Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19.

BACKGROUND: Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known. METHODS: We conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15. RESULTS: A total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P = 0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, -5.0 percentage points; 95% CI, -9.8 to -0.3; P = 0.03), as were new infections (5.9% vs. 11.2%; difference, -5.3 percentage points; 95% CI, -8.7 to -1.9; P = 0.003). CONCLUSIONS: Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04401579.).

Effect of Doxycycline on Aneurysm Growth Among Patients With Small Infrarenal Abdominal Aortic Aneurysms: A Randomized Clinical Trial.

Importance: Abdominal aortic aneurysms affect more than 3% of US older adults. Objective: To test whether doxycycline reduces the growth of abdominal aortic aneurysm over 2 years as measured by maximum transverse diameter. Design, Setting, and Participants: Parallel, 2-group, randomized clinical trial that was conducted at 22 US clinical centers between May 2013 and January 2017, and enrolled patients 50 years or older with small (3.5-5.0 cm for men, 3.5-4.5 cm for women) infrarenal aneurysms. The final date of follow-up was July 31, 2018. Interventions: Patients were randomized to receive twice daily for 2 years doxycycline 100 mg orally (as capsules) (n = 133) or placebo (n = 128). Main Outcomes and Measures: The primary outcome was change in abdominal aortic aneurysm maximum transverse diameter measured from CT images at baseline and follow-up at 2 years. Patients were assigned ranks based on the maximum transverse diameter (measured or imputed) of the aorta and also if they underwent aneurysm repair or died. The ranks were converted to scores having a normal distribution to facilitate the primary analysis ("normal scores"). Results: Of 261 patients randomized, no follow-up CT scans were obtained on 7 (3%), leaving a final analysis set of 129 patients assigned to doxycycline and 125 to placebo (mean [SD] age, 71.0 years [7.4 years], 35 women [14%]). The outcome normal scores used in the primary analysis were based on maximum transverse diameter (measured or imputed) in 113 patients (88%) in the doxycycline group and 112 patients (90%) in the placebo group; aneurysm repair in 13 (10%) and 9 (7%), and death in 3 (2%) and 4 (3%), respectively. The primary outcome, normal scores reflecting change in aortic diameter, did not differ significantly between the 2 groups, mean change in normal scores, 0.0262 vs -0.0258 (1-sided P = .71). Mean (SD) baseline maximum transverse diameter was 4.3 cm (0.4 cm) for doxycycline and 4.3 cm (0.4 cm) for placebo. At the 2-year follow-up, the change in measured maximum transverse diameter was 0.36 cm (95% CI, 0.31 to 0.40 cm) for 96 patients in the doxycycline group vs 0.36 cm (95% CI, 0.30 to 0.41 cm) for 101 patients in the placebo group (difference, 0.0; 95% CI, -0.07 to 0.07 cm; 2-sided P = .93). No patients were withdrawn from the study because of adverse effects. Joint pain occurred in 84 of 129 patients (65%) with doxycycline and 79 of 125 (63%) with placebo. Conclusions and Relevance: Among patients with small infrarenal abdominal aortic aneurysms, doxycycline compared with placebo did not significantly reduce aneurysm growth at 2 years. These findings do not support the use of doxycycline for reducing the growth of small abdominal aortic aneurysms. Trial Registration: ClinicalTrials.gov Identifier: NCT01756833.

The Use of TKM-100802 and Convalescent Plasma in 2 Patients With Ebola Virus Disease in the United States.

BACKGROUND: The current West Africa Ebola virus disease (EVD) outbreak has resulted in multiple individuals being medically evacuated to other countries for clinical management. METHODS: We report two patients who were transported from West Africa to the United States for treatment of EVD. Both patients received aggressive supportive care measures, as well as an investigational therapeutic (TKM-100802) and convalescent plasma. RESULTS: While one patient experienced critical illness with multi-organ failure requiring mechanical ventilation and renal replacement therapy, both patients recovered without serious long-term sequelae to date. CONCLUSIONS: It is unclear what role the experimental drug and convalescent plasma had in the recovery of these patients. Prospective clinical trials are needed to delineate the role of investigational therapies in the care of patients with EVD.

Prepared to Act: Lessons Learned by the Special Pathogens Research Network, Based on Collaborations with the NIAID-Led Adaptive COVID-19 Treatment Trial.

The need for well-controlled clinical trials is fundamental to advancing medicine. Care should be taken to maintain high standards in trial design and conduct even during emergency medical events such as an infectious disease outbreak. In 2020, SARS-CoV-2 emerged and rapidly impacted populations around the globe. The need for effective therapeutics was immediately evident, prompting the National Institutes of Health to initiate the Adaptive COVID-19 Treatment Trial. The Special Pathogens Research Network, made up of 10 Regional Emerging Special Pathogens Treatment Centers, was approached to participate in this trial and readily joined the trial on short notice. By trial closure, the Special Pathogens Research Network sites, making up 19% of all study sites, enrolled 26% of the total participants. The initial resources available and experience in running clinical trials at each treatment center varied from minimal experience and few staff to extensive experience and a large staff. Based on experiences during the first phase of this trial, the Special Pathogens Research Network members provided feedback regarding operational lessons learned and recommendations for conducting future studies during a pandemic. Communication, collaboration, information technology, regulatory processes, and access to resources were identified as important topics to address. Key stakeholders including institutions, institutional review boards, and study personnel must maintain routine communication to efficiently and effectively activate when future research needs arise. Regular and standardized training for new personnel will aid in transitions and project continuity, especially in a rapidly evolving environment. Trainings should include local just-in-time training for new staff and sponsor-designed modules to refresh current staff knowledge. We offer recommendations that can be used by institutions and sponsors to determine goals and needs when preparing to set up this type of trial for critical, short-notice needs.

Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial.

BACKGROUND: Baricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19. METHODS: In this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168. FINDINGS: Between Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012). INTERPRETATION: In hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered. FUNDING: National Institute of Allergy and Infectious Diseases.

Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19. METHODS: We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 µg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04492475. FINDINGS: Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87-1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3-7%) in the interferon beta-1a plus remdesivir group and 3% (2-6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69-2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group. INTERPRETATION: Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo. FUNDING: The National Institute of Allergy and Infectious Diseases (USA).

Intraocular pressure and aqueous humor flow during a euglycemic-hyperinsulinemic clamp in patients with type 1 diabetes and microvascular complications.

BACKGROUND: Microvascular complications, including retinopathy and nephropathy are seen with type 1 diabetes. It is unknown whether functional changes in aqueous humor flow or intraocular pressure (IOP) develop in parallel with these complications. This study was designed to test the hypothesis that clinical markers of microvascular complications coexist with the alteration in aqueous humor flow and IOP. METHODS: Ten patients with type 1 diabetes and ten healthy age- and weight-matched controls were studied. Aqueous flow was measured by fluorophotometry during a hyperinsulinemic-euglycemic clamp (insulin 2 mU/kg/min). Intraocular pressure was measured by tonometry at -10, 90 and 240 minutes from the start of the clamp, and outflow facility was measured by tonography at 240 minutes. RESULTS: During conditions of identical glucose and insulin concentrations, mean aqueous flow was lower by 0.58 microl/min in the diabetes group compared to controls (2.58 +/- 0.65 versus 3.16 +/- 0.66 microl/min, respectively, mean +/- SD, p = 0.07) but statistical significance was not reached. Before the clamp, IOP was higher in the diabetes group (22.6 +/- 3.0 mm Hg) than in the control group (19.3 +/- 1.8 mm Hg, p = 0.01) but at 90 minutes into the clamp, and for the remainder of the study, IOP was reduced in the diabetes group to the level of the control group. Ocular pulse amplitude and outflow facility were not different between groups. Systolic blood pressure was significantly higher in the diabetes group, but diastolic and mean arterial pressures were not different. CONCLUSIONS: We conclude that compared to healthy participants, patients with type 1 diabetes having microalbuminuria and retinopathy have higher IOPs that are normalized by hyperinsulinemia. During the clamp, a reduction in aqueous flow was not statistically significant.

Advanced Preparation Makes Research in Emergencies and Isolation Care Possible: The Case of Novel Coronavirus Disease (COVID-19).

The optimal time to initiate research on emergencies is before they occur. However, timely initiation of high-quality research may launch during an emergency under the right conditions. These include an appropriate context, clarity in scientific aims, preexisting resources, strong operational and research structures that are facile, and good governance. Here, Nebraskan rapid research efforts early during the 2020 coronavirus disease pandemic, while participating in the first use of U.S. federal quarantine in 50 years, are described from these aspects, as the global experience with this severe emerging infection grew apace. The experience has lessons in purpose, structure, function, and performance of research in any emergency, when facing any threat.

Finding the optimal dose of vitamin D following Roux-en-Y gastric bypass: a prospective, randomized pilot clinical trial.

BACKGROUND: Vitamin D deficiency is common following bariatric surgery and is due to a combination of baseline deficiency and postoperative malabsorption. There are few prospective studies evaluating the appropriate dose of vitamin D to prevent and treat vitamin D deficiency following bariatric surgery. METHODS: We evaluated three doses of vitamin D3 (800, 2,000, and 5,000 IU/day) in a prospective, randomized pilot trial of 45 patients undergoing Roux-en-Y gastric bypass. Serum 25 hydroxy Vitamin D (25OHD), intact PTH (iPTH), calcium, and urine calcium/creatinine ratios were measured at 6, 12, and 24 months postoperatively. Due to a high dropout rate at 24 months, we focus on the 12-month data. RESULTS: At 12 months, the 800-, 2,000-, and 5,000-IU groups had a mean +/- SD increase in 25OHD of 27.5 +/- 40.0, 60.2 +/- 37.4, and 66.1 +/- 42.2 nmol/L, respectively (p = 0.09) with a maximum increase in each group of 87.4, 114.8, and 129.8 nmol/L. Forty-four percent, 78%, and 70% achieved 25OHD levels >or=75 nmol/L (p = 0.38). Results for the 6- and 24-month time points were similar to the 12-month results. Mean weight loss at 24 months of the study was not different among groups (p = 0.52). Serum calcium did not change significantly, and there were no cases of hypercalcemia or sustained hypercalciuria. CONCLUSIONS: Higher doses of vitamin D supplementation trend towards higher levels of 25OHD. Vitamin D replacement as high as 5,000 IU /day is safe and necessary in many patients to treat vitamin D deficiency following Roux-en-Y gastric bypass yet is still suboptimal in others.

Ebola Virus Disease: Clinical Challenges, Recognition, and Management.

The 2014 to 2016 Ebola outbreak response resulted in many lessons learned about biocontainment patient care, leading to enhanced domestic capabilities for highly infectious and hazardous communicable diseases. However, additional opportunities for improvement remain. The article identifies and describes key considerations and challenges for laboratory analysis, clinical management, transportation, and personnel management during the care of patients infected with Ebola or other special pathogens. Dedication to maintaining preparedness enables biocontainment patient care teams to perform at the highest levels of safety and confidence.

A Novel Approach to Infectious Disease Preparedness: Incorporating Investigational Therapeutics and Research Objectives into Full-Scale Exercises.

The use of investigational therapeutics in the care of patients with Ebola virus disease was documented in the literature following the 2013-2016 outbreak. In order to access these types of therapeutics, facilities must have processes in place to quickly and efficiently activate study protocols, obtain the medications, and administer them in a timely manner. Testing these procedures in advance of a real-world event is crucial to ensuring successful implementation and execution. Drills and exercises are routinely used as part of the emergency preparedness planning process, as they provide a low-risk environment in which to test plans and procedures. Including research activities in full-scale emergency preparedness exercises is a novel approach that should be considered when creating a comprehensive special pathogen program. One important aspect of creating an agile response program is developing and sustaining strong relationships with key collaborators. Including departments not previously engaged in infectious disease preparedness exercises provides a forum to strengthen these relationships, clarify roles, and identify gaps. This article describes the process used to incorporate research-centric objectives focused on the use of investigational therapeutics for Ebola virus disease into a full-scale exercise, the evaluation process used to measure the identified objectives, and the results of the exercise.

The Special Pathogens Research Network: Enabling Research Readiness.

The 2013-2016 epidemic of Ebola virus disease (EVD) that originated in West Africa underscored many of the challenges to conducting clinical research during an ongoing infectious disease epidemic, both in the most affected countries of Guinea, Liberia, and Sierra Leone, as well as in the United States and Europe, where a total of 27 patients with EVD received care in biocontainment units. The Special Pathogens Research Network (SPRN) was established in the United States in November 2016 to provide an organizational structure to leverage the expertise of the 10 Regional Ebola and Other Special Pathogen Treatment Centers (RESPTCs); it was intended to develop and support infrastructure to improve readiness to conduct clinical research in the United States. The network enables the rapid activation and coordination of clinical research in the event of an epidemic and facilitates opportunities for multicenter research when the RESPTCs are actively caring for patients requiring a biocontainment unit. Here we provide an overview of opportunities identified in the clinical research infrastructure during the West Africa EVD epidemic and the SPRN activities to meet the ongoing challenges in the context of Ebola virus and other special pathogens.

Prevalence of vitamin D insufficiency and deficiency in morbidly obese patients: a comparison with non-obese controls.

BACKGROUND: Vitamin D deficiency is common in patients after bariatric surgery. However, obesity itself has also been associated with decreased vitamin D. The prevalence of vitamin D deficiency in obese persons has not previously been compared to non-obese controls when controlling for factors that could affect vitamin D status. METHODS: We evaluated 25 hydroxy vitamin D, iPTH, calcium, albumin, and creatinine in 41 patients undergoing Roux-en-Y gastric bypass. We then compared them to healthy non-obese controls matched for age, sex, race/ethnicity, and season of vitamin D measurement. RESULTS: Ninety percent of the pre-bariatric surgery patients had 25-OH-D levels <75 nmol/l, and 61% had 25-OH-D levels <50 nmol/l versus 32 and 12% in controls, respectively. Additionally, 49% of the pre-bariatric surgery patients had secondary hyperparathyroidism versus 2% of controls. These differences persisted after controlling for sunlight exposure and dietary intake of calcium and vitamin D. Mean calcium, corrected for albumin, and creatinine were not significantly different between the groups, but mean albumin levels were significantly lower among surgery patients. CONCLUSION: Vitamin D deficiency is common in obese patients at the time of bariatric surgery and is also accompanied by secondary hyperparathyroidism approximately half the time. These findings suggest that vitamin D deficiency after bariatric surgery is multifactorial and in part caused by preoperative vitamin D deficiency rather than postoperative malabsorption alone. In this study, increased vitamin D deficiency in obese persons cannot be explained by a difference in calcium/vitamin D intake or sunlight exposure.

Evaluation of the safety and immunomodulatory effects of sargramostim in a randomized, double-blind phase 1 clinical Parkinson's disease trial.

A potential therapeutic role for immune transformation in Parkinson's disease evolves from more than a decade of animal investigations demonstrating regulatory T cell (Treg) nigrostriatal neuroprotection. To bridge these results to human disease, we conducted a randomized, placebo-controlled double-blind phase 1 trial with a well-studied immune modulator, sargramostim (granulocyte-macrophage colony-stimulating factor). We enrolled 17 age-matched non-Parkinsonian subjects as non-treated controls and 20 Parkinson's disease patients. Both Parkinson's disease patients and controls were monitored for 2 months for baseline profiling. Parkinson's disease patients were then randomized into two equal groups to self-administer placebo (saline) or sargramostim subcutaneously at 6 µg/kg/day for 56 days. Adverse events for the sargramostim and placebo groups were 100% (10/10) and 80% (8/10), respectively. These included injection site reactions, increased total white cell counts, and upper extremity bone pain. One urticarial and one vasculitis reaction were found to be drug and benzyl alcohol related, respectively. An additional patient with a history of cerebrovascular disease suffered a stroke on study. Unified Parkinson's disease rating scale, Part III scores in the sargramostim group showed modest improvement after 6 and 8 weeks of treatment when compared with placebo. This paralleled improved magnetoencephalography-recorded cortical motor activities and Treg numbers and function compared with pretreated Parkinson's disease patients and non-Parkinsonian controls. Peripheral Treg transformation was linked to serum tryptophan metabolites, including L-kynurenine, quinolinic acid, and serotonin. These data offer a potential paradigm shift in modulating immune responses for potential therapeutic gain for Parkinson's disease. Confirmation of these early study results requires larger numbers of enrolled patients and further clinical investigation.

Non-invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA(3)CT): Design of a Phase IIb, placebo-controlled, double-blind, randomized clinical trial of doxycycline for the reduction of growth of small abdominal aortic aneurysm.

OBJECTIVES: The Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA(3)CT) is a Phase IIb randomized, placebo-controlled clinical trial, testing doxycycline (100mg bid) for inhibition of growth in the greatest transverse, orthogonal diameter of small abdominal aortic aneurysms (AAA). METHODS: We will enroll 258 patients, ≥55years of age who have AAA, men: 3.5-5.0cm and women: 3.5-4.5cm on CT scans confirmed centrally. The primary outcome is growth in maximal transverse, orthogonal diameter from baseline to 24-month follow-up. Secondary analyses address doxycycline effects on clinical events, aneurysm volume, and biomarkers. Primary analysis will be performed according to the principle of intention-to-treat accounting for death and ruptures by use of normal scores in analysis of covariance. At the time of the data file reported, 200 subjects have been randomized. We started enrollment in mid-2013 and will complete enrollment by mid-2016. RESULTS: Participant average age=70.9years, (SD=7.6years) and maximum transverse diameter=4.3cm for men (SD=0.4) and 4.0cm for women (SD=0.3). CONCLUSION: N-TA(3)CT is a critical experiment to determine whether doxycycline reduces growth of small AAA and systemic markers of inflammation previously seen in bench experiments and observational human studies to be associated with AAA growth. Our patient population baseline measurements agree with the design assumptions supporting our expectation of 90% power or greater to reject a null hypothesis in favor of an alternative hypothesis when growth is reduced by at least 40%. REGISTRATION: clinicaltrials.gov #NCT01756833.

Acute effects of different intensities of exercise in normoalbuminuric/normotensive patients with type 1 diabetes.

OBJECTIVE: The purpose of this study was to investigate the effect of exercise occurrence and intensity on albumin excretion in normotensive, normoalbuminuric patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: Eighteen patients (aged 29 +/- 2 years, duration of diabetes 14 +/- 2 years, blood pressure 120 +/- 2/74 +/- 1 mmHg, HbA(1c) 7.0 +/- 0.2% [mean +/- SE]) without microalbuminuria, hypertension, or anti-angiotensin II therapy participated in two exercise studies in a clinical research center. Exercise intensities were defined as moderate (50% heart rate reserve [HRR]) and intense (75% HRR) and were performed in random order. Subjects collected urine for albumin determination on the days before and after exercise. On the day of exercise, subjects exercised for 30 min on a treadmill at the assigned intensity. Timed urine collections were obtained over the day. Blood pressures were measured using an ambulatory blood pressure monitor. RESULTS: Moderate exercise demonstrated no changes in albumin excretion. Intense exercise demonstrated a significant increase in albumin excretion during the first 4 h compared with the rest of the day (P = 0.03) but returned to normal thereafter. Albumin excretion did not exceed normal levels throughout the study. There was no difference in albumin excretion surrounding days of intense exercise. Ambulatory blood pressures demonstrated nocturnal dipping after moderate and intense exercise (P < 0.001). CONCLUSIONS: We have demonstrated that normotensive, normoalbuminuric patients without anti-angiotensin II therapy do not have elevated albumin excretion following exercise intensities experienced by most patients with type 1 diabetes.