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Results of the SEL-I-METRY Phase II Trial on Resensitization of Advanced Iodine Refractory Differentiated Thyroid Cancer to Radioiodine Therapy.
Wadsley, J, Ainsworth, G, Coulson, AB, Garcez, K, Moss, L, Newbold, K, Farnell, K, Swain, J, Howard, H, Beasley, M, et al
Thyroid : official journal of the American Thyroid Association. 2023;(9):1119-1123
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NET-02 trial protocol: a multicentre, randomised, parallel group, open-label, phase II, single-stage selection trial of liposomal irinotecan (nal-IRI) and 5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients with progressive poorly differentiated extrapulmonary neuroendocrine carcinoma (NEC).
Craig, Z, Swain, J, Batman, E, Wadsley, J, Reed, N, Faluyi, O, Cave, J, Sharma, R, Chau, I, Wall, L, et al
BMJ open. 2020;(2):e034527
Abstract
INTRODUCTION Poorly differentiated (PD), extrapulmonary (EP), neuroendocrine carcinomas (NECs) are rare but aggressive neuroendocrine neoplasms. First-line treatment for advanced disease is an etoposide and platinum-based chemotherapy combination. There is no established second-line treatment for patients with PD-EP-NEC, and this is an area of unmet need. METHODS AND ANALYSIS NET-02 is a UK, multicentre, randomised (1:1), parallel group, open-label, phase II, single-stage selection trial of liposomal irinotecan (nal-IRI)/5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients with progressive PD-EP-NEC. One hundred and two eligible participants will be randomised to receive either nal-IRI/5-FU/folinic acid or docetaxel. The primary objective is to determine the 6-month progression-free survival (PFS) rate. The secondary objectives of this study are to determine PFS, overall survival, objective response rate, toxicity, quality of life and whether neuron-specific enolase is predictive of treatment response. If either treatment is found to have a 6-month PFS rate of at least 25%, that treatment will be considered for a phase III trial. If both treatments meet this target, prespecified selection criteria will be applied to establish which treatment to take forward. ETHICS AND DISSEMINATION This study has ethical approval from the Greater Manchester Central Research Ethics Committee (reference no. 18/NW/0031) and clinical trial authorisation from the Medicine and Healthcare Products Regulatory Agency. Results will be published in peer-reviewed journals and uploaded to the European Union Clinical Trials Register. TRIAL REGISTRATION NUMBERS ISRCTN10996604, NCT03837977, EudraCT Number: 2017-002453-11.
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Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials.
Clément, K, van den Akker, E, Argente, J, Bahm, A, Chung, WK, Connors, H, De Waele, K, Farooqi, IS, Gonneau-Lejeune, J, Gordon, G, et al
The lancet. Diabetes & endocrinology. 2020;(12):960-970
Abstract
BACKGROUND The melanocortin 4 receptor (MC4R), a component of the leptin-melanocortin pathway, plays a part in bodyweight regulation. Severe early-onset obesity can be caused by biallelic variants in genes that affect the MC4R pathway. We report the results from trials of the MC4R agonist setmelanotide in individuals with severe obesity due to either pro-opiomelanocortin (POMC) deficiency obesity or leptin receptor (LEPR) deficiency obesity. METHODS These single-arm, open-label, multicentre, phase 3 trials were done in ten hospitals across Canada, the USA, Belgium, France, Germany, the Netherlands, and the UK. Participants aged 6 years or older with POMC or LEPR deficiency obesity received open-label setmelanotide for 12 weeks. Participants with at least 5 kg weight loss (or ≥5% if weighing <100 kg at baseline) entered an 8-week placebo-controlled withdrawal sequence (including 4 weeks each of blinded setmelanotide and placebo treatment) followed by 32 additional weeks of open-label treatment. The primary endpoint, which was assessed in participants who received at least one dose of study medication and had a baseline assessment (full analysis set), was the proportion of participants with at least 10% weight loss compared with baseline at approximately 1 year. A key secondary endpoint was mean percentage change in the most hunger score of the 11-point Likert-type scale at approximately 1 year on the therapeutic dose, which was assessed in a subset of participants aged 12 years or older in the full analysis set who demonstrated at least 5 kg weight loss (or ≥5% in paediatric participants if baseline bodyweight was <100 kg) over the 12-week open-label treatment phase and subsequently proceeded into the placebo-controlled withdrawal sequence, regardless of later disposition. These studies are registered with ClinicalTrials.gov, NCT02896192 and NCT03287960. FINDINGS Between Feb 14, 2017, and Sept 7, 2018, ten participants were enrolled in the POMC trial and 11 participants were enrolled in the LEPR trial, and included in the full analysis and safety sets. Eight (80%) participants in the POMC trial and five (45%) participants in the LEPR trial achieved at least 10% weight loss at approximately 1 year. The mean percentage change in the most hunger score was -27·1% (n=7; 90% CI -40·6 to -15·0; p=0·0005) in the POMC trial and -43·7% (n=7; -54·8 to -29·1; p<0·0001) in the LEPR trial. The most common adverse events were injection site reaction and hyperpigmentation, which were reported in all ten participants in the POMC trial; nausea was reported in five participants and vomiting in three participants. In the LEPR trial, the most commonly reported treatment-related adverse events were injection site reaction in all 11 participants, skin disorders in five participants, and nausea in four participants. No serious treatment-related adverse events occurred in both trials. INTERPRETATION Our results support setmelanotide for the treatment of obesity and hyperphagia caused by POMC or LEPR deficiency. FUNDING Rhythm Pharmaceuticals.
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Randomized sham-controlled trial of the 6-month swallowable gas-filled intragastric balloon system for weight loss.
Sullivan, S, Swain, J, Woodman, G, Edmundowicz, S, Hassanein, T, Shayani, V, Fang, JC, Noar, M, Eid, G, English, WJ, et al
Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery. 2018;(12):1876-1889
Abstract
BACKGROUND Obesity is a significant health problem and additional therapies are needed to improve obesity treatment. OBJECTIVE Determine the efficacy and safety of a 6-month swallowable gas-filled intragastric balloon system for weight loss. SETTING Fifteen academic and private practice centers in the United States. METHODS This was a double-blind, randomized sham-controlled trial of the swallowable gas-filled intragastric balloon system plus lifestyle therapy compared with lifestyle therapy alone for weight loss at 6 months in participants aged 22 to 60 years with body mass index 30 to 40 kg/m2, across 15 sites in the United States. The following endpoints were included: difference in percent total weight loss in treatment group versus control group was >2.1%, and a responder rate of >35% in the treatment group. RESULTS Three hundred eighty-seven patients swallowed at least 1 capsule. Of participants, 93.3% completed all 24 weeks of blinded study testing. Nonserious adverse events occurred in 91.1% of patients, but only .4% were severe. One bleeding ulcer and 1 balloon deflation occurred. In analysis of patients who completed treatment, the treatment and control groups achieved 7.1 ± 5.0% and 3.6 ± 5.1% total weight loss, respectively, and a mean difference of 3.5% (P = .0085). Total weight loss in treatment and control groups were 7.1 ± 5.3 and 3.6 ± 5.1 kg (P < .0001), and body mass index change in the treatment and control groups were 2.5 ± 1.8 and 1.3 ± 1.8 kg/m2 (P < .0001), respectively. The responder rate in the treatment group was 66.7% (P < .0001). Weight loss maintenance in the treatment group was 88.5% at 48 weeks. CONCLUSIONS Treatment with lifestyle therapy and the 6-month swallowable gas-filled intragastric balloon system was safe and resulted in twice as much weight loss compared with a sham control, with high weight loss maintenance at 48 weeks.
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Dietary intake of calcium and magnesium and the metabolic syndrome in the National Health and Nutrition Examination (NHANES) 2001-2010 data.
Moore-Schiltz, L, Albert, JM, Singer, ME, Swain, J, Nock, NL
The British journal of nutrition. 2015;(6):924-35
Abstract
Higher dietary intakes of Mg and Ca, individually, have been associated with a decreased risk for the metabolic syndrome (MetSyn). Experimental studies suggest that a higher intra-cellular ratio of Ca:Mg, which may be induced by a diet high in Ca and low in Mg, may lead to hypertension and insulin resistance. However, no previous epidemiological studies have examined the effects of the combined intake of Mg and Ca on MetSyn. Thus, we evaluated the association between dietary intakes of Ca and Mg (using 24-h recalls), independently and in combination, and MetSyn in the National Health and Nutrition Examination Study 2001-2010 data, which included 9148 adults (4549 men and 4599 women), with complete information on relevant nutrient, demographic, anthropometric and biomarker variables. We found an inverse association between the highest (>355 mg/d) v. the lowest (<197 mg/d) quartile of Mg and MetSyn (OR 0.70; 95% CI 0.57, 0.86). Women who met the RDA for both Mg (310-320 mg/d) and Ca (1000-1200 mg/d) had the greatest reduced odds of MetSyn (OR 0.59; 95% CI 0.45, 0.76). In men, meeting the RDA for Mg (400-420 mg/d) and Ca (1000-1200 mg/d), individually or in combination, was not associated with MetSyn; however, men with intakes in the highest quartile for Mg (≥ 386 mg/d) and Ca (≥ 1224 mg/d) had a lower odds of MetSyn (OR 0.74; 95% CI 0.59, 0.93). Our results suggest that women who meet the RDA for Mg and Ca have a reduced odds of MetSyn but men may require Ca levels higher than the RDA to be protected against MetSyn.
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The REDUCE pivotal trial: a prospective, randomized controlled pivotal trial of a dual intragastric balloon for the treatment of obesity.
Ponce, J, Woodman, G, Swain, J, Wilson, E, English, W, Ikramuddin, S, Bour, E, Edmundowicz, S, Snyder, B, Soto, F, et al
Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery. 2015;(4):874-81
Abstract
BACKGROUND Saline-filled intragastric balloon devices are reversible endoscopic devices designed to occupy stomach volume and reduce food intake. OBJECTIVE To evaluate the safety and effectiveness of a dual balloon system plus diet and exercise in the treatment of obesity compared to diet and exercise alone. SETTING Academic and community practice, United States. METHODS Participants (n = 326) with body mass index (BMI) 30-40 kg/m(2) were randomized to endoscopic DBS treatment plus diet and exercise (DUO, n = 187) or sham endoscopy plus diet and exercise alone (DIET, n = 139). Co-primary endpoints were a between-group comparison of percent excess weight loss (%EWL) and DUO subject responder rate, both at 24 weeks. Thereafter DUO patients had the DBS retrieved followed by 24 additional weeks of counseling; DIET patients were offered DBS treatment. RESULTS Mean BMI was 35.4. Both primary endpoints were met. DUO weight loss was over twice that of DIET. DUO patients had significantly greater %EWL at 24 weeks (25.1% intent-to-treat (ITT), 27.9% completed cases (CC, n = 167) compared with DIET patients (11.3% ITT, P = .004, 12.3% CC, n = 126). DUO patients significantly exceeded a 35% response rate (49.1% ITT, P<.001, 54.5% CC) for weight loss dichotomized at 25%EWL. Accommodative symptoms abated rapidly with support and medication. Balloon deflation occurred in 6% without migrations. Early retrieval for nonulcer intolerance occurred in 9%. Gastric ulcers were observed; a minor device change led to significantly reduced ulcer size and frequency (10%). CONCLUSION The DBS was significantly more effective than diet and exercise in causing weight loss with a low adverse event profile.
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Effects of high vs low glycemic index of dietary carbohydrate on cardiovascular disease risk factors and insulin sensitivity: the OmniCarb randomized clinical trial.
Sacks, FM, Carey, VJ, Anderson, CA, Miller, ER, Copeland, T, Charleston, J, Harshfield, BJ, Laranjo, N, McCarron, P, Swain, J, et al
JAMA. 2014;(23):2531-41
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Abstract
IMPORTANCE Foods that have similar carbohydrate content can differ in the amount they raise blood glucose. The effects of this property, called the glycemic index, on risk factors for cardiovascular disease and diabetes are not well understood. OBJECTIVE To determine the effect of glycemic index and amount of total dietary carbohydrate on risk factors for cardiovascular disease and diabetes. DESIGN, SETTING, AND PARTICIPANTS Randomized crossover-controlled feeding trial conducted in research units in academic medical centers, in which 163 overweight adults (systolic blood pressure, 120-159 mm Hg) were given 4 complete diets that contained all of their meals, snacks, and calorie-containing beverages, each for 5 weeks, and completed at least 2 study diets. The first participant was enrolled April 1, 2008; the last participant finished December 22, 2010. For any pair of the 4 diets, there were 135 to 150 participants contributing at least 1 primary outcome measure. INTERVENTIONS (1) A high-glycemic index (65% on the glucose scale), high-carbohydrate diet (58% energy); (2) a low-glycemic index (40%), high-carbohydrate diet; (3) a high-glycemic index, low-carbohydrate diet (40% energy); and (4) a low-glycemic index, low-carbohydrate diet. Each diet was based on a healthful DASH-type diet. MAIN OUTCOMES AND MEASURES The 5 primary outcomes were insulin sensitivity, determined from the areas under the curves of glucose and insulin levels during an oral glucose tolerance test; levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides; and systolic blood pressure. RESULTS At high dietary carbohydrate content, the low- compared with high-glycemic index level decreased insulin sensitivity from 8.9 to 7.1 units (-20%, P = .002); increased LDL cholesterol from 139 to 147 mg/dL (6%, P ≤ .001); and did not affect levels of HDL cholesterol, triglycerides, or blood pressure. At low carbohydrate content, the low- compared with high-glycemic index level did not affect the outcomes except for decreasing triglycerides from 91 to 86 mg/dL (-5%, P = .02). In the primary diet contrast, the low-glycemic index, low-carbohydrate diet, compared with the high-glycemic index, high-carbohydrate diet, did not affect insulin sensitivity, systolic blood pressure, LDL cholesterol, or HDL cholesterol but did lower triglycerides from 111 to 86 mg/dL (-23%, P ≤ .001). CONCLUSIONS AND RELEVANCE In this 5-week controlled feeding study, diets with low glycemic index of dietary carbohydrate, compared with high glycemic index of dietary carbohydrate, did not result in improvements in insulin sensitivity, lipid levels, or systolic blood pressure. In the context of an overall DASH-type diet, using glycemic index to select specific foods may not improve cardiovascular risk factors or insulin resistance. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00608049.
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Effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol.
McMorris, T, Harris, RC, Swain, J, Corbett, J, Collard, K, Dyson, RJ, Dye, L, Hodgson, C, Draper, N
Psychopharmacology. 2006;(1):93-103
Abstract
RATIONALE Sleep deprivation has a negative effect on cognitive and psychomotor performance and mood state, partially due to decreases in creatine levels in the brain. Therefore, creatine supplementation should lessen the negative effects of sleep deprivation. OBJECTIVES The objective of this study was to examine the effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol. METHOD Subjects were divided into a creatine group (n=10) and a placebo group (n=9). They took 5 g of creatine monohydrate or a placebo, dependent on their group, four times a time a day for 7 days, immediately prior to the experiment. The study was double blind. Subjects undertook tests of random movement generation (RMG), verbal and spatial recall, choice reaction time, static balance and mood state pre-test (0 h), after 6, 12 and 24 h of sleep deprivation, with intermittent exercise. They were tested for plasma concentrations of catecholamines and cortisol at 0 and 24 h. RESULTS At 24 h, the creatine group demonstrated significantly less change in performance from 0 h (delta) in RMG, choice reaction time, balance and mood state. There were no significant differences between groups in plasma concentrations of catecholamines and cortisol. Norepinephrine and dopamine concentrations were significantly higher at 24 h than 0 h, but cortisol were lower. CONCLUSIONS Following 24-h sleep deprivation, creatine supplementation had a positive effect on mood state and tasks that place a heavy stress on the prefrontal cortex.
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Rationale and design of the Optimal Macro-Nutrient Intake Heart Trial to Prevent Heart Disease (OMNI-Heart).
Carey, VJ, Bishop, L, Charleston, J, Conlin, P, Erlinger, T, Laranjo, N, McCarron, P, Miller, E, Rosner, B, Swain, J, et al
Clinical trials (London, England). 2005;(6):529-37
Abstract
BACKGROUND The DASH (Dietary Approaches to Stop Hypertension) diet is a carbohydrate-rich, reduced-fat diet that lowers blood pressure (BP) and LDL-cholesterol. Whether partial replacement of some carbohydrate (C) with either protein (P) or unsaturated fat (U) can further improve these and other cardiovascular (CVD) risk factors is unknown. METHODS OmniHeart is a randomized, three-period, crossover feeding study designed to compare the effects on BP and blood lipids of a carbohydrate-rich diet (CARB, similar to the DASH diet) with a diet rich in protein (PROT, predominantly from nonmeat sources) and a diet rich in unsaturated fat (UNSAT, predominantly monounsaturated). Throughout feeding (run in and the three intervention periods), participants are provided with all of their meals that meet the nutrient profile of their assigned diet. Calorie intake is adjusted to maintain weight. The target sample size is 160 (50% African-American). Participants are adults, aged 30 or older, with prehypertension or Stage 1 hypertension (systolic BP 120-159 or diastolic BP 80-99 mmHg). The primary outcome variables are systolic BP and LDL-cholesterol. Secondary outcomes are diastolic BP, HDL-cholesterol, and triglycerides. Other outcome variables are total cholesterol, apolipoproteins VLDL-apoB, VLDL-apoCIII, apolipoprotein B, non-HDL cholesterol, and lipoprotein(a), and insulin resistance, as measured by Homeostasis Model Assessment (HOMA). CONCLUSIONS OMNI-Heart should advance our fundamental knowledge of the effects of diet on both traditional and emerging risk factors, and, in the process, guide policy makers, health care providers and the general public on the relative benefits of carbohydrate, protein, and unsaturated fat as a means to reduce CVD risk.
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Effects of a low-glycemic load diet on resting energy expenditure and heart disease risk factors during weight loss.
Pereira, MA, Swain, J, Goldfine, AB, Rifai, N, Ludwig, DS
JAMA. 2004;(20):2482-90
Abstract
CONTEXT Weight loss elicits physiological adaptations relating to energy intake and expenditure that antagonize ongoing weight loss. OBJECTIVE To test whether dietary composition affects the physiological adaptations to weight loss, as assessed by resting energy expenditure. DESIGN, STUDY, AND PARTICIPANTS A randomized parallel-design study of 39 overweight or obese young adults aged 18 to 40 years who received an energy-restricted diet, either low-glycemic load or low-fat. Participants were studied in the General Clinical Research Centers of the Brigham and Women's Hospital and the Children's Hospital, Boston, Mass, before and after 10% weight loss. The study was conducted from January 4, 2001, to May 6, 2003. MAIN OUTCOME MEASURES Resting energy expenditure measured in the fasting state by indirect calorimetry, body composition by dual-energy x-ray absorptiometry, cardiovascular disease risk factors, and self-reported hunger. RESULTS Resting energy expenditure decreased less with the low-glycemic load diet than with the low-fat diet, expressed in absolute terms (mean [SE], 96 [24] vs 176 [27] kcal/d; P = .04) or as a proportion (5.9% [1.5%] vs 10.6% [1.7%]; P = .05). Participants receiving the low-glycemic load diet reported less hunger than those receiving the low-fat diet (P = .04). Insulin resistance (P = .01), serum triglycerides (P = .01), C-reactive protein (P = .03), and blood pressure (P = .07 for both systolic and diastolic) improved more with the low-glycemic load diet. Changes in body composition (fat and lean mass) in both groups were very similar (P = .85 and P = .45, respectively). CONCLUSIONS Changes in dietary composition within prevailing norms can affect physiological adaptations that defend body weight. Reduction in glycemic load may aid in the prevention or treatment of obesity, cardiovascular disease, and diabetes mellitus.