an ED population with fever. In this heterogeneous population, the accuracy of PCT in diagnosing bacterial infections was poor. Trial Registration in Netherlands trial registerhttp://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4949.

Defining non-inferiority margins for quality of surgical resection for rectal cancer.

e18760Background: A key challenge for non-inferiority randomized clinical trials (NI-RCTs) is the generation of non-inferiority margins (ΔNI). Guidance for the selection of ΔNI is directed to pharm...

A comparison of liprotamase, a non-porcine pancreatic enzyme replacement therapy, to porcine extracted pancrelipase in a noninferiority randomized clinical trial in patients with cystic fibrosis

Objective: Porcine derived enzymes are used for pancreatic enzyme replacement therapy in patients with cystic fibrosis (CF). Liprotamase is a biotechnology-derived, non-porcine, enzyme replacement without enteric coating. This study compared the effects of liprotamase and porcinederived pancrelipase on Coefficient of Fat Absorption (CFA) in patients with Exocrine Pancreatic Insufficiency (EPI) due to CF. Methods: We conducted a randomized, open-label, assessor blind, parallel group, multicenter, international trial to evaluate the noninferiority of liprotamase to porcine pancrelipase in 128 CF patients’ age ≥7 years with pancreatic insufficiency (Study NCT02279498). Subjects were randomized to liprotamase or pancrelipase, dose-matched to pre-study lipase doses. The primary endpoint was the between group difference in least square (LS) mean change from baseline in CFA, with a non-inferiority margin of -15% for the lower bound of the 95% confidence interval (CI). Key secondary endpoints compared treatment effects on CFA in the absence or presence of concomitant gastric acid suppression (GAS), and coefficient of nitrogen absorption (CNA). Results: Liprotamase missed the noninferiority criterion for CFA (95% CI -16.0, -7.7%), but met that criterion for CNA (95% CI -1.9, -0.7%). Concomitant GAS was associated with higher CFA with liprotamase but not pancrelipase. Conclusion: In this study, liprotamase was inferior to pancrelipase with regards to CFA, but not CNA. Higher doses and GAS may improve the efficacy of liprotamase.

Efavirenz-based simplification after successful early lopinavir-boosted-ritonavir-based therapy in HIV-infected children in Burkina Faso and C\xf4te d\u2019Ivoire: the MONOD ANRS 12206 non-inferiority randomised trial

BackgroundThe 2016 World Health Organization guidelines recommend all children <3 years start antiretroviral therapy (ART) on protease inhibitor-based regimens. But lopinavir/ritonavir (LPV/r) syrup has many challenges in low-income countries, including limited availability, requires refrigeration, interactions with anti-tuberculous drugs, twice-daily dosing, poor palatability in young children, and higher cost than non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs. Successfully initiating LPV/r-based ART in HIV-infected children aged <2 years raises operational challenges that could be simplified by switching to a protease inhibitor-sparing therapy based on efavirenz (EFV), although, to date, EFV is not recommended in children <3 years.MethodsThe MONOD ANRS 12026 study is a phase 3 non-inferiority open-label randomised clinical trial conducted in Abidjan, Côte d’Ivoire, and Ouagadougou, Burkina Faso (ClinicalTrial.gov registry: NCT01127204). HIV-1-infected children who were tuberculosis-free and treated before the age of 2 years with 12–15 months of suppressive twice-daily LPV/r-based ART (HIV-1 RNA viral load (VL) <500 copies/mL, confirmed) were randomised to two arms: once-daily combination of abacavir (ABC) + lamivudine (3TC) + EFV (referred to as EFV) versus continuation of the twice-daily combination zidovudine (ZDV) or ABC + 3TC + LPV/r (referred to as LPV). The primary endpoint was the difference in the proportion of children with virological suppression by 12 months post-randomisation between arms (14% non-inferiority bound, Chi-squared test).ResultsBetween May 2011 and January 2013, 156 children (median age 13.7 months) were initiated on ART. After 12–15 months on ART, 106 (68%) were randomised to one of the two treatment arms (54 LPV, 52 EFV); 97 (91%) were aged <3 years. At 12 months post-randomisation, 46 children (85.2%) from LPV versus 43 (82.7%) from EFV showed virological suppression (defined as a VL <500 copies/mL; difference, 2.5%; 95% confidence interval (CI), −11.5 to 16.5), whereas seven (13%) in LPV and seven (13.5%) in EFV were classed as having virological failure (secondary outcome, defined as a VL ≥1000 copies/mL; difference, 0.5%; 95% CI, −13.4 to 12.4). No significant differences in adverse events were observed, with two adverse events in LPV (3.7%) versus four (7.7%) in EFV (p = 0.43). On genotyping, 13 out of 14 children with virological failure (six out of seven EFV, seven out of seven LPV) had a drug-resistance mutation: nine (five out of six EFV, four out of seven LPV) had one or more major NNRTI-resistance mutations whereas none had an LPV/r-resistance mutation.ConclusionsAt the VL threshold of 500 copies/mL, we could not conclusively demonstrate the non-inferiority of EFV on viral suppression compared to LPV because of low statistical power. However, non-inferiority was confirmed for a VL threshold of <1000 copies/mL. Resistance analyses highlighted a high frequency of NNRTI-resistance mutations. A switch to an EFV-based regimen as a simplification strategy around the age of 3 years needs to be closely monitored.Trial registrationClinicalTrial.gov registry n°NCT01127204, 19 May 2010.

Home-Based Hypnotherapy Self-exercises vs Individual Hypnotherapy With a Therapist for Treatment of Pediatric Irritable Bowel Syndrome, Functional Abdominal Pain, or Functional Abdominal Pain Syndrome

Individual gut-directed hypnotherapy (HT) is effective in pediatric irritable bowel syndrome (IBS) and functional abdominal pain or functional abdominal pain syndrome (FAP[S]). It is, however, unavailable to many children. To compare the effectiveness of HT by means of home-based self-exercises using a CD with that of individual HT (iHT) performed by qualified therapists. This noninferiority randomized clinical trial with a follow-up of 1 year after the end of treatment was conducted from July 15, 2011, through June 24, 2013, at 9 secondary and tertiary care centers throughout the Netherlands. A total of 303 children were eligible to participate. Of those, 260 children (aged 8-18 years) with IBS or FAP(S) were included in this study. Children were randomized (1:1 ratio) to home-based HT with a CD (CD group) or iHT performed by qualified therapists (iHT group). No children withdrew from the study because of adverse effects. The CD group was instructed to perform exercises 5 times per week or more for 3 months. The iHT group consisted of 6 sessions during 3 months. Primary outcomes were treatment success directly after treatment and after 1-year follow-up. Treatment success was defined as a 50% or greater reduction in pain frequency and intensity scores. The noninferiority limit was set at 50% treatment success in the CD group, with a maximum of 25% difference in treatment success with the iHT group after 1-year follow-up. Modified intention-to-treat analyses were performed. A total of 132 children were assigned to the CD group and 128 to the iHT group; 250 children were analyzed (126 in the CD group and 124 in the iHT group) (mean [SD] age, 13.4 [2.9] years in the CD group and 13.3 [2.8] years in the iHT group; 94 female [74.6%] in the CD group and 85 [68.5%] in the iHT group). Directly after treatment, 46 children (36.8%) in the CD group and 62 (50.1%) in the iHT group were successfully treated. After 1-year follow-up, the 62.1% treatment success in the CD group was noninferior to the 71.0% in the iHT group (difference, -8.9%; 90% CI, -18.9% to 0.7%; P = .002). Long-term effectiveness of home-based HT with a CD is noninferior to iHT performed by therapists in pediatric IBS or FAP(S). Treatment with hypnosis using a CD provides an attractive treatment option for these children. trialregister.nl Identifier: NTR2725.

Efficacy of sitagliptin for the hospital management of general medicine and surgery patients with type 2 diabetes (Sita-Hospital): a multicentre, prospective, open-label, non-inferiority randomised trial

The role of incretin-based drugs in the treatment of patients with type 2 diabetes admitted to hospital has not been extensively assessed. In this study, we compared the safety and efficacy of a dipeptidyl peptidase-4 inhibitor (sitagliptin) plus basal insulin with a basal-bolus insulin regimen for the management of patients with type 2 diabetes in general medicine and surgery in hospitals. We did a multicentre, prospective, open-label, non-inferiority randomised clinical trial (Sita-Hospital) in five hospitals in the USA, enrolling patients aged 18-80 years with type 2 diabetes and a random blood glucose concentration of 7·8-22·2 mmol/L who were being treated with diet or oral antidiabetic drugs or had a total daily insulin dose of 0·6 units per kg or less, admitted to general medicine and surgery services. We randomly assigned patients (1:1) to receive either sitagliptin plus basal glargine once daily (the sitagliptin-basal group) or a basal-bolus regimen with glargine once daily and rapid-acting insulin lispro or aspart before meals (the basal-bolus group) during the hospital stay. All other antidiabetic drugs were discontinued on admission. The randomisation was achieved by computer-generated tables with block stratification according to randomisation blood glucose concentrations (ie, higher or lower than 11·1 mmol/L). The primary endpoint of the trial was non-inferiority in mean differences between groups in their daily blood glucose concentrations during the first 10 days of therapy (point-of-care measurements; non-inferiority was deemed a difference <1 mmol/L). The safety endpoints included hypoglycaemia and uncontrolled hyperglycaemia leading to treatment failure. All participants who received at least one dose of study drug were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT01845831. Between Aug 23, 2013, and July 27, 2015, we recruited 279 patients, and randomly assigned 277 to treatment; 138 to sitagliptin-basal and 139 to basal-bolus. The length of stay in hospital was similar for both groups (median 4 days [IQR 3-8] vs 4 [3-8] days, p=0·54). The mean daily blood glucose concentration in the sitagliptin-basal group (9·5 mmol/L [SD 2·7]) was not inferior to that in the basal-bolus group 9·4 mmol/L [2·7]) with a mean blood glucose difference of 0·1 mmol/L (95% CI -0·6 to 0·7). No deaths occurred in this trial. Treatment failure occurred in 22 patients (16%) in the sitagliptin-basal group versus 26 (19%) in the basal-bolus group (p=0·54). Hypoglycaemia occurred in 13 patients (9%) in the sitagliptin-basal group and in 17 (12%) in the basal-bolus group (p=0·45). No differences in hospital complications were noted between groups. Seven patients (5%) developed acute kidney injury in the sitagliptin-basal group and six (4%) in the basal-bolus group. One patient (0·7%) developed acute pancreatitis (in the basal-bolus group). The trial met the non-inferiority threshold for the primary endpoint, because there was no significant difference between groups in mean daily blood glucose concentrations. Treatment with sitagliptin plus basal insulin is as effective and safe as, and a convenient alternative to, the labour-intensive basal-bolus insulin regimen for the management of hyperglycaemia in patients with type 2 diabetes admitted to general medicine and surgery services in hospital in the non-intensive-care setting. Merck.

Effect of a Binocular iPad Game vs Part-time Patching in Children Aged 5 to 12 Years With Amblyopia

A binocular approach to treating anisometropic and strabismic amblyopia has recently been advocated. Initial studies have yielded promising results, suggesting that a larger randomized clinical trial is warranted. To compare visual acuity (VA) improvement in children with amblyopia treated with a binocular iPad game vs part-time patching. A multicenter, noninferiority randomized clinical trial was conducted in community and institutional practices from September 16, 2014, to August 28, 2015. Participants included 385 children aged 5 years to younger than 13 years with amblyopia (20/40 to 20/200, mean 20/63) resulting from strabismus, anisometropia, or both. Participants were randomly assigned to either 16 weeks of a binocular iPad game prescribed for 1 hour a day (190 participants; binocular group) or patching of the fellow eye prescribed for 2 hours a day (195 participants; patching group). Study follow-up visits were scheduled at 4, 8, 12, and 16 weeks. A modified intent-to-treat analysis was performed on participants who completed the 16-week trial. Binocular iPad game or patching of the fellow eye. Change in amblyopic-eye VA from baseline to 16 weeks. Of the 385 participants, 187 were female (48.6%); mean (SD) age was 8.5 (1.9) years. At 16 weeks, mean amblyopic-eye VA improved 1.05 lines (2-sided 95% CI, 0.85-1.24 lines) in the binocular group and 1.35 lines (2-sided 95% CI, 1.17-1.54 lines) in the patching group, with an adjusted treatment group difference of 0.31 lines favoring patching (upper limit of the 1-sided 95% CI, 0.53 lines). This upper limit exceeded the prespecified noninferiority limit of 0.5 lines. Only 39 of the 176 participants (22.2%) randomized to the binocular game and with log file data available performed more than 75% of the prescribed treatment (median, 46%; interquartile range, 20%-72%). In younger participants (aged 5 to <7 years) without prior amblyopia treatment, amblyopic-eye VA improved by a mean (SD) of 2.5 (1.5) lines in the binocular group and 2.8 (0.8) lines in the patching group. Adverse effects (including diplopia) were uncommon and of similar frequency between groups. In children aged 5 to younger than 13 years, amblyopic-eye VA improved with binocular game play and with patching, particularly in younger children (age 5 to <7 years) without prior amblyopia treatment. Although the primary noninferiority analysis was indeterminate, a post hoc analysis suggested that VA improvement with this particular binocular iPad treatment was not as good as with 2 hours of prescribed daily patching. http://www.clinicaltrials.gov Identifier: NCT02200211.

Duration of Antibiotic Treatment in Community-Acquired Pneumonia: A Multicenter Randomized Clinical Trial.

The optimal duration of antibiotic treatment for community-acquired pneumonia (CAP) has not been well established. To validate Infectious Diseases Society of America/American Thoracic Society guidelines for duration of antibiotic treatment in hospitalized patients with CAP. This study was a multicenter, noninferiority randomized clinical trial performed at 4 teaching hospitals in Spain from January 1, 2012, through August 31, 2013. A total of 312 hospitalized patients diagnosed as having CAP were studied. Data analysis was performed from January 1, 2014, through February 28, 2015. Patients were randomized at day 5 to an intervention or control group. Those in the intervention group were treated with antibiotics for a minimum of 5 days, and the antibiotic treatment was stopped at this point if their body temperature was 37.8°C or less for 48 hours and they had no more than 1 CAP-associated sign of clinical instability. Duration of antibiotic treatment in the control group was determined by physicians. Clinical success rate at days 10 and 30 since admission and CAP-related symptoms at days 5 and 10 measured with the 18-item CAP symptom questionnaire score range, 0-90; higher scores indicate more severe symptoms. Of the 312 patients included, 150 and 162 were randomized to the control and intervention groups, respectively. The mean (SD) age of the patients was 66.2 (17.9) years and 64.7 (18.7) years in the control and intervention groups, respectively. There were 95 men (63.3%) and 55 women (36.7%) in the control group and 101 men (62.3%) and 61 women (37.7%) in the intervention group. In the intent-to-treat analysis, clinical success was 48.6% (71 of 150) in the control group and 56.3% (90 of 162) in the intervention group at day 10 (P = .18) and 88.6% (132 of 150) in the control group and 91.9% (147 of 162) in the intervention group at day 30 (P = .33). The mean (SD) CAP symptom questionnaire scores were 24.7 (11.4) vs 27.2 (12.5) at day 5 (P = .10) and 18.6 (9.0) vs 17.9 (7.6) at day 10 (P = .69). In the per-protocol analysis, clinical success was 50.4% (67 of 137) in the control group and 59.7% (86 of 146) in the intervention group at day 10 (P = .12) and 92.7% (126 of 137) in the control group and 94.4% (136 of 146) in the intervention group at day 30 (P = .54). The mean (SD) CAP symptom questionnaire scores were 24.3 (11.4) vs 26.6 (12.1) at day 5 (P = .16) and 18.1 (8.5) vs 17.6 (7.4) at day 10 (P = .81). The Infectious Diseases Society of America/American Thoracic Society recommendations for duration of antibiotic treatment based on clinical stability criteria can be safely implemented in hospitalized patients with CAP. clinicaltrialsregister.eu Identifier: 2011-001067-51.