Three-arm Clinical Trial Research Articles

Design and early progress of the Comparison of Anticoagulation and anti-Platelet Therapies for Intracranial Vascular Atherostenosis (CAPTIVA) trial.

The usual antithrombotic treatment for symptomatic intracranial atherosclerotic stenosis (ICAS) consists of dual treatment with clopidogrel and aspirin for 90 days followed by aspirin alone but the risk of recurrent stroke remains high up to 12 months. The Comparison of Anticoagulation and anti-Platelet Therapies for Intracranial Vascular Atherostenosis (CAPTIVA) trial was designed to determine whether other combinations of dual antithrombotic therapy are superior to clopidogrel and aspirin. CAPTIVA is an ongoing, prospective, double-blinded, three-arm clinical trial at over 100 sites in the United States and Canada that will randomize 1683 high-risk subjects with a symptomatic infarct attributed to 70-99% stenosis of a major intracranial artery to 12 months of treatment with (1) ticagrelor (180 mg loading dose, then 90 mg twice daily), (2) low-dose rivaroxaban (2.5 mg twice daily), or (3) clopidogrel (600 mg loading dose, then 75 mg daily). All subjects receive aspirin (81 mg daily), intensive risk factor management, and will undergo blinded CYP2C19 genotype analysis. The primary goal of the trial is to determine whether rivaroxaban or ticagrelor or both are superior to clopidogrel for lowering the primary endpoint (ischemic stroke, intracerebral hemorrhage (ICH), or vascular death) within 12 months. A prespecified interim safety analysis will be conducted when the first 450 randomized subjects have been followed for 12 months to evaluate the risk of major hemorrhage in the rivaroxaban and ticagrelor arms. Enrollment began in August 2022 and, as of 26 June 2024, the 450th subject was randomized into the study. CAPTIVA is evaluating two alternative dual antithrombotic therapies to clopidogrel and aspirin to maximize the chance of establishing more effective antithrombotic therapy for symptomatic ICAS, one of the most common and high-risk cerebrovascular diseases worldwide.

Optimization the design of fixed and group sequential three-arm non-inferiority trials with dichotomous endpoints of risk difference and odds ratio

Although the risk difference (RD) is the most common and well explored functional form for testing efficacy with dichotomous endpoint, odds ratio (OR) is also suggested and well applied measure for non-inferiority (NI) trials. Since the construction and interpretation of these function forms are quite different, this study aims to provide detailed discussions and comprehensive comparisons on the design and testing approach for RD and OR scales for the fixed and group sequential three-arm NI trials under various of situations. The sample size determinations and testing approaches for assessing NI of a new treatment in three-arm clinical trials for RD and OR scales were reviewed comprehensively. Simulation studies are conducted for hundreds of scenarios with parameter configurations of the response rates, randomized allocations, NI margins and interim analysis. The operating characteristic (OC) of RD and OR scales based on the MLE and RMLE methods were thoroughly investigated. A trial example was designed and analyzed to demonstrate the methodologies. It is found that sample size determination on OR scale gives smaller sample size and robust procedure compared to RD scale in the majority of situations. When evaluating the behaviors of the attained power, the RMLE methods based on OR scale outperforms the MLE method and tend to have more power to reject the null hypothesis especially under the small sample size situations. Compared to the fixed design, the group sequential design has better OC, which provides a comparable power while needing smaller total average sample sizes for all cases. In addition, we suggest a lower significance level with a higher power for the sample size determination in the superiority test stage in the group sequential design, which can significantly reduce the total sample sizes while the number of subjects in the placebo group does not increase much. It can offer some recommendations for the investigators to choose the optimal endpoints and parameter configurations to design a three-arm NI trial under certain situations.

The impact of modified incision height and surgical procedure on trichiasis surgery outcomes: Results of the maximizing trichiasis surgery success (MTSS) randomized trial.

Poor surgical outcomes remain a problem in trachoma-endemic countries working to reach elimination thresholds. Methods to improve outcomes could positively impact programmatic success. This parallel, three-armed clinical trial conducted in Ethiopia randomized individuals with previously unoperated trachomatous trichiasis (TT) to receive surgery utilizing one of three approaches: bilamellar tarsal rotation with a 3 mm incision height (BLTR-3), BLTR with 5 mm incision height (BLTR-5) and posterior lamellar tarsal rotation (PLTR). We followed participants for one year. The primary outcome was post-operative trichiasis (PTT). Secondary outcomes were eyelid contour abnormalities (ECA) and pyogenic granulomata. We randomized and operated on 4,914 individuals with previously unoperated TT (6,940 eyes). Primary analyses include 6,815 eyes with follow-up. Overall, 1,149 (16.9%) eyes developed PTT. The risk difference for PTT was minimal comparing BLTR-3 and PLTR (adjusted risk difference [aRD] 1.8% (98.3%CI: -0.5-4.2%)), but significantly higher for BLTR-5 surgeries compared to BLTR-3 (aRD: 6.7% (3.9-9.4%)) and PLTR (aRD: 8.6% (5.9-11.3%)). BLTR-5 had the lowest ECA (6.1% versus 9.6% BLTR-3, 11.2% PLTR) and granuloma rates (5.2% versus 6.5% BLTR-3 and 7.5% PLTR). One eyelid operated with PLTR experienced an eyelid margin division; four BLTR-3 and eight BLTR-5 eyelids experienced excessive bleeding. We do not recommend modifying the BLTR incision height of 3 mm. Overall, we did not find a significant difference in PTT between BLTR-3 and PLTR in terms of PTT or ECA. Registration number: NCT03100747; ClinicalTrials.gov Full study protocol available at (https://doi.org/10.15139/S3/QHZXWD).

Three-arm clinical trial of improved flour targeting intestinal microbiota (MALINEA).

The main objective of this project was to compare in the field conditions two strategies of re-nutrition of children with moderate acute malnutrition (MAM) aged from 6 to 24 months, targeting the microbiota in comparison with a standard regimen. A three-arm, open-label, pragmatic randomised trial was conducted in four countries (Niger, CAR, Senegal and Madagascar). Children received for 12 weeks either fortified blended flour (FBF control) = arm 1, or FBF + azithromycin (oral suspension of 20 mg/kg/day daily given with a syringe) for the first 3 days at inclusion = arm 2 or mix FBF with inulin/fructo-oligosaccharides (6 g/day if age ≥12 months and 4 g if age <12 months) = arm 3. For each arm, children aged from 6 to 11 months received 100 g x 2 per day of flours and those aged from 12 to 24 months received 100 g × 3 per day of FBF. The primary endpoint was nutritional recovery, defined by reaching a weight-for-height z-score (WHZ) ≥ -1.5 within 12 weeks. Overall, 881 children were randomised (297, 290 and 294 in arm 1, arm 2 and arm 3, respectively). Three hundred and forty-four children were males (39%) and median/mean age were 14.6/14.4 months (SD = 4.9, IQR = 10.5-18.4). At inclusion, the three arms were comparable for all criteria, but differences were observed between countries. Overall, 44% (390/881) of the children recovered at week 12 from MAM, with no significant difference between the three arms (41.4%, 45.5% and 45.9%, in arm 1, arm 2 and arm 3, respectively, p = 0.47). This study did not support the true advantages of adding a prebiotic or antibiotic to flour. When using a threshold of WHZ ≥ -2 as an exploratory endpoint, significant differences were observed between the three arms, with higher success rates in arms with antibiotics or prebiotics compared to the control arm (66.9%, 66.0% and 55.2%, respectively, p = 0.005).

Does the Combination of Platelet-rich Plasma and Supervised Exercise Yield Better Pain Relief and Enhanced Function in Knee Osteoarthritis? A Randomized Controlled Trial.

Knee osteoarthritis is a leading cause of disability with substantial healthcare costs, and efficient nonsurgical treatment methods are still needed. Platelet-rich plasma (PRP) injections and exercise therapy are used frequently in clinical practice. Whether PRP or PRP combined with exercise is more effective than exercise alone is unclear. (1) Which treatment relieves knee osteoarthritis pain better: PRP alone, exercise, or PRP combined with exercise? (2) Does PRP alone, exercise, or PRP combined with exercise yield better results in terms of the WOMAC score, performance on the 40-m fast-paced walk test and stair climbing test, and the SF-12 health-related quality of life score? In this randomized, controlled, three-arm clinical trial, we recruited patients with mild-to-moderate (Kellgren-Lawrence Grade II or III) knee osteoarthritis with a minimum of 3 points on the 11-point numeric rating scale for pain. During the study period, 157 patients with a diagnosis of knee osteoarthritis were screened and 84 eligible volunteers were enrolled in the study. Patients were randomly allocated (1:1:1) into either the exercise group (28), PRP group (28), or PRP + exercise group (28). Follow-up proportions were similar between the groups (exercise: 89% [25], PRP: 86% [24], PRP + exercise: 89% [25]; p = 0.79). All patients were analyzed in an intention-to-treat manner. There were no between-group differences in age, gender, arthritis severity, and baseline clinical scores (pain, WOMAC, functional performance tests, and health-related quality of life). The exercise group underwent a 6-week structured program consisting of 12 supervised individual sessions focused on strengthening and functional exercises. Meanwhile, the PRP group received three weekly injections of fresh, leukocyte-poor PRP. The PRP + exercise group received a combined treatment with both interventions. The primary outcome was knee pain over 24 weeks, measured on an 11-point numeric rating scale for pain (ranging from 0 to 10, where 0 represents no pain and 10 represents the worst pain, with a minimum clinically important difference [MCID] of 2). The secondary outcome measures included the WOMAC index (ranging from 0 to 100, with lower scores indicating a lower level of disability and an MCID of 12), the durations of the 40-meter fast-paced walk test and stair climbing test, and the SF-12 health-related quality of life score. For the a priori sample size calculation, we used the numeric rating scale score for pain at 24 weeks as the primary outcome variable. The MCID for the numeric rating scale was deemed to be 2 points, with an estimated standard deviation of 2.4. Based on sample size calculations, a sample of 24 patients per group would provide 80% power to detect an effect of this size between the groups at the significance level of p = 0.05. We found no clinically important differences in improvements in pain-defined as ≥ 2 points of 10-at 24 weeks when comparing exercise alone to PRP alone to PRP + exercise (1.9 ± 0.7 versus 3.8 ± 1.8 versus 1.4 ± 0.6; mean difference between PRP + exercise group and exercise group -0.5 [95% confidence interval -1.2 to 0.4]; p = 0.69). Likewise, we found no differences in WOMAC scores at 24 weeks of follow-up when comparing exercise alone to PRP alone to PRP + exercise (10 ± 9 versus 26 ± 20 versus 7 ± 6; mean difference between PRP + exercise group and exercise group -3 [95% CI -12 to -5]; p = 0.97). There were no differences in any of the other secondary outcome metrics among the PRP + exercise and exercise groups. PRP did not improve pain at 24 weeks of follow-up in patients with mild-to-moderate knee osteoarthritis compared with exercise alone. Moreover, exercise alone was clinically superior to PRP alone, considering function and the physical component of health-related quality of life. Despite the additional costs and endeavors related to PRP products, the combination of PRP and exercise did not differ from exercise alone. The results of this randomized controlled trial do not support the use of PRP injections in the treatment of patients diagnosed with mild-to-moderate knee osteoarthritis. Consequently, exercise alone is the recommended treatment for reducing pain and enhancing function throughout this timeframe. Level I, therapeutic study.

Exercise therapy for knee osteoarthritis pain: how does it work? A study protocol for a randomised controlled trial

IntroductionMuscle strengthening training (MST) and behavioural graded activity (BGA) show comparable effects on knee osteoarthritic (KOA) pain, but the mechanisms of action remain unclear. Both exercise-induced anti-inflammation and central sensitisation...

Adhatoda vasica and Tinospora cordifolia extracts ameliorate clinical and molecular markers in mild COVID-19 patients: a randomized open-label three-armed study

BackgroundSARS-CoV-2 infections caused mild-to-moderate illness. However, a sizable portion of infected people experience a rapid progression of hyper-inflammatory and hypoxic respiratory illness that necessitates an effective and safer remedy to combat COVID-19.MethodsA total of 150 COVID-19-positive patients with no to mild symptoms, between the age groups 19–65 years were enrolled in this randomized, open-labeled three-armed clinical trial. Among them, 136 patients completed the study with RT-PCR negative reports. The patients received herbal drugs orally (Group A (Adhatoda vasica; AV; 500 mg; n = 50); Group B (Tinospora cordifolia; TC; 500 mg; n = 43), and Group C (AV + TC; 250 mg each; n = 43)) for 14 days. Clinical symptoms, vital parameters, and viral clearance were taken as primary outcomes, and biochemical, hematological parameters, cytokines, and biomarkers were evaluated at three time points as secondary outcomes.ResultsWe found that the mean viral clearance time was 13.92 days (95% confidence interval [CI] 12.85–14.99) in Group A, 13.44 days (95% confidence interval [CI] 12.14–14.74) in Group B, and 11.86 days (95% confidence interval [CI] 10.62–13.11) days in Group C. Over a period of 14 days, the mean temperature in Groups A, and B significantly decreased linearly. In Group A, during the trial period, eosinophils, and PT/INR increased significantly, while monocytes, SGOT, globulin, serum ferritin, and HIF-1α, a marker of hypoxia reduced significantly. On the other hand, in Group B hsCRP decreased at mid-treatment. Eosinophil levels increased in Group C during the treatment, while MCP-3 levels were significantly reduced.ConclusionsAll the patients of the three-armed interventions recovered from COVID-19 and none of them reported any adverse effects from the drugs. Group C patients (AV + TC) resulted in a quicker viral clearance as compared to the other two groups. We provide the first clinical report of AV herbal extract acting as a modifier of HIF-1α in COVID-19 patients along with a reduction in levels of ferritin, VEGF, and PT/INR as the markers of hypoxia, inflammation, and thrombosis highlighting the potential use in progression stages, whereas the TC group showed immunomodulatory effects.Trial registration Clinical Trials Database -India (ICMR-NIMS), CTRI/2020/09/028043. Registered 24th September 2020, https://www.ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=47443&EncHid=&modid=&compid=%27,%2747443det%27Graphical

Statistical analysis plan for the LAKANA trial: a cluster-randomized, placebo-controlled, double-blinded, parallel group, three-arm clinical trial testing the effects of mass drug administration of azithromycin on mortality and other outcomes among 1–11-month-old infants in Mali

BackgroundThe Large-scale Assessment of the Key health-promoting Activities of two New mass drug administration regimens with Azithromycin (LAKANA) trial in Mali aims to evaluate the efficacy and safety of azithromycin (AZI) mass drug administration (MDA) to 1–11-month-old infants as well as the impact of the intervention on antimicrobial resistance (AMR) and mechanisms of action of azithromycin. To improve the transparency and quality of this clinical trial, we prepared this statistical analysis plan (SAP).Methods/designLAKANA is a cluster randomized trial that aims to address the mortality and health impacts of biannual and quarterly AZI MDA. AZI is given to 1–11-month-old infants in a high-mortality setting where a seasonal malaria chemoprevention (SMC) program is in place. The participating villages are randomly assigned to placebo (control), two-dose AZI (biannual azithromycin-MDA), and four-dose AZI (quarterly azithromycin-MDA) in a 3:4:2 ratio. The primary outcome of the study is mortality among the intention-to-treat population of 1–11-month-old infants. We will evaluate relative risk reduction between the study arms using a mixed-effects Poisson model with random intercepts for villages, using log link function with person-years as an offset variable. We will model outcomes related to secondary objectives of the study using generalized linear models with considerations on clustering.ConclusionThe SAP written prior to data collection completion will help avoid reporting bias and data-driven analysis for the primary and secondary aims of the trial. If there are deviations from the analysis methods described here, they will be described and justified in the publications of the trial results.Trial registrationClinicalTrials.gov ID NCT04424511. Registered on 11 June 2020.

Effects of Uni- vs. Bilateral Upper Limb Robot-Assisted Rehabilitation on Motor Function, Activities of Daily Living, and Electromyography in Hemiplegic Stroke: A Single-Blinded Three-Arm Randomized Controlled Trial.

To evaluate if bilateral or unilateral upper limb robot-assisted rehabilitation training using a new three-dimensional end-effector robot that targets shoulder and elbow flexion and abduction is superior to conventional therapy with regard to upper extremity motor function recovery and neuromuscular improvement in stroke patients. Randomized, controlled, parallel, assessor-blinded, three-arm clinical trial. Southeast University Zhongda Hospital Nanjing, Jiangsu, China. Seventy patients with hemiplegic stroke were randomly assigned to conventional training (Control, n = 23) or unilateral (URT, n = 23), or bilateral robotic training (BRT, n = 24). The conventional group received routine rehabilitation, 60 min/day, 6 days/week, for 3 weeks. For URT and BRT upper limb robot-assisted rehabilitation training was added. This was 60 min/day, 6 days/week, for 3 weeks. The primary outcome was upper limb motor function assessed with Fugl-Meyer-Upper Extremity Scale (FMA-UE). Secondary outcomes were activities of daily living (ADL) assessed with the Modified Barthel Index (MBI), Motor Evoked Potential (MEP) to assess corticospinal tract connectivity, Root Mean Square (RMS) value, and integrate Electromyography (iEMG) value recorded by surface electromyography to evaluate muscle contraction function. The primary outcome indicator FMA-UE (least square mean (LSMEAN): 31.40, 95% confidence interval (95% CI): 27.74-35.07) and the secondary outcome indicator MBI (LSMEAN: 69.95, 95% CI: 66.69-73.21) were significantly improved in BRT as opposed to control (FMA-UE, LSMEAN: 24.79, 95% CI: 22.23-27.35; MBI, LSMEAN: 62.75, 95% CI: 59.42-66.09); and unilateral (FMA-UE, LSMEAN: 25.97, 95% CI: 23.57-28.36; MBI, LSMEAN: 64.34, 95% CI: 61.01-67.68). BRT also showed greater improvement in the anterior deltoid bundle with regard to muscle contraction function indicated by RMS (LSMEAN: 257.79, 95% CI: 211.45-304.12) and iEMG (LSMEAN: 202.01, 95% CI: 167.09-236.94), as compared to the controls (RMS, LSMEAN: 170.77, 95% CI: 148.97-192.58; iEMG, LSMEAN: 132.09, 95% CI: 114.51-149.68), and URT (RMS, LSMEAN: 179.05, 95% CI: 156.03-202.07; iEMG, LSMEAN: 130.38, 95% CI: 107.50-153.26). There was no statistically significant difference between URT and conventional training for any outcome. There was no significant difference in MEP extraction rate after treatment between groups (p = 0.54 for URT, p = 0.08 for BRT). A 60 min daily training for upper extremities using a three-dimensional end-effector targeting elbow and shoulder adding conventional rehabilitation appears to promote upper limb function and ADL in stroke patients only if delivered bilaterally. URT does not seem to result in better outcomes than conventional rehabilitation. Electrophysiological results suggest that training using a bilateral upper limb robot increases the recruitment of motor neurons rather than improving the conduction function of the corticospinal tract.

Access for Cancer Caregivers to Education and Support for Shared Decision Making (ACCESS) intervention: a cluster cross-over randomised clinical trial

ObjectivesThe purpose of this study was to test an intervention named ACCESS (Access for Cancer Caregivers to Education and Support for Shared Decision Making). The intervention uses private Facebook support...

Testing the effects of mass drug administration of azithromycin on mortality and other outcomes among 1–11-month-old infants in Mali (LAKANA): study protocol for a cluster-randomized, placebo-controlled, double-blinded, parallel-group, three-arm clinical trial

BackgroundMass drug administration (MDA) of azithromycin (AZI) has been shown to reduce under-5 mortality in some but not all sub-Saharan African settings. A large-scale cluster-randomized trial conducted in Malawi, Niger, and Tanzania suggested that the effect differs by country, may be stronger in infants, and may be concentrated within the first 3 months after treatment. Another study found no effect when azithromycin was given concomitantly with seasonal malaria chemoprevention (SMC). Given the observed heterogeneity and possible effect modification by other co-interventions, further trials are needed to determine the efficacy in additional settings and to determine the most effective treatment regimen.MethodsLAKANA stands for Large-scale Assessment of the Key health-promoting Activities of two New mass drug administration regimens with Azithromycin. The LAKANA trial is designed to address the mortality and health impacts of 4 or 2 annual rounds of azithromycin MDA delivered to 1–11-month-old (29–364 days) infants, in a high-mortality and malaria holoendemic Malian setting where there is a national SMC program. Participating villages (clusters) are randomly allocated in a ratio of 3:2:4 to three groups: placebo (control):4-dose AZI:2-dose AZI. The primary outcome measured is mortality. Antimicrobial resistance (AMR) will be monitored closely before, during, and after the intervention and both among those receiving and those not receiving MDA with the study drugs. Other outcomes, from a subset of villages, comprise efficacy outcomes related to morbidity, growth and nutritional status, outcomes related to the mechanism of azithromycin activity through measures of malaria parasitemia and inflammation, safety outcomes (AMR, adverse and serious adverse events), and outcomes related to the implementation of the intervention documenting feasibility, acceptability, and economic aspects. The enrolment commenced in October 2020 and is planned to be completed by the end of 2022. The expected date of study completion is December 2024.DiscussionIf LAKANA provides evidence in support of a positive mortality benefit resulting from azithromycin MDA, it will significantly contribute to the options for successfully promoting child survival in Mali, and elsewhere in sub-Saharan Africa.Trial registrationClinicalTrials.gov NCT04424511. Registered on 11 June 2020.

Optimal postoperative pain management after VATS lung resection by thoracic epidural analgesia, continuous paravertebral block or single-shot intercostal nerve block (OPtriAL): study protocol of a three-arm multicentre randomised controlled trial

BackgroundAdequate pain control after video-assisted thoracoscopic surgery (VATS) for lung resection is important to improve postoperative mobilisation, recovery, and to prevent pulmonary complications. So far, no consensus exists on optimal postoperative pain management after VATS anatomic lung resection. Thoracic epidural analgesia (TEA) is the reference standard for postoperative pain management following VATS. Although the analgesic effect of TEA is clear, it is associated with patient immobilisation, bladder dysfunction and hypotension which may result in delayed recovery and longer hospitalisation. These disadvantages of TEA initiated the development of unilateral regional techniques for pain management. The most frequently used techniques are continuous paravertebral block (PVB) and single-shot intercostal nerve block (ICNB). We hypothesize that using either PVB or ICNB is non-inferior to TEA regarding postoperative pain and superior regarding quality of recovery (QoR). Signifying faster postoperative mobilisation, reduced morbidity and shorter hospitalisation, these techniques may therefore reduce health care costs and improve patient satisfaction.MethodsThis multi-centre randomised study is a three-arm clinical trial comparing PVB, ICNB and TEA in a 1:1:1 ratio for pain (non-inferiority) and QoR (superiority) in 450 adult patients undergoing VATS anatomic lung resection. Patients will not be eligible for inclusion in case of contraindications for TEA, PVB or ICNB, chronic opioid use or if the lung surgeon estimates a high probability that the operation will be performed by thoracotomy. Primary outcomes: (1) the proportion of pain scores ≥ 4 as assessed by the numerical rating scale (NRS) measured during postoperative days (POD) 0–2; and (2) the QoR measured with the QoR-15 questionnaire on POD 1 and 2. Secondary outcome measures are cumulative use of opioids and analgesics, postoperative complications, hospitalisation, patient satisfaction and degree of mobility.DiscussionThe results of this trial will impact international guidelines with respect to perioperative care optimization after anatomic lung resection performed through VATS, and will determine the most cost-effective pain strategy and may reduce variability in postoperative pain management.Trial registration The trial is registered at the Netherlands Trial Register (NTR) on February 1st, 2021 (NL9243). The NTR is no longer available since June 24th, 2022 and therefore a revised protocol has been registered at ClinicalTrials.gov on August 5th, 2022 (NCT05491239). Protocol version: version 3 (date 06-05-2022), ethical approval through an amendment (see ethical proof in the Study protocol proof).

Intracapsular tonsillectomy in the treatment of recurrent and chronic tonsillitis in adults: a protocol of a prospective, single-blinded, randomised study with a 5-year follow-up (the FINITE trial)

IntroductionThe standard surgical treatment for recurrent or chronic tonsillitis is extracapsular tonsillectomy. Recent studies show that intracapsular tonsillectomy has the potential to reduce the postoperative morbidity of patients undergoing tonsil...

Capacitive resistive monopolar radiofrequency at 448 kHz plus exercising versus exercising alone for subacromial pain: A sham-controlled randomized clinical trial

Objective To investigate the effectiveness of thermal and sub-thermal capacitive-resistive monopolar radiofrequency at 448 kHz plus exercising compared to sham radiofrequency plus exercising on pain, functionality, and quality of life in patients with subacromial pain. Design Randomized, controlled, parallel, double-blind, three-arm clinical trial. Setting Hospital and Primary Care. Subjects Eighty-one participants with subacromial pain in three intervention groups. Interventions Three interventions with capacitive-resistive radiofrequency (thermal, sub-thermal, and sham) over 9 sessions (3 per week) plus an exercising protocol identical for all groups over 15 sessions (5 per week). Outcome measures Visual analogue scale and pressure pain threshold for pain, Shoulder Pain and Disability Index and Quick-Disabilities of the Arm, Shoulder and Hand for functionality, and quality of life via the European Quality of Life-Five Dimensions were assessed at baseline, immediately posttreatment, and 1 month and 3 months post-intervention. Results No between-group differences were found in the pain visual analogue scale (F = 1.0; P = 0.37), Shoulder Pain and Disability Index (F = 1.0; P = 0.36), European Quality of Life-Five Dimensions (F = 0.76; P = 0.47), and pressure pain (F = 0.14; P = 0.86) outcomes, with a statistical power < 0.30 for all comparisons. Between-group differences were found in the Quick-Disabilities of the Arm, Shoulder and Hand (F = 3.4; P < 0.038), with an improvement of −14.1 points (confidence interval at 95% (95% CI) −28.1 to −0.1) in the thermal versus the sham group at 1 month follow-up. The mobility dimension of European Quality of Life-Five Dimensions improved in a greater proportion of participants in the thermal group (22.2% thermal, 7.4% sub-thermal, and 0.0% sham; P = 0.02) Conclusion Adding thermal radiofrequency to exercising can further improve slightly functionality and mobility in people with subacromial pain in the short term, but not pain perception. Future studies with larger sample sizes are warranted to increase statistical power.

Breathing exercises versus strength exercises through telerehabilitation in coronavirus disease 2019 patients in the acute phase: A randomized controlled trial

Objective To compare the effectiveness of two different exercise-based programs through telerehabilitation in patients with coronavirus disease 2019. Design Randomized, controlled, parallel, double-blinded, three-arm clinical trial. Setting Patients’ homes through telerehabilitation devices. Subjects Subjects with coronavirus disease 2019 in the acute phase. Interventions Subjects were divided into three groups: breathing exercises group, strength exercises group or no treatment/control group. Main measures We analysed visual analogue scale for fatigue, 6-minute walking test, 30-seconds sit-to-stand test, multidimensional dyspnoea-12 questionnaire and Borg scale at baseline and 14 days later. Results From 93 subjects recruited, 88 were enrolled, and 77 patients (mean [SD] age 39.40 [11.71]) completed the 14-days intervention and were included in the analysis: 26 in strength exercises group, 29 in breathing exercises group and 22 in control group. The intergroup analysis shows significant differences between the study groups and control group in all variables (p < 0.05); Borg scale, multidimensional dyspnoea-12 questionnaire (pre–post intervention score: strength exercises group: 7.85 [6.82] – 4.54[4.82], breathing exercises group: 11.04 [6.49] – 5.32 [3.63], control group: 10.27 [6.49] – 10.59[6.58]), visual analogue scale for fatigue, 6-minute walking test and 30-seconds sit-to-stand test (pre–post intervention score: strength exercises group: 12.19 [4.42] – 13.58 [5.37], breathing exercises group: 11.18 [3.42] – 12.79 [4.00], control group: 10.45 [2.15] – 9.86[1.88]). The greatest effect sizes were found in the variables Borg Scale (R2 = 0.548) and multidimensional dyspnoea-12 questionnaire (R2 = 0.475). Conclusions Strength exercises group and breathing exercises group obtained significant improvements in fatigue, dyspnoea, perceived effort, and physical state, compared to control group, although the greatest benefits were found for dyspnoea and aerobic capacity in breathing exercises group.

Effects of Metronidazole as an Adjunct to Non-Surgical Periodontal Therapy on Insulin Resistance in Type 2 Diabetics.

Treating periodontitis with metronidazole (MET) as an adjunct to scaling root planing (SRP) is suggested to have inconsistent effects on insulin resistance (IR) in type 2 diabetes mellitus (T2DM). This paper will present the effects of MET, in addition to SRP, on the homeostatis model assessment of IR (HOMA-IR). A three-arm clinical trial was conducted and analyses were performed on T2DM participants with periodontitis (n = 74) who completed follow-up visits at 3 and 6 months after the intervention. The observed between-group and within-group mean changes in IR were found using ANOVA with repeated measures, followed by a post-hoc analysis, and a p-value of ≤0.05 was considered significant. Between-group analyses showed no difference in the HOMA-IR at 3 months, but at 6 months the difference was significant (p = 0.046). Within-group analyses showed that the HOMA-IR was significantly reduced in both test groups (p ≤ 0.05) over the period of time. Adjunct use of MET may result in a sudden short-term lowering of the HOMA-IR level within 3 months that may not be retained over 6 months when compared to the sustained lowering of the HOMA-IR levels in T2DM when intervened with SRP without MET.

Effects of Body Weight on the Safety of High-Dose Donepezil in Alzheimer’s Disease: Post hoc Analysis of a Multicenter, Randomized, Open-Label, Parallel Design, Three-Arm Clinical Trial

Background: Donepezil 23 mg is considered for Alzheimer’s disease (AD) to optimize cognitive benefits; however, increased adverse events (AEs) can negatively influence drug adherence. We investigated whether body weight (BW) differs based on the presence of AEs, and which baseline factors were relevant to the safety of high-dose donepezil. Methods: This study was a post hoc analysis of a multicenter randomized trial between 2014 and 2016. We included patients with moderate to severe AD treated with 10 mg/day of donepezil, and the daily dose was escalated to 23 mg with/without dose titration. Dose titration indicates 15 mg/day of donepezil before escalation or 10 mg and 23 mg/day on alternate days before escalation during the first 4 weeks. The patients were divided into 2 groups based on occurrence of AEs of special interest (AESIs) to compare baseline characteristics. We also assessed relationships between BW and AESIs. Results: Among the 160 participants in the safety population, the baseline BWs differed between the AESI (+) (n = 67) and AESI (−) (n = 93) groups. Baseline BW was inversely correlated with the occurrence of AESIs (p = 0.020), and this relationship was prominent in the no-dose titration group (p = 0.009) but absent in the dose-titration groups (p > 0.05). Conclusions: BW is the most important factor that correlated with cholinergic AEs. Hence, stepwise dose titration should be considered, particularly in patients with low BW, to minimize the inverse relationship between BW and the occurrence of AEs (“Clinicaltrials.gov” No. NCT02550665 registered on September 15, 2015).

A statistical review: why average weighted accuracy, not accuracy or AUC?

Sensitivity and specificity are key aspects in evaluating the performance of diagnostic tests. Accuracy and AUC are commonly used composite measures that incorporate sensitivity and specificity. Average Weighted Accuracy (AWA) is motivated by the need for a statistical measure that compares diagnostic tests from the medical costs and clinical impact point of view, while incorporating the relevant prevalence range of the disease as well as the relative importance of false-positive versus false-negative cases. We illustrate the testing procedures in four different scenarios: (i) one diagnostic test vs. the best random test, (ii) two diagnostic tests from two independent samples, (iii) two diagnostic tests from the same sample, and (iv) more than two diagnostic tests from different or the same samples. The impacts of sample size, prevalence, and relative importance on power and average medical costs/clinical loss are examined through simulation studies. Accuracy has the highest power while AWA provides a consistent criterion in selecting the optimal threshold and better diagnostic tests with direct clinical interpretations. The use of AWA is illustrated on a three-arm clinical trial evaluating three different assays in detecting Neisseria gonorrhoeae and Chlamydia trachomatis in the rectum and pharynx.

Longitudinal Changes in the Sensorimotor Pathways of Very Preterm Infants During the First Year of Life With and Without Intervention: A Pilot Study

ABSTRACT Objective: Evaluate longitudinal changes in brain microstructure and volumes in very preterm infants during the first year of life with and without intervention. Design: Descriptive pilot study. Methods: Five preterm infants in a three-arm clinical trial, one SPEEDI Early, two SPEEDI Late, and two usual care. Brain structural and diffusion MRI’s were acquired within 72 hours after neonatal intensive care unit discharge (n = 5), three months post-baseline (n = 5), and six months post-baseline (n = 3). Fractional anisotropy (FA), Mean diffusivity (MD), and volume metrics were computed for five brain regions. Results: More than 60% of eligible participants completed 100% of the scheduled MRIs. FA and volume increased from baseline to six months across all brain regions. Rate of white matter volume change from baseline to six months was highest in SPEEDI Early. Conclusions: Non-sedated longitudinal MRI is feasible in very preterm infants and appears to demonstrate longitudinal changes in brain structure and connectivity.

Autologous versus allogeneic versus umbilical cord sera for the treatment of severe dry eye disease: a double-blind randomized clinical trial.

To measure the effects of Autologous serum (AS), Allogeneic Serum (HS) andUmbilical Cord serum (CS) eye drops in severe dry eye disease (DES), as well as tocharacterize and quantify several molecules in the three sera (albumin, fibronectin; Vitamin A and E; IgG, IgA and IgM; Transforming growth factor β; Epithelial growth factor). Randomized, double-blind, single-centre, three-arm (AS, HS and CS) clinical trial. Sixty-three subjects were included with severe DES, 21 in each arm of the study. Visual acuity, Schirmer test, Breakup time (BUT), lissamine green, fluorescein staining measurements and a questionnaire were performed prior to treatment, and after one-month and three-month follow-up. There was a significant main effect of time on visual acuities, Schirmer and BUT tests and fluorescein and lissamine green staining measurements and questionnaire scores (p = 0.015, p = 0.002, p < 0.001, p < 0.001, p = 0.031 and p < 0.001, respectively), although there was no significant interaction between time and serum type, nor between serum type and the test performed. Regarding the concentration of molecules, in our study AS contained significantly higher concentrations of IgA, IgG and fibronectin whereas HS contained significantly higher concentration of IgM, vitamins A and E, TGF and albumin. Contrary to previous reports, CS did not show higher concentration of any of the molecules analysed. The three sera were effective in the treatment of severe DES. CS did not contain a higher proportion of molecules compared to AS/HS. More research is needed to assess the effect of AS in patients with DES and autoimmune diseases.