Factorial Clinical Trial Research Articles

Aliskiren alone or with other antihypertensives in the elderly with borderline and stage 1 hypertension: the APOLLO trial

We studied the unclear question whether blood pressure (BP) lowering reduces cardiovascular disease (CVD) in elderly individuals with systolic BP <160 mm Hg. We initiated a randomized placebo-controlled stratified 2 × 2 factorial clinical trial evaluating the effects of BP lowering in 11 000 elderly individuals with systolic blood pressure (SBP) between 130 and 159 mm Hg, for 5 years. Following 5-week active run-in, participants were randomized to aliskiren (300 mg) or placebo, and to an additional antihypertensive [hydrochlorothiazide (25 mg) or amlodipine (5 mg)], or their respective placeboes. Study was terminated by sponsor after 1759 subjects (age 72.1 ± 5.2 years, 88% receiving at least one antihypertensive) were randomized and followed for 0.6 year. Study drugs were well tolerated with few serious adverse events during run-in and after randomization, with no significant differences between treatment groups. By design, three levels of BP reductions were achieved, adjusted mean BP reductions of 3.5/1.7 mm Hg (P < 0.001) by aliskiren, 6.8/3.3 mm Hg (P < 0.001) by hydrochlorothiazide or amlodipine, and 10.3/5.0 mm Hg (P < 0.001) by double therapy compared with placebo. Twenty-five major CVD events occurred. Non-significant trends towards fewer CVD events with greater BP reductions are evident: hazard ratios (HR) 0.82 [95% confidence interval (CI): 0.37-1.81] for 3.5 mm Hg SBP reduction; HR 0.45 (95% CI: 0.19-1.04) for 6.8 mm Hg; and HR 0.25 (0.05-1.18) for 10.3 mm Hg reduction for primary composite of CV death, MI, stroke, or significant heart failure. Sizeable reductions in BP, with potential for substantial CVD reduction, can be safely achieved using combinations of BP drugs in the elderly with normal high and Stage 1 hypertension. NCT01259297.

Effects of calcium and vitamin D3 on transforming growth factors in rectal mucosa of sporadic colorectal adenoma patients: A randomized controlled trial

Transforming growth factor alpha (TGFα) and TGFβ1 are growth-promoting and -inhibiting autocrine/paracrine growth factors, respectively, that may (1) affect risk for colorectal cancer and (2) be modifiable by anti-proliferative exposures. The effects of supplemental calcium and vitamin D3 on these two markers in the normal-appearing colorectal mucosa in humans are unknown. We conducted a pilot, randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial (n = 92; 23/treatment group) of calcium 2 g and/or vitamin D3 800 IU/d versus placebo over 6 mo. TGFα and TGFβ1 expression was measured in biopsies of normal-appearing rectal mucosa using automated immunohistochemistry and quantitative image analysis at baseline and 6-mo follow-up. In the calcium, vitamin D3 , and calcium plus vitamin D3 groups relative to the placebo group (1) the mean overall expression of TGFβ1 increased by 14% (P= 0.25), 19% (P = 0.17), and 22% (P = 0.09); (2) the ratio of TGFα expression in the upper 40% (differentiation zone) to that in the lower 60 (proliferation zone) of the crypts decreased by 34% (P = 0.11), 31% (P = 0.22), and 26% (P = 0.33); and (3) the TGFα/TGFβ1 ratio in the upper 40% of the crypts decreased by 28% (P = 0.09), 14% (P = 0.41), and 22% (P = 0.24), respectively. These preliminary results, although not statistically significant, suggest that supplemental calcium and vitamin D3 may increase TGFβ1 expression and shift TGFα expression downward from the differentiation to the proliferation zone in the crypts in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients, and support further investigation in a larger clinical trial.

Effects of calcium and vitamin D supplementation on crypt morphology in normal colon mucosa: A randomized clinical trial

Calcium and vitamin D modify the molecular phenotypic profiles of colon crypts in the normal colorectal mucosa of colorectal adenoma patients, but their effects on crypt morphology (length, perimeter, and area) are unknown. We analyzed data from a previously conducted pilot, randomized, double-blind, placebo-controlled 2 × 2 factorial chemoprevention clinical trial of supplemental calcium 2000 mg/d and vitamin D3 800 IU/d, alone and in combination, versus placebo over 6 mo. Colorectal crypt length, perimeter, and area in the normal-appearing rectal mucosa were quantified by image analysis. The mean crypt length increased by 1% (P=0.92) in the calcium group, and decreased by 2% (P=0.69) and 4% (P=0.40) in the vitamin D and calcium plus vitamin D groups, respectively, relative to the placebo group. The mean crypt perimeter decreased by 2% (P=0.70) and 4% (P=0.40) in the vitamin D and calcium plus vitamin D groups, respectively, relative to the placebo group, but did not change appreciably in the calcium group. The mean crypt area decreased by 2% (P=0.74), 5% (P=0.41) and 7% (P=0.30) in the calcium, vitamin D and calcium plus vitamin D groups, respectively, relative to the placebo group. Calcium and/or vitamin D3 supplementation do not appear to appreciably change crypt morphology in the normal colorectal mucosa of sporadic adenoma patients. These results, taken together with previous findings, support the use of molecular phenotypic over morphologic pre-neoplastic biomarkers of risk for colorectal neoplasms.

P 168. TMS neurophysiology and interventional rTMS in children with perinatal stroke: Safety and tolerability in the PLASTIC CHAMPS trial

Perinatal stroke causes hemiplegic cerebral palsy and lifelong disability. TMS can define neurophysiology and central therapeutic targets while rTMS carries therapeutic potential in adult stroke but have not been applied to the more plastic developing brain. Ipsilateral projections from the unlesioned hemisphere to the affected hand are prominent in this population and the effects of non-lesioned inhibitory rTMS are unknown. PLASTIC CHAMPS is a randomized, blinded, factorial clinical trial of rTMS and constraint therapy (CIMT) to enhance upper extremity function in children (6–18 years) with perinatal stroke hemiparesis. Thirty-five children (mean age 11.25 y, 20 males) attended a 2-week intensive motor learning camp, randomized 1:1 to daily non-lesioned M1 inhibitory (1 Hz, 1200 stimulations) rTMS or sham. TMS neurophysiology mapping lasting 90–120 min (baseline and 1 week post-camp) included RMT, AMT, stimulus response curves, iSP, SICI, ICF, and IHI. Primary safety outcomes were decreased function in: (1) affected hand in children with ipsilateral projections (Assisting Hand Assessment (AHA), Melbourne Assessment (MA)) and (2) unaffected hand in all children (grip strength [GS], pinch strength [PS]). The Pediatric TMS Tolerability Evaluation was administered at 4 timepoints: 2 TMS neurophysiology sessions (pre and post camp) and 2 rTMS treatments (days 1 and 10). This measure characterizes any adverse events and subjectively ranks TMS against 7 common childhood experiences. Differences in hand function and tolerability scores were compared between rTMS and sham and over time (paired t -tests, ANOVA). TMS and rTMS procedures were well tolerated with no serious adverse events and no drop-outs. Affected hand function in children with ispsilateral projections did not decrease between rTMS and sham (AHA no change, MA increased). Unaffected hand function did not decrease with rTMS (GS and PS same). TMS and rTMS tolerability scores were favourable, scoring better than “a long car ride” on average. All side effects were mild, brief (minutes), and self-limiting with none requiring medication. Headache was common (43% during 1st TMS session) but resolved with removal of the swim cap used for mapping. Headache rates decreased (20%) with the same protocol 3 weeks later. Headache was uncommon during rTMS (11%) with tolerance (0% at 2nd session) and comparable rates between rTMS and sham. Other side-effects (neck pain, tingling, nausea, presyncope) were infrequent (<5% on final TMS session). Non-invasive brain stimulation trials are safe and feasible in children with perinatal stroke. Inhibitory rTMS over the non-lesioned M1 does not negatively affect normal hand function or affected hand function in children with ipsilateral projections. Headaches are common but mild and self-limiting.

Preoperative radiotherapy (preop RT) in rectal cancer: Impact of chemotherapy on the outcome—Long-term results of the randomized 22,921 phase III trial of EORTC.

3560 Background: This 2x2 factorial design clinical trial evaluated the addition of Fluorouracil-based chemotherapy (CT) to preop RT and the use of adjuvant CT in patients with resectable T3-T4 M0 rectal cancer. The 5-year results showed that adding CT preoperatively or postoperatively had no significant effect on overall survival (OS) nor on disease-free survival (DFS) but a divergence seemed to emerge respectively at 2 and 5 years in the postop CT group. We report results with a median of 10.4 years. Methods: A total of 1011 patients were allocated in four treatment arms: preop RT ; preop RT + 2 CT courses ; preop RT + 4 postop CT courses ; preop RT-CT + postop CT. Preop RT was 45 Gy over 5 weeks. A one 5-day course of CT consisted of 5-Fu 350 mg/m²/d and Leucovorin 20 mg/m²/d. The effect of preop CT and adjuvant CT on OS and DFS was assessed by Logrank test (2-sided 5% significance level) stratified respectively for postop and for preop treatment. Written informed consent was obtained from all patients before randomization. Results: There is no significant difference in OS, nor in DFS between the groups receiving preop CT or not (p = 0.91 and p = 0.38 respectively). There is no significant difference in OS nor in DFS between the groups treated by postop CT or not (p = 0.32 and p = 0.29 respectively). The 10-year cumulative incidence of local recurrences is ~9 % in all the CT groups and 17.4 % in the preop RT alone group (p = 0.0044). The 10 year cumulative incidence of distant metastases (DM) is ~35 % in all treatment groups. Conclusions: With more that 10-years follow-up there is no benefit in rectal cancer by adding Fluorouracil-based chemotherapy preoperatively nor postoperatively to preop RT in terms of OS, DFS, nor in term of DM. Clinical trial information: 00002523.

Selenium and Prostate Cancer Prevention: Insights from the Selenium and Vitamin E Cancer Prevention Trial (SELECT)

The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was conducted to assess the efficacy of selenium and vitamin E alone, and in combination, on the incidence of prostate cancer. This randomized, double-blind, placebo-controlled, 2 × 2 factorial design clinical trial found that neither selenium nor vitamin E reduced the incidence of prostate cancer after seven years and that vitamin E was associated with a 17% increased risk of prostate cancer compared to placebo. The null result was surprising given the strong preclinical and clinical evidence suggesting chemopreventive activity of selenium. Potential explanations for the null findings include the agent formulation and dose, the characteristics of the cohort, and the study design. It is likely that only specific subpopulations may benefit from selenium supplementation; therefore, future studies should consider the baseline selenium status of the participants, age of the cohort, and genotype of specific selenoproteins, among other characteristics, in order to determine the activity of selenium in cancer prevention.

Monitoring futility in a two-by-two factorial design: The SPS3 experience

For studies with two-by-two factorial designs, the complexity of determining an appropriate futility analysis plan is increased as compared to studies where patients are randomized to one treatment. Issues that must be addressed include the possibility of a significant interaction and the need to determine how to proceed given evidence of futility in one arm. Suggested approaches include a two-stage plan, which first assesses futility of the interaction term and proceeds to examine the main effects, given sufficient evidence that no interaction is present, and variations on one-stage plans, which assume the trial will not be stopped for futility in the interaction. To discuss different approaches to monitoring futility in two-by-two factorial clinical trials and compare their properties. We utilized a simulation study, designed to mimic the Secondary Prevention of Small Subcortical Strokes (SPS3) Study, to determine which approach to monitoring futility in two-by-two factorial studies had the most desirable statistical properties. We found that in most scenarios typical of clinical trials, monitoring futility in each arm simultaneously was superior to or as good as monitoring the interaction and then assessing futility in each arm only when the interaction was deemed futile. Monitoring each arm simultaneously lead to early stopping more often when no treatment effect was present, and lower average sample numbers (ASNs). The exception to this was the unlikely case when a qualitative interaction was present. We assumed that one-sided tests were to be performed, and only assessed some of the possible methods for monitoring futility under the study design. Futility monitoring in two-by-two factorial studies should proceed by assessing each arm simultaneously, rather than monitoring the interaction first. If sizeable interactions are anticipated, study design, rather than study monitoring, should account for this.

A Randomized Clinical Trial of the Effects of Supplemental Calcium and Vitamin D3 on the APC/β-Catenin Pathway in the Normal Mucosa of Colorectal Adenoma Patients

APC/β-catenin pathway perturbation is a common early event in colorectal carcinogenesis and is affected by calcium and vitamin D in basic science studies. To assess the effects of calcium and vitamin D on adenomatous polyposis coli (APC), β-catenin, and E-cadherin expression in the normal appearing colorectal mucosa of sporadic colorectal adenoma patients, we conducted a randomized, double-blinded, placebo-controlled 2 × 2 factorial clinical trial. Pathology-confirmed colorectal adenoma cases were treated with 2 g/day elemental calcium and/or 800 IU/day vitamin D(3) versus placebo over 6 months (N = 92; 23/group). Overall APC, β-catenin, and E-cadherin expression and distributions in colon crypts in normal-appearing rectal mucosa biopsies were detected by standardized automated immunohistochemistry and quantified by image analysis. In the vitamin D(3)-supplemented group relative to placebo, the proportion of APC in the upper 40% of crypts (Φh APC) increased 21% (P = 0.01), β-catenin decreased 12% (P = 0.18), E-cadherin increased 72% (P = 0.03), and the Φh APC/β-catenin ratio (APC/β-catenin score) increased 31% (P = 0.02). In the calcium-supplemented group Φh APC increased 10% (P = 0.12), β-catenin decreased 15% (P = 0.08), and the APC/β-catenin score increased 41% (P = 0.01). In the calcium/vitamin D(3)-supplemented group, β-catenin decreased 11% (P = 0.20), E-cadherin increased 51% (P = 0.08), and the APC/β-catenin score increased 16% (P = 0.26). These results support (i) that calcium and vitamin D modify APC, β-catenin, and E-cadherin expression in humans in directions hypothesized to reduce risk for colorectal neoplasms, (ii) calcium and vitamin D as potential chemopreventive agents against colorectal neoplasms, and (iii) the potential of APC, β-catenin, and E-cadherin expression as modifiable, preneoplastic risk biomarkers for colorectal neoplasms.

Mild to moderate cognitive impairment is a major risk factor for mortality and nursing home admission in the first year after hip fracture

BackgroundIt is not well established if and to what extent mild to moderate cognitive impairment predicts mortality and risk of nursing home admission after hip fracture. ObjectiveTo investigate prospectively whether and to what extent mild to moderate cognitive impairment, contributes to mortality and admission to nursing home in the first year after acute hip fracture. MethodsWe enrolled 173 patients with acute hip fracture age 65 and older who reached a Mini-Mental State Examination (MMSE) score of at least 15 during acute care after hip fracture repair. An MMSE score of 15 to 24 (median) was classified as mild to moderate cognitive impairment. Primary outcomes were mortality in all and admission to nursing home among seniors who lived at home prior to their hip fracture. Follow-up was 12months with clinical visits at baseline, 6, and 12months, plus monthly phone calls. We used Cox proportional hazards models controlling for age, sex, body mass index, baseline number of comorbidities and 25-hydroxyvitamin D status, and severe incident infections to assess the risk of mortality and nursing home admission. Because the study population was enrolled in a factorial design clinical trial testing high dose vitamin D and/or an exercise home program, all analyses also controlled for these treatment strategies. ResultsOf 173 acute hip fracture patients enrolled, 79% were women, 77% were admitted from home, and 80% were vitamin D deficient (<20ng/ml). Mean age was 84years. 54% had mild to moderate cognitive impairment. Over the 12-month follow-up, 20 patients died (27% of 173) and 47 (35% of 134) were newly admitted to a nursing home. Mild to moderate cognitive impairment was associated with a more than 5-fold increased risk of mortality (HR=5.77; 95% CI: 1.55–21.55) and a more than 7-fold increased risk of nursing home admission (HR=7.37; 95% CI: 1.75–30.95). Additional independent risk factors of mortality were male gender (HR=3.55; 95% CI: 1.26–9.97), low BMI (HR=7.25; 95% CI: 1.61–33.74), and baseline 25-hydroxyvitamin D level (per 1ng/ml: HR=0.93; 95% CI: 0.87–0.998; p=0.04). ConclusionsMild to moderate cognitive impairment in patients with acute hip fracture is associated with a high risk of mortality and nursing home admission during the first year after hip fracture. Female gender, a greater BMI and a higher 25-hydroxyvitamin D status may protect against mortality after hip fracture independent of cognitive function.

Abstract 1675: Effects of calcium and vitamin D on TGFβ and TGFβ1 expression in rectal mucosa of sporadic colorectal adenoma patients: A randomized controlled trial

Abstract Aim: To estimate the effects of supplemental calcium and vitamin D3 on the expression of TGFβ and TGFβ1 (growth-promoting and -inhibiting autocrine/paracrine growth factors, respectively) in the normal-appearing colorectal mucosa in sporadic colorectal adenoma patients. Methods: We conducted a pilot, randomized, double-blind, placebo-controlled, 2 x 2 factorial clinical trial (n = 92) of calcium 2 g and/or vitamin D3 800 IU/day versus placebo over 6 months. TGFβ and TGFβ1 expression was measured in biopsies of normal-appearing rectal mucosa using automated immunohistochemistry and quantitative image analysis at baseline and 6-months follow-up. Results: The mean overall expression of TGFβ1 in the whole crypts increased by 14% (P = 0.25), 19% (P = 0.17), and 22% (P = 0.09) in the calcium, vitamin D, and calcium plus vitamin D groups, respectively, relative to the placebo group. The increases in TGFβ1 appeared to be uniform along the full length of the crypts. While there were no substantial changes in the overall expression of TGFβ in the whole crypts, in the calcium, vitamin D, and calcium plus vitamin D groups, TGFβ decreased by 14% (P = 0.35), 2% (P = 0.86), and 1% (P = 0.93), respectively, in the upper 40% (differentiation zone) of the crypts, but increased by 29% (P = 0.30), 38% (P = 0.17), and 25% (P = 0.32) in the bottom 60% of the crypts (proliferative zone). Also, a TGFβ/TGFβ1 ratio was created as an indicator of the balance between the growth-promoting and -inhibiting factors; in the upper 40% of the crypts it was found to have decreased by 35% (P = 0.24), 25% (P = 0.42), and 51% (P = 0.09) in the calcium, vitamin D, and calcium plus vitamin D groups, respectively, relative to the placebo group, but not to have changed substantially in the whole or bottom 60% of the crypts. Conclusions: These preliminary results suggest that supplemental calcium and vitamin D3 may increase the expression of TGFβ1, shift the expression of TGFβ downward in the colorectal crypts, and decrease the ratio of TGFβ to TGFβ1 in the upper 40% (differentiation zone) of the crypts in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients, and support further investigation of calcium and vitamin D3 as chemopreventive agents against colorectal neoplasms. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1675. doi:1538-7445.AM2012-1675

Statins but not aspirin reduce thrombotic risk assessed by thrombin generation in diabetic patients without cardiovascular events: the RATIONAL trial.

BackgroundThe systematic use of aspirin and statins in patients with diabetes and no previous cardiovascular events is controversial. We sought to assess the effects of aspirin and statins on the thrombotic risk assessed by thrombin generation (TG) among patients with type II diabetes mellitus and no previous cardiovascular events.Methodology/Principal FindingsProspective, randomized, open, blinded to events evaluation, controlled, 2×2 factorial clinical trial including 30 patients randomly allocated to aspirin 100 mg/d, atorvastatin 40 mg/d, both or none. Outcome measurements included changes in TG levels after treatment (8 to 10 weeks), assessed by a calibrated automated thrombogram. At baseline all groups had similar clinical and biochemical profiles, including TG levels. There was no interaction between aspirin and atorvastatin. Atorvastatin significantly reduced TG measured as peak TG with saline (85.09±55.34 nmol vs 153.26±75.55 nmol for atorvastatin and control groups, respectively; p = 0.018). On the other hand, aspirin had no effect on TG (121.51±81.83 nmol vs 116.85±67.66 nmol, for aspirin and control groups, respectively; p = 0.716). The effects of treatments on measurements of TG using other agonists were consistent.Conclusions/SignificanceWhile waiting for data from ongoing large clinical randomized trials to definitively outline the role of aspirin in primary prevention, our study shows that among diabetic patients without previous vascular events, statins but not aspirin reduce thrombotic risk assessed by TG.Trial RegistrationClinicalTrials.gov NCT00793754

Design of the Trial to Assess Chelation Therapy (TACT)

TACT is an National Institutes of Health-sponsored, randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial testing the benefits and risks of 40 infusions of a multicomponent disodium EDTA chelation solution compared with placebo and of an oral, high-dose multivitamin and mineral supplement. TACT has randomized and will follow up 1,708 patients for an average of approximately 4 years. The primary end point is a composite of all-cause mortality, myocardial infarction, stroke, coronary revascularization, and hospitalization for angina. A 900-patient substudy will examine quality-of-life outcomes. The trial is designed to have >85% power to detect a 25% relative reduction in the primary end point for each treatment factor. Enrollment began in September 2003 and was completed in October 2010.

Acute kidney injury in patients with acute lung injury: Impact of fluid accumulation on classification of acute kidney injury and associated outcomes*

It has been suggested that fluid accumulation may delay recognition of acute kidney injury. We sought to determine the impact of fluid balance on the incidence of nondialysis requiring acute kidney injury in patients with acute lung injury and to describe associated outcomes, including mortality. Analysis of the Fluid and Catheter Treatment Trial, a factorial randomized clinical trial of conservative vs. liberal fluid management and of management guided by a central venous vs. pulmonary artery catheter. Acute Respiratory Distress Syndrome Network hospitals. One thousand patients. None. The incidence of acute kidney injury, defined as an absolute rise in creatinine of ≥0.3 mg/dL or a relative change of >50% over 48 hrs, was examined before and after adjustment of serum creatinine for fluid balance. The incidence of acute kidney injury before adjustment for fluid balance was greater in those managed with the conservative fluid protocol (57% vs. 51%, p = .04). After adjustment for fluid balance, the incidence of acute kidney injury was greater in those managed with the liberal fluid protocol (66% vs. 58%, p = .007). Patients who met acute kidney injury criteria after adjustment of creatinine for fluid balance (but not before) had a mortality rate that was significantly greater than those who did not meet acute kidney injury criteria both before and after adjustment for fluid balance (31% vs. 12%, p < .001) and those who had acute kidney injury before but not after adjustment for fluid balance (31% vs. 11%, p = .005). The mortality of those patients meeting acute kidney injury criteria after but not before adjustment for fluid balance was similar to patients with acute kidney injury both before and after adjustment for fluid balance (31% vs. 38%, p = .18). Fluid management influences serum creatinine and therefore the diagnosis of acute kidney injury using creatinine-based definitions. Patients with "unrecognized" acute kidney injury that is identified after adjusting for positive fluid balance have higher mortality rates, and patients who have acute kidney injury before but not after adjusting for fluid balance have lower mortality rates. Future studies of acute kidney injury should consider potential differences in serum creatinine caused by changes in fluid balance and the impact of these differences on diagnosis and prognosis.

Clinical Implications of the ACCORD Trial

The Action to Control Cardiovascular Risk in Type 2 Diabetes (ACCORD) was a double factorial randomized clinical trial comparing intensive vs. standard glycemic control, intensive versus standard blood pressure control and fenofibrate versus placebo against a background of statin treatment. The primary outcome of cardiovascular disease (CVD), a composite of CVD death, non-fatal myocardial infarction and non-fatal stroke was not reduced by either of the intensive strategies or by addition of fenofibrate; moreover, total mortality was increased by the intensive glycemic strategy. Some secondary CVD outcomes were benefited as were some secondary microvascular outcomes by the more aggressive treatments. Epidemiological analyses were perplexing: for example, earlier severe hypoglycemic episodes were a risk factor for mortality and occurred three times as often in the intensive glycemic treatment group, but the excess of deaths in that group was not accounted for by those subjects who had suffered earlier episodes of severe hypoglycemia. Despite such perplexing results, some clinical implications that can be drawn from the kaleidoscope of ACCORD findings are offered here. Cases are suggested where intensive blood pressure treatment or addition of fenofibrate to statin therapy may be warranted, whereas intensive glycemic therapy is rarely, if ever, justified in ACCORD type patients.

Effects of Supplemental Vitamin D and Calcium on Biomarkers of Inflammation in Colorectal Adenoma Patients: A Randomized, Controlled Clinical Trial

Vitamin D and calcium affect several pathways involved in inflammation, tumor growth, and immune surveillance relevant to carcinogenesis. Also, epidemiologic evidence indicates that calcium and vitamin D may reduce risk for developing colorectal adenomas and cancer. To investigate the effects of calcium and vitamin D on biomarkers of inflammation in colorectal adenoma patients, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial (n = 92) of 2 g/d calcium and/or 800 IU/d vitamin D(3) supplementation versus placebo over 6 months. Plasma concentrations of proinflammatory markers [C-reactive protein (CRP), TNF-α, interleukin (IL)-6, IL-1β, and IL-8] and an anti-inflammatory marker (IL-10) were measured using ELISAs. After 6 months of treatment, in the vitamin D(3) supplementation group, CRP decreased 32% overall (P = 0.11), 37% in men (P = 0.05), and 41% among non-nonsteroidal anti-inflammatory drug (NSAID) users (P = 0.05) relative to placebo. In the vitamin D(3) supplementation group, TNF-α decreased 13%, IL-6 32%, IL-1β 50%, and IL-8 15%; in the calcium supplementation group, IL-6 decreased 37%, IL-8 11%, and IL-1β 27%. Although these changes were not statistically significant, a combined inflammatory markers z-score decreased 77% (P = 0.003) in the vitamin D(3) treatment group overall, 83% (P = 0.01) among men, and 48% among non-NSAID users (P = 0.01). There was no evidence of synergy between vitamin D(3) and calcium or effects on IL-10. These preliminary results are consistent with a pattern of reduction in tumor-promoting inflammation biomarkers with vitamin D(3) or calcium supplementation alone and support further investigation of vitamin D(3) as a chemopreventive agent against inflammation and colorectal neoplasms.

Interference and Facilitation Between Dengue Serotypes in a Tetravalent Live Dengue Virus Vaccine Candidate

Live, multivalent vaccines have historically exhibited interference in humans; live dengue virus (DENV) vaccines have proven no exception. To characterize interactions between DENV serotypes in a tetravalent live-attenuated virus vaccine candidate, we analyzed data from a factorial clinical trial in which all combinations of high- and low-dose DENV serotypes were combined in 16 live-attenuated tetravalent vaccine formulations (N = 64) and administered to flavivirus-naive adult volunteers. Regression models considered the outcomes of reactogenicity and seroconversion, controlling for all serotype doses simultaneously. Additionally, results were compared against earlier evaluations of the same viruses administered as monovalent formulations. DENV-1 was immunologically dominant in both monovalent and tetravalent formulations. In tetravalent formulations, DENV-1 and DENV-2 antagonized each other, with a high dose of one decreasing seroconversion to the other. However, high-dose DENV-1 significantly increased seroconversion against 3 or more serotypes, increasing seroconversion to DENV-1, DENV-3, and DENV-4. The highest reactogenicity occurred when DENV-1 was at high dose and all others were low; reactogenicity decreased with the incorporation of other high-dose serotypes. Interference and facilitation occurred between serotypes in the live vaccine candidate evaluated. These analyses suggest that it may be possible to exploit facilitation to increase overall seroconversion.

Randomized Clinical Trial of Aspirin and Simvastatin for Pulmonary Arterial Hypertension

Background— Pulmonary arterial hypertension (PAH) is a progressive disease that causes exercise limitation, heart failure, and death. We aimed to determine the safety and efficacy of aspirin and simvastatin in PAH. Methods and Results— We performed a randomized, double-blind, placebo-controlled 2×2 factorial clinical trial of aspirin and simvastatin in patients with PAH receiving background therapy at 4 centers. A total of 92 patients with PAH were to be randomized to aspirin 81 mg or matching placebo and simvastatin 40 mg or matching placebo. The primary outcome was 6-minute walk distance at 6 months. Sixty-five subjects had been randomized when the trial was terminated by the Data Safety and Monitoring Board after an interim analysis showed futility in reaching the primary end point for simvastatin. After adjustment for baseline 6-minute walk distance, there was no significant difference in the 6-minute walk distance at 6 months between aspirin (n=32) and placebo (n=33; placebo-corrected difference −0.5 m, 95% confidence interval −28.4 to 27.4 m; P =0.97) or between simvastatin (n=32) and placebo (n=33; placebo-corrected difference −27.6 m, 95% confidence interval −59.6 to 4.3 m; P =0.09). There tended to be more major bleeding episodes with aspirin than with placebo (4 events versus 1 event, respectively; P =0.17). Conclusions— Neither aspirin nor simvastatin had a significant effect on the 6-minute walk distance, although patients randomized to simvastatin tended to have a lower 6-minute walk distance at 6 months. These results do not support the routine treatment of patients with PAH with these medications. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00384865.

Prospective Clinical Trial Comparing Outcome Measures Between Furlow and von Langenbeck Palatoplasties for UCLP

The goal of this prospective randomized clinical trial was to compare 2 cohorts of standardized cleft patients with regard to functional speech outcome and the presence or absence of palatal fistulae. The 2 cohorts are randomized to undergo either a conventional von Langenbeck repair with intravelar velarplasty or the double-opposing Z-plasty Furlow procedure. A prospective 2 × 2 × 2 factorial clinical trial was used in which each subject was randomly assigned to 1 of 8 different groups: 1 of 2 different lip repairs (Spina vs. Millard), 1 of 2 different palatal repair (von Langenbeck vs. Furlow), and 1 of 2 different ages at time of palatal surgery (9-12 months vs. 15-18 months). All surgeries were performed by the same 4 surgeons. A cul-de-sac test of hypernasality and a mirror test of nasal air emission were selected as primary outcome measures for velopharyngeal function. Both a surgeon and speech pathologist examined patients for the presence of palatal fistulae. In this study, the Furlow double-opposing Z-palatoplasty resulted in significantly better velopharyngeal function for speech than the von Langenbeck procedure as determined by the perceptual cul-de-sac test of hypernasality. Fistula occurrence was significantly higher for the Furlow procedure than for the von Langenbeck. Fistulas were more likely to occur in patients with wider clefts and when relaxing incisions were not used.

A Randomized Clinical Trial of the Effects of Supplemental Calcium and Vitamin D3 on Markers of Their Metabolism in Normal Mucosa of Colorectal Adenoma Patients

In cancer cell lines and rodent models, calcium and vitamin D favorably modulate cell proliferation, differentiation, and apoptosis in colonic epithelia. These effects may be modulated by local expression of the calcium receptor (CaR), the vitamin D receptor (VDR), and the P450 cytochromes, CYP27B1 and CYP24A1; however, they have yet to be investigated in humans. To address this gap, we conducted a randomized, double-blinded, placebo-controlled 2×2 factorial clinical trial. Patients with at least one pathology-confirmed colorectal adenoma were treated with 2 g/d elemental calcium and/or 800 IU/d vitamin D3 versus placebo over 6 months (n=92; 23 per group). CaR, VDR, CYP27B1, and CYP24A1 expression and distribution in biopsies of normal appearing rectal mucosa were detected by standardized, automated immunohistochemistry and quantified by image analysis. In the calcium-supplemented group, CaR expression increased 27% (P=0.03) and CYP24A1 expression decreased 21% (P=0.79). In the vitamin D3-supplemented group, CaR expression increased 39% (P=0.01) and CYP27B1 expression increased 159% (P=0.06). In patients supplemented with both calcium and vitamin D3, VDR expression increased 19% (P=0.13) and CaR expression increased 24% (P=0.05). These results provide mechanistic support for further investigation of calcium and vitamin D3 as chemopreventive agents against colorectal neoplasms, and CaR, VDR, CYP27B1, and CYP24A1 as modifiable, preneoplastic risk biomarkers for colorectal neoplasms.

A clinical trial comparing oxytetracycline, foot trimming and flunixine meglumine on time to recovery in sheep with footrot

A randomized factorial clinical trial comparing treatments for footrot was run on 53 sheep. All received topical oxytetracycline, then sheep were given one or more of long-acting oxytetracycline, flunixine meglumine, no foot trimming, or foot trimming on day 1 or day 6 after treatment The order of rate of recovery by 10 days was injectable antibiotic (90%), sprayed only (60%), injected and foot trimmed (50%), then foot trimmed and sprayed (25%). We hypothesise that intramuscular oxytetracycline penetrated the epidermis/dermis and killed D. nodosus allowing the foot to heal and conformation to return to normal, whilst foot trimming delayed healing.