scholarly journals Non-inferiority of low-dose compared to standard high-dose calcium supplementation in pregnancy: study protocol for two randomized, parallel group, non-inferiority trials in India and Tanzania

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Pratibha Dwarkanath ◽  
Alfa Muhihi ◽  
Christopher R. Sudfeld ◽  
Shobha Rani ◽  
Christopher P. Duggan ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Pregnant Women ◽  
Low Dose ◽  
Calcium Supplementation ◽  
Dietary Calcium Intake ◽  
High Dose ◽  
Link Type ◽  
Parallel Group ◽  
Elemental Calcium ◽  
In Pregnancy

Abstract Background Hypertensive disorders of pregnancy are important causes of maternal morbidity and mortality, as well as preterm birth, the leading cause of death for children under 5 years globally. The World Health Organization currently recommends that pregnant women receive high-dose calcium supplementation (1500–2000 mg elemental calcium) for prevention of preeclampsia in populations with low dietary calcium intake. Trials of low-dose calcium supplementation (< 1000 mg elemental calcium/day) during pregnancy have also shown similar reductions in the risk of preeclampsia; however, no trials to date have directly compared low-dose to the standard high-dose calcium supplementation. Our objective is to assess the non-inferiority of low-dose as compared to standard high-dose calcium supplementation in pregnancy. Methods/design We will conduct two independent trials in Bangalore, India (n = 11,000 pregnancies), and Dar es Salaam, Tanzania (n = 11,000 pregnancies). The trial designs are individually randomized, parallel group, quadruple-blind, non-inferiority trials of low-dose calcium supplementation (500 mg elemental calcium/day) as compared to standard high-dose calcium supplementation (1500 mg elemental calcium/day) among nulliparous pregnant women. Pregnant women will be enrolled in the trial before 20 weeks of gestation and will receive the randomized calcium regimen from randomization until the time of delivery. The co-primary outcomes are (i) preeclampsia and (ii) preterm birth; we will test non-inferiority of the primary outcomes for low-dose as compared to the standard high-dose supplementation regimen in each trial. The trials’ secondary outcomes include gestational hypertension, severe features of preeclampsia, pregnancy-related death, third trimester severe anemia, fetal death, stillbirth, low birthweight, small-for-gestational age birth, and infant death. Discussion The trials will provide causal evidence on the non-inferiority of low-dose as compared to the standard high-dose supplementation in India and Tanzania. A single tablet, low-dose calcium supplementation regimen may improve individual-level adherence, reduce programmatic costs, and ultimately expand implementation of routine calcium supplementation in pregnancy in populations with low dietary calcium intake. Trial registration ClinicalTrials.gov identifier: NCT03350516; registered on 22 November 2018. Clinical Trials Registry—India identifier: CTRI/2018/02/012119; registered on 23 February 2018. Tanzania Medicines and Medical Devices Authority Trials Registry identifier: TFDA0018/CTR/0010/5; registered on 20 December 2018.

scholarly journals Histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapy

2020 ◽  
Vol 8 (1) ◽  
pp. e000247
Author(s):  
Brett A Schroeder ◽  
Ralph Graeme Black ◽  
Sydney Spadinger ◽  
Shihong Zhang ◽  
Karan Kohli ◽  
...  
Keyword(s):  
T Cell ◽  
Interferon Gamma ◽  
Low Dose ◽  
Cellular Therapy ◽  
Tumor Regression ◽  
High Dose ◽  
Adoptive Cellular Therapy ◽  
Link Type ◽  
T Cell Infiltration ◽  
Ifn Γ

BackgroundAdoptive cellular therapy (ACT) is a promising treatment for synovial sarcoma (SS) with reported response rates of over 50%. However, more work is needed to obtain deeper and more durable responses. SS has a ‘cold’ tumor immune microenvironment with low levels of major histocompatibility complex (MHC) expression and few T-cell infiltrates, which could represent a barrier toward successful treatment with ACT. We previously demonstrated that both MHC expression and T-cell infiltration can be increased using systemic interferon gamma (IFN-γ), which could improve the efficacy of ACT for SS.Case presentationWe launched a phase I trial incorporating four weekly doses of IFN-γ in an ACT regimen of high-dose cyclophosphamide (HD Cy), NY-ESO-1-specific T cells, and postinfusion low-dose interleukin (IL)-2. Two patients were treated. While one patient had significant tumor regression and resultant clinical benefit, the other patient suffered a fatal histiocytic myocarditis. Therefore, this cohort was terminated for safety concerns.ConclusionWe describe a new and serious toxicity of immunotherapy from IFN-γ combined with HD Cy-based lymphodepletion and low-dose IL-2. While IFN-γ should not be used concurrently with HD Cy or with low dose IL-2, IFN-γ may still be important in sensitizing SS for ACT. Future studies should avoid using IFN-γ during the immediate period before/after cell infusion.Trial registration numbersNCT04177021,NCT01957709, andNCT03063632.

scholarly journals Sepsis in pregnancy and early goal-directed therapy

2009 ◽  
Vol 2 (3) ◽  
pp. 93-99 ◽  
Author(s):  
Julie Joseph ◽  
Aneeta Sinha ◽  
Michael Paech ◽  
Barry N J Walters
Keyword(s):  
Clinical Trials ◽  
Pregnant Women ◽  
Randomized Clinical Trials ◽  
Surviving Sepsis Campaign ◽  
Goal Directed Therapy ◽  
Early Goal Directed Therapy ◽  
Conventional Management ◽  
Serious Infection ◽  
Underlying Pathophysiology ◽  
In Pregnancy

Sepsis is a major cause of serious morbidity and mortality in pregnant women and their babies. Conventional management has evolved over many years. Improved understanding of the underlying pathophysiology and randomized clinical trials have led to recommendations for the formalization and standardization of the management of severe sepsis in non-pregnant patients. Most of these recommendations are applicable to pregnancy. The Surviving Sepsis Campaign and Early Goal Directed Therapy have relevance to the care of pregnant women with serious infection and are reviewed here.

Dietary calcium, defective cellular Ca2+ handling, and arterial pressure control

1994 ◽  
Vol 72 (8) ◽  
pp. 937-944 ◽  
Author(s):  
David A. McCarron ◽  
Daniel Hatton ◽  
Jean-Baptiste Roullet ◽  
Chantal Roullet
Keyword(s):  
Blood Pressure ◽  
Clinical Trials ◽  
Calcium Intake ◽  
Inverse Relationship ◽  
Spontaneously Hypertensive Rat ◽  
Calcium Supplementation ◽  
Dietary Calcium ◽  
Calcium Handling ◽  
Dietary Calcium Intake ◽  
Experimental Hypertension

The association between dietary calcium intake, calcium metabolism, and blood pressure form the basis of this review. Epidemiologic data consistently show an inverse relationship between dietary calcium and blood pressure. Clinical trials of calcium supplementation have not been as consistent in outcome. Approximately two-thirds of the supplementation studies have found a beneficial effect of calcium on blood pressure. The lack of consistency in outcome from the clinical trials relative to the epidemiological literature may be related to calcium intake. The epidemiological literature indicates an inverse relationship between calcium intake and blood pressure, with those individuals with the lowest calcium intake (< 700 mg/day) having the highest blood pressure. Clinical studies utilizing patients with high baseline calcium levels (> 700 mg/day) may not see an effect of calcium supplementation on blood pressure because of a ceiling effect. Supplemental calcium appears to correct a defect in calcium handling characterized by a renal calcium leak, increased circulating parathroid hormone, and increased intracellular calcium levels. In part, the deficit in cellular calcium homeostasis may be a consequence of abnormal calmodulin activity. Specifically, it appears that calmodulin activity is diminished in experimental hypertension and that increasing dietary calcium may improve calmodulin activity in the spontaneously hypertensive rat. The deficit in calmodulin activity has the potential to interfere with a number of cellular processes crucial to the regulation of cell function and maintenance of appropriate vascular tone. It is concluded that additional research should be directed toward understanding the ramifications of altered calmodulin activity in hypertension and the influence that dietary calcium can have on the activity of calmodulin.Key words: hypertension, dietary Ca2+, calmodulin, Ca2+ metabolism, calcium channel blockers.

Abstract 11532: Randomized Trial of the Association Between Low Dose Statins and Nutraceuticals in High intensity Statin. intolerRant patiENts With Very High Risk Coronary Artery disease (ADHERENCE)

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
giuseppe marazzi ◽  
francesco pelliccia ◽  
maurizio volterrani ◽  
giuseppe campolongo ◽  
salvatore rosanio ◽  
...  
Keyword(s):  
High Risk ◽  
Low Dose ◽  
Primary Objective ◽  
High Dose ◽  
Red Yeast Rice ◽  
Atherosclerotic Cardiovascular Disease ◽  
Double Blind ◽  
Parallel Group ◽  
Artery Disease ◽  
Treatment Tolerance

Background: Several trials have shown that in patients (pts) with atherosclerotic cardiovascular disease, reduction of LDL-C level with statin is associated with significant reductions in mortality and cardiovascular events. In clinical practice, however, high dose statin (HDS) treatment is often discontinued by pts due to side effects. Indeed, in statin intolerant pts alternative therapies such as nutraceuticals are available. Purpose: The primary objective of this study is to compare the efficacy and tollerability of low dose statin (LDS) therapy vs the association between a LDS and a nutraceuticals in HDS intollerant pts with CAD deemed to be at high risk. Methods: A randomised, prospective, parallel group, double blind trial was designed. The inclusion criteria were pts with CAD that underwent to PCI and that do not achieved at least a 50% reduction in LDL C and were HDS intolerant in treatment with LDS. These pts were randomized 1:1 in 2 groups: group NS received an association with LDS and a commercially available nutraceutical pill (1 tablet/day containing red yeast rice 200 mg, policosanol 10 mg and berberine 500 mg) and group S continued LDS (10 to 20 mg/day of simvastatin or 5 to 10 mg/day atorvastatin or 5 mg/day rosuvastatin). At baseline and after 3 months all pts underwent to clinical evaluation and blood exams. Results: 100 pts were consecutively enrolled. Baseline clinical features and lipid profiles were similar between groups. At the 3° month, the 2 groups significantly differed for LDL-C, total cholesterol and triglycerides, with lower levels in the NS group than in the S group; also, the 2 groups differed for HDL-C values but not significantly, with higher levels in the NS group than in the S group (Table 1). Morever, in both group the treatment tolerance was high: in each groups only 3 pts discontinued therapy. Conclusion: In pts with CAD and HDS intolerant, a treatment with LDS and Nutraceuticals can be a reliable treatment option. (clinicaltrials.gov: NCT02001883)

Clinical Adverse Events of High-Dose vs Low-Dose Sodium–Glucose Cotransporter 2 Inhibitors in Type 2 Diabetes: A Meta-Analysis of 51 Randomized Clinical Trials

2020 ◽  
Vol 105 (11) ◽  
Author(s):  
Fang-Hong Shi ◽  
Hao Li ◽  
Jiang Yue ◽  
Yi-Hong Jiang ◽  
Zhi-Chun Gu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Clinical Trials ◽  
Adverse Events ◽  
Low Dose ◽  
Randomized Clinical Trials ◽  
Sglt2 Inhibitors ◽  
High Dose ◽  
Sodium Glucose Cotransporter ◽  
Subgroup Analyses

Abstract Aims The aims of this work are to assess the clinical adverse events (AEs) of high-dose vs low-dose sodium–glucose cotransporter 2 inhibitors (SGLT2 inhibitors) in patients with type 2 diabetes mellitus (T2DM). Methods We searched MEDLINE, EMBASE, and Cochrane Library from January 1, 2006 to March 10, 2020, for identifying eligible randomized clinical trials (RCTs) that reported AEs by high-dose and low-dose SGLT2 inhibitors in T2DM patients. Random-effects models was used to obtain summary relative risks (RRs) with associated 95% CIs. Prespecified subgroup analyses according to individual SGLT2 inhibitors and follow-up duration, and leave-one-out sensitivity analysis were conducted. Results A total of 51 RCTs involving 24 371 patients (12 208 received high-dose and 12 163 received low-dose SGLT2 inhibitors) were included. Overall, the heterogeneity among included studies was relatively low (I2 &lt; 50% for each outcome). No significant differences between high-dose and low-dose SGLT2 inhibitors were observed for overall safety (including any AEs, serious AEs, AEs leading to discontinuation, and death) and specified safety (including infections and infestations, musculoskeletal disorders, gastrointestinal disorders, osmotic diuresis-related AEs, volume-related AEs, renal-related AEs, and metabolism and nutrition), except for a mild increase in risk for AEs related to study drugs (RR: 1.08; 95% CI, 1.01-1.16) that mainly derived from canagliflozin (RR: 1.17; 95% CI, 1.05-1.30). Subgroup analyses were consistent with the primary outcomes. Conclusions This study provided substantial evidence that AEs of SGLT2 inhibitors were not dose related.

scholarly journals Smoking cessation in pregnancy

2010 ◽  
Vol 3 (3) ◽  
pp. 90-93 ◽  
Author(s):  
Renee Bittoun ◽  
Giuseppe Femia
Keyword(s):  
Smoking Cessation ◽  
Pregnant Women ◽  
Treatment Modality ◽  
Low Dose ◽  
Long Term Effects ◽  
Current Smoking ◽  
Safety And Efficacy ◽  
Short And Long Term ◽  
In Pregnancy

Managing smoking cessation during pregnancy is vital to the wellbeing of the fetus and the mother. Women who continue to smoke during pregnancy expose the fetus to thousands of chemicals which have been shown to cause deleterious short- and long-term effects. Although a large majority of women cease smoking early in the pregnancy, many of them relapse following delivery. Following a review of current research, an overview of the safety and efficacy of smoking cessation treatments for pregnant women will be considered. Limited research has been performed in this field; however, it can be concluded that low-dose intermittent nicotine replacement therapy is a safe treatment modality for women who smoke during pregnancy. At present there has been no research on other current smoking cessation treatments; however, we will suggest techniques to improve cessation rates and strategies to reduce relapse.

scholarly journals Steady-State Pharmacokinetic and Safety Profiles of Voriconazole and Ritonavir in Healthy Male Subjects

2007 ◽  
Vol 51 (10) ◽  
pp. 3617-3626 ◽  
Author(s):  
Ping Liu ◽  
Grover Foster ◽  
Kuan Gandelman ◽  
Robert R. LaBadie ◽  
Mark J. Allison ◽  
...  
Keyword(s):  
Steady State ◽  
Low Dose ◽  
Safety Data ◽  
Fold Increase ◽  
High Dose ◽  
Time Curve ◽  
Period 2 ◽  
Parallel Group ◽  
Male Subjects ◽  
Parallel Group Trial

ABSTRACT Since there is a likelihood of coadministration of voriconazole and ritonavir, two studies were conducted to evaluate the potential of drug interaction. Study A was a randomized, placebo-controlled, two-period, parallel-group trial (n = 34). Study B had the same design without the placebo group (n = 17). In period 1, subjects received 200 mg voriconazole or placebo twice daily (BID) for 3 days (400 mg BID on day 1). In period 2, following a 7-day washout, subjects received ritonavir alone at 400 mg BID (study A) or 100 mg BID (study B) for 10 days (days 11 to 20), and then ritonavir was coadministered with 200 mg BID voriconazole or placebo for the next 10 days (days 21 to 30). Serial plasma samples were collected on days 3, 20, and 30, and safety data were collected throughout the study. High-dose (400 mg BID) ritonavir substantially reduced the steady-state mean voriconazole exposure (area under the concentration-time curve from 0 to 12 h [AUC0-12], −82%; maximum concentration [C max], −66%). However, the effect of low-dose (100 mg BID) ritonavir was less pronounced (AUC0-12, −39%; C max, −24%). The decrease in voriconazole exposure was probably due to the induction of CYP2C19 and CYP2C9 by ritonavir. It is interesting that one subject in each study exhibited the opposite effect of ritonavir on voriconazole exposure (a 2.5- to 3-fold increase), probably due to lack of CYP2C19. Voriconazole had no apparent effect on the exposure of high-dose ritonavir but slightly decreased the exposure of low-dose ritonavir (AUC0-12, −14%; C max, −24%). The safety profile of combination therapy was not notably different from that of voriconazole or ritonavir alone. Due to the significant effect of ritonavir on voriconazole exposure, coadministration of voriconazole with 400 mg BID ritonavir is contraindicated; coadministration with 100 mg BID ritonavir should be avoided, unless an assessment of the benefit/risk to the patient justifies the use.

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