Subject In Arm Research Articles

Rituximab compared to intravenous cyclophosphamide in adults with connective tissue disease-associated interstitial lung disease: the RECITAL RCT

Background Interstitial lung disease frequently complicates systemic autoimmune disorders including scleroderma, idiopathic inflammatory myositis and mixed connective tissue disease, resulting in considerable morbidity and mortality. Based on the results of trials undertaken in scleroderma, cyclophosphamide is the standard of care for individuals with severe or progressive connective tissue disease-associated interstitial lung disease. Observational studies suggest that the anti-CD20 monoclonal antibody, rituximab is an effective rescue therapy in treatment of refractory connective tissue disease-associated interstitial lung disease, but it has not been studied as first-line therapy in clinical trials. Objectives To compare the safety and efficacy of rituximab against that of cyclophosphamide as treatment for individuals with severe, progressive interstitial lung disease associated with scleroderma, idiopathic inflammatory myositis or mixed connective tissue disease. Methods This was a Phase IIb, multicentre, randomised, double-blind, double-dummy study assessing the superiority of rituximab compared with cyclophosphamide, conducted in rheumatology or interstitial lung disease units at 11 UK centres. The study recruited individuals with extensive and/or progressive connective tissue disease-associated interstitial lung disease, excluding those with significant comorbidities, including airflow obstruction. Participants were randomised 1 : 1 to receive either rituximab 1 g given intravenously, twice at an interval of 2 weeks, or intravenous cyclophosphamide given monthly for 6 months at a dose of 600 mg/m2 body surface area. The primary end point for the study was the change in forced vital capacity at 24 weeks. Secondary end points included safety and tolerability, corticosteroid exposure, forced vital capacity change at 48 weeks and patient-reported quality of life. A cost-effectiveness analysis was undertaken to assess the impact of rituximab use in the United Kingdom National Health Service. Results One hundred and one subjects (70 females) with a mean age of 56.3 years were randomised; 51 to rituximab and 50 to cyclophosphamide. Ninety-seven were included in the modified intention-to-treat population for the primary and secondary efficacy analyses (49 in the rituximab group and 48 in the cyclophosphamide group). 38.6% had scleroderma, 44.6% idiopathic inflammatory myositis and 16.8% mixed connective tissue disease. Four subjects withdrew prior to the first dose of therapy (two in each arm). At 24 weeks, both rituximab and cyclophosphamide improved forced vital capacity from baseline [(mean ± standard deviation) 97 ± 234 and 99 ± 329 ml, respectively]. Using an adjusted mixed-effects model corrected for diagnosis and baseline forced vital capacity the difference in forced vital capacity at 24 weeks between rituximab and cyclophosphamide was −40 ml (95% CI −153 to 74 ml), p = 0.49. Other physiological and quality-of-life parameters improved in both arms following treatment but were not statistically significantly different between groups. Numerically fewer adverse events were reported by subjects receiving rituximab. Corticosteroid exposure over the 48 weeks of the trial was numerically less in the rituximab arm [13,291 (±14,657) mg of hydrocortisone equivalent per subject in the cyclophosphamide arm versus 11,469 (±10,041) mg per subject in the rituximab group; these differences did not reach statistical significance]. Limitations of the study include a disproportionate number of subjects being recruited from a single centre and insufficient subjects in each subgroup to determine whether there were treatment differences between individual connective tissue diseases. Based on the results of the trial, from a UK healthcare payer perspective, rituximab is more cost-effective than cyclophosphamide as a treatment for severe or progressive connective tissue disease-interstitial lung disease. Conclusions Rituximab improved forced vital capacity and patient-reported quality of life at 24 weeks but was not superior to cyclophosphamide. Rituximab should be considered as a therapeutic alternative to cyclophosphamide in individuals with connective tissue disease-associated interstitial lung disease requiring systemic therapy. Future work should explore the role of repeated dosing of rituximab and the use of rituximab earlier in the course of connective tissue disease-associated interstitial lung disease. Trial registration This trial is registered as ISRCTN16474148. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation Programme (NIHR award ref: 11/116/03) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 4. See the NIHR Funding and Awards website for further award information.

Phase Ib study of patients with metastatic castrate-resistant prostate cancer treated with different sequencing regimens of atezolizumab and sipuleucel-T

BackgroundCombining an immune checkpoint inhibitor with a tumor vaccine may modulate the immune system to leverage complementary mechanisms of action that lead to sustained T-cell activation and a potent prolonged...

Convalescent Plasma to Limit Coronavirus Associated Complications: A Proof of Concept Phase-2 Clinical Study at a designated COVID-19 hospital in Mumbai city

Objective: With few treatment options available to manage coronavirus disease 2019 (COVID-19), health systems devised strategies to manage covid-19 using repurposed drugs and revisiting older strategies, such as convalescent plasma. This study was planned to evaluate safety and efficacy of Anti-SARS-CoV-2 convalescent plasma in hospitalized subjects with COVID-19.
 Method: An open label, single centre, two arm, prospective, randomised, controlled exploratory phase 2 study was conducted at a covid-19 designated center. 20 subjects (≥18 years) were admitted to hospital (screened 15 June to 27 July 2020) with confirmed moderate covid-19 (partial pressure of oxygen in arterial blood/ fraction of inspired oxygen (PaO2/FiO2) ratio between 200 mm Hg and 300 mm Hg or a respiratory rate of more than 24/min with oxygen saturation 93% or less on room air): 10 subjects were assigned to convalescent plasma with standard treatment (test arm) and 10 subjects to standard treatment only (control arm). Subjects in the test arm received either single or two doses of convalescent plasma 24 hours apart based on their clinical condition as per investigator’s discretion.
 Results: Subjects in test arm showed earlier resolution of symptoms of fever, shortness of breath and cough and the mean duration for RT-PCR test turning negative was better in the test arm. One subject in the control arm progressed to severe ARDS, while none in test arm progressed to severe ARDS. There was no difference in the use of respiratory support (invasive and non-invasive ventilation) between the 2 arms. There was no mortality observed in the study and no serious adverse reaction observed with the transfusion of convalescent plasma in the study.
 Conclusion: This was an exploratory proof of concept study to explore the effectiveness of convalescent plasma in COVID-19 subjects and sample size was not large enough to detect a statistically significant difference however subjects in test arm of this study showed better outcomes in few of the efficacy parameters as compared to subjects in control arm. The use of convalescent plasma transfusion was also observed to be safe.

1088. Extracorporeal Photopheresis and Infectious Complications in Patients with Chronic Graft Versus Host Disease

BackgroundExtracorporeal photopheresis (ECP), is a cell-based immune-modulatory therapy used in the treatment of steroid refractory chronic graft versus host disease (cGHVD). It is unclear whether ECP is associated with an increased risk of infections compared to alternative treatment. We aimed to study the infectious complications in patients who are on ECP post allogeneic hematopoietic stem cell transplant (alloHSCT).MethodsWe conducted a retrospective cohort study of adult patients with cGVHD post alloHSCT who were initiated on ECP or second line immunosuppressive agents (SLIS). The study period was from March 1, 2014 to October 1, 2018. Each subject in the ECP arm was matched to the SLIS arm according to gender, age, underlying disease, and date of diagnosis of cGVHD. All subjects were followed for one-year post treatment. The main outcome was incidence of each type of infection (event rate/ person-years). Kaplan Meier analysis was used, evaluating time to infection with log rank test. The spectrum of infectious complications was described.ResultsSeventy-seven patients were included (36 in ECP and 41 in SLIS arm). Median age was 57.4 years (18.1 -73.4), and 59.7% of patients were male. The most common underlying diseases were acute myeloid leukemia (45.4%), myelodysplastic syndrome (20.8%) and non-Hodgkin’s lymphoma (15.6%). A total occurrence of 94 infections was observed in the ECP arm, compared to 118 in SLIS arm. Bacterial infections accounted for majority of the infections in ECP arm (50%) compared to SLIS arm in which viruses were most common (49.2%). Bacterial pneumonia was the most common clinical syndrome (34% and 27.3%, in the ECP and SLIS arms, respectively). Bacteremia accounted for 12.8% of infections in the ECP arm compared to 16.4% in the SLIS arm. There was no difference in the event rates of infections among the two groups [2.58/ person-years in ECP group vs 3.60/person-years, p = 0.3766], or the probability of infection at any time between the ECP and SLIS group on Kaplan Meier (log rank test, p-value=0.36)(Figure 1).Kaplan-Meier plot of time to the earliest infection diagnosis between ECP and control group ConclusionBacterial and viral pneumonia were the most common infections in patients undergoing ECP. Overall, ECP does not confer an increased risk of infectious complications compared to second line IS agents.Disclosures Wissam El Atrouni, MD, ViiV (Advisor or Review Panel member)

Quality of life measured in first-line therapy during the Cryo-FIRST study: a comparison between cryoballoon catheter ablation versus antiarrhythmic drug therapy

Abstract Background By consensus statements, catheter ablation is a recommended treatment for patients with symptomatic drug-refractory paroxysmal atrial fibrillation (AF), as patients try to alleviate the burdensome AF symptoms that reduce the Quality of Life (QoL). Yet, first-line treatment of symptomatic patients via catheter ablation prior to initiation of antiarrhythmic drugs (AADs) is only a reasonable alternative (Class IIa). Clearly, more clinical data is necessary that compares catheter ablation to AAD therapy in treatment naïve patients. Purpose The Cryo-FIRST trial was designed to compare AAD treatment against pulmonary vein isolation (PVI) while using a cryoballoon catheter (Arctic Front Advance; Medtronic, Inc.). This current data analysis examines the QoL endpoints when comparing AADs to cryoballoon ablation in patients with symptomatic treatment naïve paroxysmal AF. Methods This randomized multicenter trial enrolled 220 patients from 18 sites in 9 countries (Europe, Australia, and Latin America) in a prospective open-blinded endpoint study design. Patients had not been administered a class I or III AAD for longer than 48 hours for inclusion into the study. Subjects were randomized (1:1) into a cohort that was administered AAD therapy or a cohort that received PVI via cryoablation. The prespecified QoL endpoint at 12 months was measured using the Atrial Fibrillation Effect on Quality of Life (AFEQT) scores, and QoL recordings were taken at baseline, 1, 3, 6, 9, and 12 months following the index treatment. Results Of the 218 patients randomized (age 52±13 years, 68% male) 86% completed the 12-month follow-up. Crossovers occurred in 9% of subjects (N=20), including: 1 subject in the cryoablation arm and 19 subjects in the AAD arm. At 12 months, 86.5% of the patients in the cryoablation arm and 70.4% of the patients in the AAD arm where without symptoms (EHRA score 1). The mean AFEQT summary score was more favorable in the catheter ablation group compared to the drug therapy group at 12 months (88.9 vs. 78.1 points, respectively). The adjusted difference was 9.9 points (95% CI: 5.5–14.2; P<0.0001). Conclusions Cryoballoon ablation resulted in a significant improvement in QoL at 12 months compared to AAD therapy in treatment naïve patients with first-line symptomatic paroxysmal AF. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Medtronic International Trading Sàrl

CSP01, a Novel Superabsorbent Hydrogel, Reduces Colonic Transit Time in Patients With Chronic Idiopathic Constipation in a Randomized, Double-blind, Controlled Pilot Clinical Trial.

Background/AimsCSP01 is a novel superabsorbent hydrogel that absorbs gastrointestinal fluids and maintains high viscoelastic properties into the colon, where these fluids are released.MethodsWe conducted a single-center, randomized, double-blind, parallel-group, placebo-controlled pilot study comparing change in colonic transit time (CTT) among patients with chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C) treated for 21 days with either CSP01 hydrogel, active control (carboxymethylcellulose [CMC]) or placebo. CTT was measured using wireless motility capsule transit testing at pre-treatment and end-of-treatment. The primary endpoint was change in CTT.ResultsForty subjects (20 CSP01, 11 CMC, 9 placebo) were enrolled and 38 completed the study. There was no significant change in mean CTT by treatment group (P = 0.297). In the placebo group, CTT increased by 15.3 minutes between baseline and end of treatment, increased by 366.4 minutes for CMC, and decreased by 727.4 minutes for CSP01. In post hoc analyses among those with CIC, mean CTT decreased by 1079 minutes for CSP01 (P = 0.025 compared to placebo), 919 minutes for CMC (P = 0.117 compared to placebo) and increased by 1113 minutes for placebo. Among patients with IBS-C, there was no significant difference in change in CTT for any treatment group. One subject in the CSP01 arm developed back pain attributed to constipation and withdrew without a second CTT measurement; there were no other adverse events.ConclusionCSP01 significantly decreased CTT compared to placebo among patients with CIC, but not in patients with IBS-C.

Feasibility of computer-generated telephonic message-based follow-up system among healthcare workers with diabetes: a randomized controlled trial

IntroductionTo assess the feasibility of computer-generated educational messaging system in healthcare workers of a tertiary care hospital. The secondary objectives were glycemic control, patient satisfaction and adherence to lifestyle modifications.Research...

Efficacy of sinecatechins 10% as proactive sequential therapy of external genital warts after laser CO2 ablative therapy: The PACT study (post-ablation immunomodulator treatment of condylomata with sinecatechins): a randomized, masked outcome assessment, multicenter trial.

External genital warts (EGW) are the most common viral sexually transmitted infection. Ablative treatments like cryotherapy, curettage, and CO2 laser therapies offer rapid onset of effect, fast clearance, and reduction of virus load. However, these procedures are associated with high recurrence rates (RRs) ranging from 20% to 77% in the short and medium terms and do not provide sustained clearance. After laser therapy removal of EGW, an RR up to 77% has been reported. Topical sinecatechins (TS) 10% is a patient-applied regimen for the treatment of EGW with a low RR (<6.5%) at three months after completion of the therapy in the pivotal trials conducted so far. Sinecatechins can be considered a suitable proactive sequential therapy (PST) after ablative strategies to obtain a low RR. So far, no prospective data are available regarding the efficacy of sinecatechins 10% as PST. We evaluated the efficacy and tolerability of TS 10% ointment applied twice daily in subjects with "difficult to treat" EGW after CO2 laser ablative treatment in a prospective controlled trial. A total of 87 subjects (76 men and 11 women; mean age 42 years) were enrolled in this three-month masked outcome assessment parallel group trial with imbalanced randomization allocation (2:1). One week after a successful CO2 laser treatment, 60 subjects were randomized to TS 10% treatment and 27 subjects to no treatment (control group: ConTRol (CTR); no sequential therapy). All patients had a history of an average of 4.5 previous ablative treatments in the last 12 months due to recurrent EGW. Mean (standard deviation) baseline number of treated lesions was 6.5 (2.7). One subject in the TS arm dropped out due to burning sensation after the application of the product. Therefore, 86 subjects completed the study. After three months, in the TS group, three subjects presented new EGW lesions (RR: 5%) on treated sites. In the CTR group, eight subjects presented new EGW lesions (RR: 29%) on treated sites (p = 0.0024; odds ratio: 0.16; 95% confidence interval: 0.04-0.68). In the TS group, 34 subjects (56%) reported mild to moderate erythema or burning sensation at the application site. In this prospective multicenter trial, the use of TS 10% as PST after ablative treatment with CO2 laser was associated with a lower recurrence rate of new EGW lesions in the short term in comparison with the control group. Comparative larger trials are warranted to evaluate the role of this approach as PST (Trial Registration Number: ISRCTN44037479).

Prevalence of Glenohumeral Internal Rotation Deficit and its Association with Scapular Dyskinesia and Rotator Cuff Strength Ratio in Collegiate Athletes Playing Overhead Sports

Introduction: Glenohumeral Internal Rotation Deficit (GIRD) indicates a 15° or greater loss of internal rotation of the throwing shoulder compared with the non-dominant shoulder.Aim: To estimate the prevalence of GIRD in collegiate overhead sports player and determine whether GIRD is associated with scapular dyskinesia and rotator cuff strength ratio. Materials and Methods: The present study was a Cross-sectional study. A total of 127 collegiate athletes were assessed for passive range of motion, external to internal rotation strength ratio (ER/IR ratio) and scapular dyskinesia for the throwing and non-throwing shoulder. Internal and external rotation of shoulder was measured using an inclinometer with the subject in prone and arm abducted to 90°. Scapular dyskinesia was measured using Lateral Scapula Slide test (LSST) and external to internal rotator strength was measured using a held hand isometric dynamometer. Chi-square test was used to find the association between GIRD and scapular dyskinesia and rotator cuff strength ratio.Results: Prevalence of GIRD (n=37) was found to be 29.1%. GIRD was not found to be associated with Scapular dyskinesia (p=0.237) and ER/IR strength ratio (p=0.411).Conclusion: Prevalence of GIRD in collegiate athletes playing overhead sports was found to be 29.1% and there was no association of GIRD with scapular dyskinesia, rotator cuff strength ratio.

PINGS (Phone-Based Intervention Under Nurse Guidance After Stroke): Interim Results of a Pilot Randomized Controlled Trial.

Stroke exacts an immense toll in sub-Saharan Africa where there are few resources, and stroke prevention research is limited. The aim of this study is to test the feasibility and preliminary efficacy of an m-Health technology-enabled, nurse-guided intervention in improving blood pressure (BP) control among Ghanaian stroke patients within 1 month of symptom onset. We conducted a 2-arm cluster pilot randomized controlled trial involving 60 recent stroke survivors encountered within a single tertiary medical system in Ghana. Subjects in the intervention arm (n=30) received a Blue-toothed UA-767Plus BT BP device and smartphone for monitoring and reporting BP measurements and medication intake for 3 months compared with standard of care (n=30). Primary outcome measure was systolic BP <140 mm Hg at month 3; secondary outcomes included medication adherence and autonomous self-regulation. Analysis accounting for clustering was made using generalized linear mixed model by intention to treat. Mean±SD age was 55±13 years, 65% male. Systolic BP <140 mm Hg at month 3 was found in 20/30 subjects (66.7%) in the intervention arm versus 14/30 subjects (46.7%) in the control arm (P=0.12). Medication possession ratio scores at month 3 were better in the intervention (0.88±0.40) versus control (0.64±0.45) arm (P=0.03). One subject in control arm died from a recurrent hemorrhagic stroke. It is feasible to conduct an m-Health-based, nurse-guided BP control intervention among recent stroke patients in sub-Saharan Africa. We observed a potential signal of efficacy with the intervention, which will need to be tested in a future large definitive study. URL: https://www.clinicaltrials.gov. Unique identifier: NCT02568137.

Single visit rabies pre-exposure priming induces a robust anamnestic antibody response after simulated post-exposure vaccination: results of a dose-finding study

The current standard 3-dose intramuscular rabies PrEP schedule suffers from a number of disadvantages that severely limit accessibility and availability. The cost of is often prohibitive, it requires 3 visits to the clinic, and there are regular vaccine shortages. Volunteers ( N = 30) were randomly assigned to 4 study arms: 1 standard dose intramuscular (IM) dose of PVRV (purified Vero cell rabies vaccine, Verorab), and 1/5th, 2/5th or 3/5th- fractional intradermal (ID) dose of PVRV in a single visit. All subjects received a simulated rabies post-exposure prophylaxis (D0, D3) 1 year later. Rabies virus neutralizing antibodies (RVNA) were determined by virus neutralization microtest (FAVN) on D0, D7, D28, Y1 and Y1 + D7. 28 out of 30 subjects (93%) seroconverted 1 month after primary vaccination; 1 subject in the 1-dose IM arm and 1 in the 1/5th-fractional dose ID arm did not. After 1 year, 22 out of 30 subjects (73%) no longer had RVNA above 0.5 IU/ml, with no discernible difference between study groups. After 1 year, all 30 subjects mounted a booster response within 7 days after simulated PEP, with the highest titers found in the single dose IM group ( P < 0.03). This dose finding study demonstrates that priming with a single dose of rabies vaccine was sufficient to induce an adequate anamnestic antibody response to rabies PEP in all subjects 1 year later, even in those in whom the RVNA threshold of 0.5 IU/ml was not reached after priming.

A Pilot Study of Eltrombopag Plus G-CSF for Human CD34+ Cell Mobilization in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplant

Background: Administration of recombinant human thrombopoietin (rhTPO) with G-CSF for stem cell mobilization is associated with high CD34+ stem cell yield, rapid neutrophil recovery following autologus transplantation (ASCT), and decreased red blood cell (rbc) and platelet (plt) transfusions (Solomo, G. et al. Blood 1999). However, clinical development of rhTPO was complicated by the formation of neutralizing anti-TPO antibodies (Li, J. et al. Blood 2001), prompting discontinuation of further clinical development of recombinant TPO. Eltrombopag (Elt) is an orally bioavailable small molecule thrombopoietin receptor (TPO-R) agonist approved by the FDA for treatment of chronic immune thrombocytopenic purpura (ITP). In vitro studies have demonstrated that Elt promotes megakaryocyte proliferation and differentiation of CD34+ bone marrow progenitor cells (Erickson-Miller CL Stem Cells 2009), suggesting that Elt might be a surrogate for rhTPO for stem cell mobilization. In this pilot trial, we evaluated the combination of Elt plus standard G-CSF and cyclophosphamide (C) for stem cell mobilization in patients (pts) with multiple myeloma (MM), a disease for which ASCT remains a standard of care (Blade et al. Blood 2010).Methods: Primary objectives included determination of the median number of CD34+ cells/kg mobilized and the maximum tolerated dose (MTD) of Elt. Pts had MM that was stable or responsive to at least two cycles of chemotherapy with plans for stem cell mobilization and ASCT. Four pts were to be enrolled in each of four dose escalation arms in which they received 0 (Arm D), 50 (Arm A), 100 (Arm B), or 150 mg (Arm C) of eltrombopag in combination with standard C + G-CSF. Adverse events (AEs) were graded by NCI-CTCAE v4.Results: 17 pts have been screened and enrolled to date. Two patients withdrew consent prior to receiving Elt and were excluded from statistical analysis. 15 patients have completed participation in the study to date and two patients remain to be enrolled in Arm C. The first subject in Arm A experienced delayed engraftment that was determined to be unrelated to ELT; rather, the event was attributed to administration of a one-time high dose of corticosteroid for management of a severe hypersensitivity reaction to DMSO that occurred during stem cell infusion. A second subject in Arm A had undergone mobilization with Elt prior to the previously described delayed engraftment event, and to ensure safety underwent a second mobilization with G-CSF and plerixafor. During ASCT, this patient received cells from the second mobilization procedure. While neither event met criteria for a dose-limiting toxicity, the protocol was amended such that three additional patients enrolled in Arm A underwent two rounds of mobilization - the first with Elt plus C and G-CSF and a second with G-CSF plus plerixafor - and received as part of ASCT cells mobilized with Elt. Each of these patients engrafted successfully. The median number of CD34+ cells/kg collected during the first collection day of apheresis in Arms D, A, B, and C was 8.0, 11.0, 15.3, and 26.4. The median total number of CD34+ stem cells collected following mobilization with Elt plus C and G-CSF in Arms D, A, B, and C was 13.2, 12.7, 15.4, and 26.4. The percentage of patients in Arms D, A, B, and C who achieved a target collection of 8 x 10^6 CD34+ stem cells in one collection day was 50, 60, 75, and 100%. There have been no severe adverse events related to Elt .Conclusions: Administration of Elt in combination with C plus G-CSF for stem cell mobilization in pts with MM undergoing ASCT was safe and well tolerated, with no DLTs or severe AEs attributable to Elt. The small size of this pilot study precludes formal statistical comparison of outcomes across treatment Arms, but there appears to be a trend toward increase in yield of CD34+ cells and decrease in apheresis procedures required with increasing doses of Elt. DisclosuresRichardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Final overall survival results of a randomized phase III trial comparing weekly docetaxel plus cisplatin (DP) with 3-weekly docetaxel (D) monotherapy in elderly patients (pts) with advanced non-small-cell lung cancer (NSCLC): intergroup trial JCOG0803/WJOG4307L.

e19012 Background: The intergroup trial JCOG0803/WJOG4307L demonstrated that overall survival of subject in the doublet arm, treated with weekly DP, was not superior to that of subjects in the D mo...

Preliminary results of the feasibility to reposition kidney stones with ultrasound in humans

Preliminary investigational use of ultrasound to reposition human kidney stones is reported. The three study arms include: de novo stones, post-lithotripsy fragments, and large stones within the preoperative setting. A pain questionnaire is completed immediately prior to and following propulsion. A maximum of 40 push attempts are administered. Movement is classified as no motion, movement with rollback or jiggle, or movement to a new location. Seven subjects have been enrolled and undergone ultrasonic propulsion to date. Stones were identified, targeted, and moved in all subjects. Subjects who did not have significant movement were in the de novo arm. None of the subjects reported pain associated with the treatment. One subject in the post-lithotripsy arm passed two small stones immediately following treatment corresponding to the two stones displaced from the interpolar region. Three post-lithotripsy subjects reported passage of multiple small fragments within two weeks of treatment. In four subjects, ultrasonic propulsion identified a collection of stones previously characterized as a single stone on KUB and ultrasound. There have been no treatment related adverse events reported with mean follow-up of 3 months. [Trial supported by NSBRI through NASA NCC 9-58. Development supported by NIH DK043881and DK092197.]

Switching the third drug of antiretroviral therapy to maraviroc in aviraemic subjects: a pilot, prospective, randomized clinical trial

To evaluate the safety and efficacy of switching the third drug of antiretroviral treatment to maraviroc in aviraemic subjects infected with R5 HIV. This is a pilot, prospective, randomized clinical trial (ClinicalTrials ID: NCT00966329). Eighty HIV-1-infected aviraemic adults on stable antiretroviral treatment for ≥1 year and no antiretroviral drug resistance were screened for the presence of non-R5 HIV by triplicate proviral V3 population sequencing. From them, 30 subjects with R5 HIV-1 were randomized 1 : 1 to switch the non-nucleoside reverse transcriptase inhibitor or ritonavir-boosted protease inhibitor to maraviroc (n = 15) or to continue the same antiretroviral treatment (controls, n = 15). The principal endpoint was the proportion of subjects with HIV-1 RNA <50 copies/mL at week 48. Ultrasensitive proviral HIV-1 tropism testing (454 sequencing) was performed retrospectively at weeks 0, 4, 12, 24, 36 and 48. One subject in the maraviroc arm and one control had non-R5 HIV in proviral DNA by retrospective 454 sequencing. The subject receiving maraviroc was the only individual to develop virological failure. However, plasma HIV at failure was R5. Switching to maraviroc was well tolerated and associated with small, but statistically significant, declines in total, high-density lipoprotein and low-density lipoprotein cholesterol. Median (IQR) triglyceride [1 (0.67-1.22) versus 1.6 (1.4-3.1) mmol/L, P = 0.003] and total cholesterol [4.3 (4.1-4.72) versus 5.4 (4-5.7) mmol/L, P = 0.059] values were lower in the maraviroc arm than in controls at week 48. In this pilot, prospective, randomized clinical trial, switching the third drug to maraviroc was safe, efficacious and improved lipid parameters.

Long Term Outcome of Patients Enrolled Into STOP and STOP II Trials: A Single Center Experience

AbstractAbstract ▪3219▪This icon denotes a clinically relevant abstractThe landmark STOP trial established chronic transfusion as an effective therapeutic modality for primary stroke prevention in children with sickle cell disease (SCD) who are at risk for ischemic stroke as determined by elevated transcranial Doppler (TCD) velocities (>200 cm/sec) in major intracranial arteries. The ensuing STOP II trial sought to optimize the duration of chronic transfusion therapy for primary stroke prevention; however, the study was stopped early when 14/41 patients who discontinued transfusions after normalization of TCD reverted to high TCD velocities and 2 subjects had overt stroke. Since it is well known that not all subjects with high TCD velocities proceed to have overt stroke, it is important to refine the stroke risk among patients with high TCD velocities thereby limiting chronic transfusion to those at the highest risk, while minimizing complications of chronic transfusion (iron overload, alloimmunization, disease transmission). While additional analytic approaches such as the incorporation of MRI/MRA and genetic and genomic analyses have been applied to refine the risk of CVA and have yielded interesting results, these are far from definitive and conclusive. Therefore, to date, TCD velocity remains the gold standard for determining stroke risk in young SCD patients.We performed a longitudinal follow up analysis of patients enrolled in STOP and STOP II studies from GHSU and report our results here. Twenty six patients (12 male, 14 female) were enrolled in these two trials from the GHSU Pediatric Sickle Cell Program; all had the Hb SS genotype. Of these, 23 patients participated in STOP, and 9 in STOP II, with six patients participating in both studies. The mean age at entry to STOP was 7.7 years and to STOP II was 10.6 years. Thirteen of the 26 patients (50%) are currently followed at GHSU Adult Sickle Cell Clinic. Two patients are deceased (cause of death unknown) and 11 are lost to follow up. The mean age of active patients is 23.8 years; median duration of follow-up is 16.2 years. Of the 13 active patients, 7 had normalized their TCD, 4 had conditional readings, and 2 continued to be abnormal (see table). Overall, 14 of the 26 patients enrolled in STOP and STOP II had normalized their TCD at the time of their last available study. Ten of these 14 patients were on transfusion for variable periods of time. A total of two patients had overt, symptomatic stroke during the observation period; one subject was randomized to transfusion, and the other to standard care while in STOP; one subject's last TCD was abnormal, the other was normal; neither of these patients were on HU at the time of stroke. The subject in the transfusion arm remained on transfusion for 3 years and had a stroke 2 months after discontinuing transfusion. Both strokes occurred in the territory of the vessel that had abnormal TCD reading. Of the 13 patients actively followed at GHSU Adult Sickle Cell Clinic, 12 are on Hydroxyurea therapy and are doing well.Our observational study on long term follow up of pediatric SCD patients at risk for stroke determined by high TCD velocities in intracranial vessels suggests that few (2/13; 15.4%) develop overt stroke on long term follow up, following a variable period of primary stroke prophylaxis per STOP protocol with > 50% of patients normalizing their TCD over time. While it is encouraging that long-term HU therapy appears to be effective in preventing strokes in the majority of the patients, the numbers are too small for a definitive conclusion. The long term risks of CVA associated with high TCD velocities in childhood and its modifications by therapeutic interventions such as transfusions and HU therapy can be answered by similar longitudinal follow up studies of the entire STOP/STOP II cohort (such as the ongoing post-STOP study) and prospective studies such as TWiTCH.Last TCD ReadingStroke (Yes/No) Since STOP/STOP II StudyYears on Transfusion (Prior to Last TCD Reading)Years off Transfusion at time of last TCD ReadingOn Hydroxyurea Therapy at time of last TCD ReadingNormalizedNo7 years10 yearsYesNormalizedNo5.5 years5.5 yearsNoNormalizedNo5 years1 yearYesNormalizedYes6 years7 yearsYesNormalizedNo0Never transfusedYesNormalizedNo4 years5.5 yearsYesNormalizedNo4 years1 yearYesConditionalNo0Never TransfusedYesConditionalNo0Never TransfusedNoConditionalNo5 years2 yearsYesConditionalNo6 yearsOn TransfusionNoAbnormalYes5 yearsUnknownNoAbnormalNo11 years1 yearYes Disclosures:No relevant conflicts of interest to declare.

Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation

BackgroundVX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro.MethodsA randomised, double-blind, placebo-controlled study evaluated the safety,...

Treatment with Recombinant Growth Hormone Is Associated with Modest Improvement in CD4 Lymphocyte Reconstitution in HIV-Infected Persons on Antiretroviral Therapy: Results of ACTG A5174

Pilot studies have suggested that treatment with recombinant human growth hormone (rhGH) is associated with increased T-lymphocyte restoration and enhanced thymic output. We evaluated the immunologic effects of rhGH on HIV(+) subjects with incomplete immune reconstitution on antiretroviral therapy (ART). Sixty subjects were randomized to receive rhGH 1.5 mg scqd and ART for 48 weeks (Arm A) or continue ART alone for 24 weeks then add rhGH 3.0 mg scqd for 24 weeks (Arm B). Median baseline CD4 for Arms A and B were 223 and 219, respectively. There was little difference between Arm A and Arm B in change in total or naive CD4 cells or percentage from baseline to week 24. Only one subject in Arm A met the primary endpoint, an increase in naive CD4 percentage of at least 10 percentage points. By week 48 both Arms had statistically significant increases in naive CD4 cell count and percentage and thymus size. Within Arm B, treatment with rhGH was associated with significant increases in naive CD4(+) cell count and percentage compared with ART alone. Treatment with rhGH +ART may be associated with modest increases in CD4 lymphocytes over ART alone in subjects with CD4 <350, yet the origin of these naive cells and their impact on immune function require further investigation.

Once-weekly liposomal amphotericin B as Candida prophylaxis in very low birth weight premature infants: A prospective, randomized, open-label, placebo-controlled pilot study

Objective: This study was conducted to evaluate once-weekly liposomal amphotericin B (L-AmB) for Candida prophylaxis in very low birth weight (VLBW) neonates. Methods: This prospective, randomized, open-label, placebo-controlled study included neonates who were <32 weeks’ gestational age, <7 days old, and weighing <1500 g at birth. Subjects were randomized to receive L-AmB 5 mg/kg per week or placebo (dextrose water) and were followed until 6 weeks of age. Surveillance cultures were obtained at baseline, at 72 hours, and weekly thereafter. Study drug was continued until 6 weeks after birth or the discontinuation of high-risk treatments and invasive devices, whichever occurred first. Blood cultures were obtained as clinically indicated. The primary end point was development of Candida colonization by 6 weeks’ postnatal age; secondary end points included development of invasive candidiasis and occurrence of treatment-related adverse events. Safety variables included renal and hepatic function tests, incidence of grade III–IV intraventricular hemorrhage (IVH) and necrotizing enterocolitis (NEC), and mortality. Results: Forty subjects were enrolled and randomized to receive L-AmB (12 males, 8 females; 50% white) or placebo (12 males, 8 females; 35% white). Subjects were evenly distributed by gestational age, age at enrollment, birth weight, race, and sex. Consent was withdrawn after completion of study treatment in 1 subject (L-AmB); 1 subject in each study arm died during the study; and 3 subjects were transferred back to their referring institutions (1 L-AmB, 2 placebo). Thus, 17 subjects in each arm completed all study procedures, although all 40 subjects were evaluable. Colonization before administration of study drug was noted in 4 L-AmB subjects (20%) and 1 placebo subject (5%); 1 (5%) and 3 (15%) subjects in the respective groups developed colonization while receiving study drug. No L-AmB subjects and 1 placebo subject developed candidiasis. One subject in each group died; these deaths were not considered related to study drug or fungal infection. There were no clinical differences between groups in the incidence of grade III–IV IVH, NEC, hypokalemia, nephrotoxicity, need for platelet or packed red blood cell transfusion, or mortality. Conclusions: L-AmB 5 mg/kg once weekly was generally well tolerated in these VLBW infants. The data did not allow evaluation of efficacy. A larger, multicenter, randomized clinical trial of L-AmB for Candida prophylaxis that is appropriately powered is warranted.

A Preliminary Study on the Efficacy of Plumeria acuminata (Kalachuchi) Bark Extract Ointment versus Clotrimazole Cream in the Treatment of Otomycosis

Objective: To compare the therapeutic efficacy of kalachuchi (Plumeria acuminata Ait.) bark extract ointment (KO) and clotrimazole cream 1% (CC) in the treatment of otomycosis.&#x0D; Methods:&#x0D; Design: Randomized double blind controlled trial&#x0D; Setting: Outpatient otorhinolaryngology clinic of a tertiary private hospital&#x0D; Subjects: Patients aged 18-years-old and above diagnosed clinically to have otomycosis with a positive potassium hydroxide (KOH) smear were randomly assigned to kalachuchi (Plumeria acuminata Ait.) bark extract ointment or clotrimazole cream 1% in unlabeled containers. Self-application thrice daily for two weeks followed initial detailed instructions and demonstration. Symptoms, physical findings and repeat KOH smears were recorded after the first and second weeks of treatment.&#x0D; Results: Eighteen patients with otomycosis were enrolled in the study. There was one dropout per treatment group with no intention to treat. There were no statistically significant differences between KO and CC, with 75% (n=8) and 87.5% (n=8) cure rates, respectively. One subject in the KO arm reported severe ear pain.&#x0D; Conclusion: Kalachuchi extract ointment may be a promising topical antifungal agent. Multicenter clinical trials to establish its efficacy and safety as an effective alternative in the management of otomycosis should be conducted.&#x0D; Key words: Otomycosis, kalachuchi, Plumeria acuminata Ait., clotrimazole, clinical trial, herbal medicine&#x0D;