A phase II randomized clinical trial and mechanistic studies using improved probiotics to prevent oral mucositis induced by concurrent radiotherapy and chemotherapy in nasopharyngeal carcinoma.

e18568 Background: Earlier evidence has proven that probiotic supplements can reduce radiochemotherapy (CCRT) -induced oral mucositis (OM) in nasopharyngeal cancer (NPC). We have recently modified the ingredient of the probiotics by combining Bifidobacterium animalis, Lactobacillus plantarum, Lactobacillus rhamnosus and Lactobacillus acidophilus. This report includes the Phase II clinical trial to evaluate the effect of the modified probiotics along with mechanistic studies. Methods: We enrolled 85 patients with locally advanced NPC who were undergoing CCRT. The patients were randomized (1:1) to receive either probiotic mixture or placebo. The incidence of severe OM (grade 3 or higher) was the primary endpoint to document. We utilized a rat model. We collected rat’s samples from the tongue, blood and fecal and proximal colon tissues on a various days following treatment and tested for the mechanism of probiotics mixture on OM. Results: We found that patients taking the probiotic mixture showed significantly reduced OM. The incidences for Grade 0, 1, 2, 3 and 4 OM in the placebo group and the probiotic mixture group were 0%, 14.7%, 38.2%, 32.4%, and 14.7% and 13.9%, 36.1%, 25%, 22.2%, and 2.8%, respectively. Furthermore, patients in the probiotic mixture group showed lower reduction rate in CD3+ T cells (75.5% vs 81%, P < 0.01), CD4+ T cells (64.53% vs 79.53%, P < 0.01), and CD8+ T cells (75.59% vs 62.36%, P < 0.01) compared with the placebo group. In the rat model, the control group rats showed more severe mucositis, increased histologic changes of the oral mucosa on the 7th, 14th and 21th day, with the 14th day most significant. CCRT also caused an enhanced inflammation response and cell apoptosis in tongue in the control group. Moreover, CCRT increased the intestinal permeability through reducing the zonula occludens-1(ZO-1) and Claudin-1 expression in colon tissues and increasing the inflammation factors in bloods. The structure of gut microbiota was also disturbed in the control group mainly with the increasing abundance of Bacteroidetes and decreasing abundance of Firmicutes. However, probiotics mixture ameliorated the severity of OM, decreased the inflammation response, cell apoptosis, intestinal permeability, and restored the structure of gut microbiota to normal. Conclusions: The modified probiotic mixture significantly reduces the severity of OM through enhancing the immune response of patients and modifying structure of gut microbiota. Clinical trial information: NCT03112837.

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A Phase II Randomized Clinical Trial and Mechanistic Studies Using Improved Probiotics to Prevent Oral Mucositis Induced by Concurrent Radiotherapy and Chemotherapy in Nasopharyngeal Carcinoma

Frontiers in Immunology ◽

10.3389/fimmu.2021.618150 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chaofei Xia ◽

Chunling Jiang ◽

Wenyu Li ◽

Jing Wei ◽

Hu Hong ◽

...

Keyword(s):

Clinical Trial ◽

T Cells ◽

Placebo Group ◽

Inflammatory Response ◽

Gut Microbiota ◽

Intestinal Permeability ◽

Oral Mucositis ◽

Cell Apoptosis ◽

Trial Registration ◽

Clinical Trial Registration

Earlier evidence has proven that probiotic supplements can reduce concurrent chemoradiotherapy (CCRT)-induced oral mucositis (OM) in nasopharyngeal cancer (NPC). The incidence of severe OM (grade 3 or higher) was the primary endpoint in this study. We first enrolled 85 patients with locally advanced NPC who were undergoing CCRT. Of them, 77 patients were finally selected and randomized (1:1) to receive either a probiotic cocktail or placebo. To investigate the protective effects and the mechanism of probiotic cocktail treatment on OM induced by radiotherapy and chemotherapy, we randomly divided the rats into the control (C) group, the model (M) group, and the probiotic (P) group. After treatment, samples from the tongue, blood, and fecal and proximal colon tissues on various days (7th, 14th, and 21st days) were collected and tested for the inflammatory response, cell apoptosis, intestinal permeability, and intestinal microbial changes. We found that patients taking the probiotic cocktail showed significantly lower OM. The values of the incidence of 0, 1, 2, 3, and 4 grades of OM in the placebo group and in the probiotic cocktail group were reported to be 0, 14.7, 38.2, 32.4, and 14.7% and 13.9, 36.1, 25, 22.2, and 2.8%, respectively. Furthermore, patients in the probiotic cocktail group showed a decrease in the reduction rate of CD3+ T cells (75.5% vs. 81%, p < 0.01), CD4+ T cells (64.53% vs. 79.53%, p < 0.01), and CD8+ T cells (75.59 vs. 62.36%, p < 0.01) compared to the placebo group. In the rat model, the probiotic cocktail could ameliorate the severity of OM, decrease the inflammatory response, cause cell apoptosis and intestinal permeability, and restore the structure of gut microbiota to normalcy. In conclusion, the modified probiotic cocktail significantly reduces the severity of OM by enhancing the immune response of patients with NPC and modifying the structure of gut microbiota.Clinical Trial Registration: The Clinical Trial Registration should be the NCT03112837.

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Adjuvant Therapy of Renal Cell Carinoma Using Activated T Cells (Phase II Clinical Trial)

Journal of Immunotherapy ◽

10.1097/01.cji.0000190956.04419.5b ◽

2005 ◽

Vol 28 (6) ◽

pp. 615

Author(s):

Ann V LeFever ◽

Jonathan Treisman ◽

John P Hanson

Keyword(s):

Clinical Trial ◽

T Cells ◽

Adjuvant Therapy ◽

Phase Ii ◽

Renal Cell ◽

Phase Ii Clinical Trial ◽

Activated T Cells

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Effect of a 0.5% chlorhexidine gel on dental plaque superinfecting microorganisms in mentally handicapped patients

Pesquisa Odontológica Brasileira ◽

10.1590/s1517-74912003000300006 ◽

2003 ◽

Vol 17 (3) ◽

pp. 228-233 ◽

Cited By ~ 7

Author(s):

Cláudio Mendes Pannuti ◽

Roberto Fraga Moreira Lotufo ◽

Silvana Cai ◽

Maria da Conceição Saraiva ◽

Nívea Maria de Freitas ◽

...

Keyword(s):

Clinical Trial ◽

Placebo Group ◽

Dental Plaque ◽

Test Group ◽

Control Group ◽

Mentally Handicapped ◽

Bacterial Populations ◽

Gram Negative ◽

Supragingival Plaque ◽

Chlorhexidine Gel

A randomized clinical trial was conducted to investigate the effect of a 0.5% chlorhexidine (CHX) gel on dental plaque superinfecting microorganisms in mentally handicapped patients. Thirty inmates from the institution "Casas André Luiz" were assigned to either test group (CHX gel, n = 15) or control group (placebo gel, n = 15). The gel was administered over a period of 8 weeks. Supragingival plaque samples were collected at baseline, after gel use (8 weeks) and 16 weeks after baseline. The presence of Gram-negative Enterobacteriaceae, Staphylococcus and yeasts was evaluated. No significant growth of any superinfecting microorganism was observed in the CHX group, when compared to the placebo group. The results indicated that the 0.5% chlorhexidine gel did not produce an undesirable shift in these bacterial populations.

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Effect of vitamin D supplementation on disease activity (SLEDAI) and fatigue in Systemic Lupus Erythematosus patients with hipovitamin D: An Open Clinical Trial

Indonesian Journal of Rheumatology ◽

10.37275/ijr.v8i2.59 ◽

2018 ◽

Vol 8 (2) ◽

Author(s):

Achmad Rifa’i ◽

Handono Kalim ◽

Kusworini Kusworini ◽

Cesarius Singgih Wahono

Keyword(s):

Systemic Lupus Erythematosus ◽

Clinical Trial ◽

Vitamin D ◽

Placebo Group ◽

Disease Activity ◽

Lupus Erythematosus ◽

Vitamin D Supplementation ◽

Control Group ◽

Systemic Lupus ◽

Significant Difference

Background : Low level of vitamin D impact the disease activity and the degree of fatigue in SLE patients. This study aims to determine the effect of vitamin D supplementation on disease activity and fatigue condition in Systemic Lupus Erythematosus (SLE) patients with hipovitamin D.Methods: We performed an open clinical trial. Subjects were randomized into two different groups (supplementation or placebo) using simple random sampling. The treatment group got vitamin D3 softgel/ cholecalciferol 1200 IU/day or 30 mg/day, while the control group gotplacebo for 3 months. SLEDAI scores and FSS scores were calculated at pre and posttreatment.Results: There were 20 subjectsfor supplementation group and 19 subjects in the placebo group. From this study, before and after treatment, we found a significant difference of mean level of vitamin D in supplementation group (p=0.000), and no significant difference inpatients with placebo (p=0.427). Moreover, from the SLEDAI score analysis, observed a significant difference bothin the supplemented group (p=0.000) and the placebo group (p=0.006). FSS scores significantly different in the supplemented group (p=0.000). Incorrelation test,there was a negative correlation (r=-0763) between vitamin D level and disease activity (SLEDAI), and both showing stastistical significance between thepre supplementation (p=0.000) and post supplementation (r=-0846; p=0.000). Similarly to theFSS scores, there was a meaningfulnegative correlation (r=-0.931, p=0.000) between the level of vitamin D with FSS scores pre and post supplementation (r=-0.911; p= 0.000). Furthermore, there was a significant correlation between disease activity (SLEDAI) pre supplementation with fatigue condition pre supplementation (r=0.846; p = 0.000) and postsupplementation (r=0.913; p= 0.000).Conclusion: The supplementation of vitamin D 1200 IU per day in patients with SLE improve disease activity and degree of fatigue. Keywords: vitamin D, disease activity, fatigue, SLE

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Integrative analysis of the gut microbiome and metabolome in a rat model with stress induced irritable bowel syndrome

Scientific Reports ◽

10.1038/s41598-021-97083-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yue Hu ◽

Fang Chen ◽

Haiyong Ye ◽

Bin Lu

Keyword(s):

Irritable Bowel Syndrome ◽

Gut Microbiota ◽

Rat Model ◽

Gut Microbiome ◽

16S Rrna Gene Sequencing ◽

Metabolic Phenotype ◽

Control Group ◽

Rrna Gene ◽

Microbial Dysbiosis ◽

Irritable Bowel

AbstractStress is one of the major causes of irritable bowel syndrome (IBS), which is well-known for perturbing the microbiome and exacerbating IBS-associated symptoms. However, changes in the gut microbiome and metabolome in response to colorectal distention (CRD), combined with restraint stress (RS) administration, remains unclear. In this study, CRD and RS stress were used to construct an IBS rat model. The 16S rRNA gene sequencing was used to characterize the microbiota in ileocecal contents. UHPLC-QTOF-MS/MS assay was used to characterize the metabolome of gut microbiota. As a result, significant gut microbial dysbiosis was observed in stress-induced IBS rats, with the obvious enrichment of three and depletion of 11 bacterial taxa in IBS rats, when compared with those in the control group (q < 0.05). Meanwhile, distinct changes in the fecal metabolic phenotype of stress-induced IBS rats were also found, including five increased and 19 decreased metabolites. Furthermore, phenylalanine, tyrosine and tryptophan biosynthesis were the main metabolic pathways induced by IBS stress. Moreover, the altered gut microbiota had a strong correlation with the changes in metabolism of stress-induced IBS rats. Prevotella bacteria are correlated with the metabolism of 1-Naphthol and Arg.Thr. In conclusion, the gut microbiome, metabolome and their interaction were altered. This may be critical for the development of stress-induced IBS.

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Effects of high intake of cod or salmon on gut microbiota profile, faecal output and serum concentrations of lipids and bile acids in overweight adults: a randomised clinical trial

European Journal of Nutrition ◽

10.1007/s00394-020-02417-8 ◽

2020 ◽

Author(s):

Marianne Bratlie ◽

Ingrid V. Hagen ◽

Anita Helland ◽

Friedemann Erchinger ◽

Øivind Midttun ◽

...

Keyword(s):

Clinical Trial ◽

Gut Microbiota ◽

Bile Acids ◽

Gastrointestinal Disease ◽

Control Group ◽

Serum Concentrations ◽

High Intake ◽

Faecal Output ◽

End Point ◽

Total Bile Acids

Abstract Purpose To explore whether high intake of cod or salmon would affect gut microbiota profile, faecal output and serum concentrations of lipids and bile acids. Methods Seventy-six adults with overweight/obesity with no reported gastrointestinal disease were randomly assigned to consume 750 g/week of either cod or salmon, or to avoid fish intake (Control group) for 8 weeks. Fifteen participants from each group were randomly selected for 72 h faeces collection at baseline and end point for gut microbiota profile analyses using 54 bacterial DNA probes. Food intake was registered, and fasting serum and morning urine were collected at baseline and end point. Results Sixty-five participants were included in serum and urine analyses, and gut microbiota profile was analysed for 33 participants. Principal component analysis of gut microbiota showed an almost complete separation of the Salmon group from the Control group, with lower counts for bacteria in the Bacteroidetes phylum and the Clostridiales order of the Firmicutes phyla, and higher counts for bacteria in the Selenomonadales order of the Firmicutes phylum. The Cod group showed greater similarity to the Salmon group than to the Control group. Intake of fibres, proteins, fats and carbohydrates, faecal daily mass and output of fat, cholesterol and total bile acids, and serum concentrations of cholesterol, triacylglycerols, non-esterified fatty acids and total bile acids were not altered in the experimental groups. Conclusion A high intake of cod or salmon fillet modulated gut microbiota but did not affect faecal output or serum concentrations of lipids and total bile acids. Clinical trial registration This trial was registered at clinicaltrials.gov as NCT02350595.

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LIPid Intensive Drug therapy for Sepsis Pilot (LIPIDS-P): Phase I/II clinical trial protocol of lipid emulsion therapy for stabilising cholesterol levels in sepsis and septic shock

BMJ Open ◽

10.1136/bmjopen-2019-029348 ◽

2019 ◽

Vol 9 (9) ◽

pp. e029348 ◽

Cited By ~ 1

Author(s):

Faheem W Guirgis ◽

Lauren Page Black ◽

Martin Daniel Rosenthal ◽

Morgan Henson ◽

Jason Ferreira ◽

...

Keyword(s):

Clinical Trial ◽

Drug Therapy ◽

High Density Lipoprotein ◽

Phase I ◽

Cholesterol Level ◽

Phase Ii ◽

Lipid Emulsion ◽

Density Lipoprotein ◽

Control Group ◽

Cholesterol Levels

IntroductionSepsis is a life-threatening, dysregulated response to infection. Both high-density lipoprotein and low-density lipoprotein cholesterol should protect against sepsis by several mechanisms; however, for partially unknown reasons, cholesterol levels become critically low in patients with early sepsis who experience poor outcomes. An anti-inflammatory lipid injectable emulsion containing fish oil is approved by the Food and Drug Administration as parenteral nutrition for critically ill patients and may prevent this decrease in serum cholesterol levels by providing substrate for cholesterol synthesis and may favourably modulate inflammation. This LIPid Intensive Drug therapy for Sepsis Pilot clinical trial is the first study to attempt to stabilise early cholesterol levels using lipid emulsion as a treatment modality for sepsis.Methods and analysisThis is a two-centre, phase I/II clinical trial. Phase I is a non-randomised dose-escalation study using a Bayesian optimal interval design in which up to 16 patients will be enrolled to evaluate the safest and most efficacious dose for stabilising cholesterol levels. Based on phase I results, the two best doses will be used to randomise 48 patients to either lipid injectable emulsion or active control (no treatment). Twenty-four patients will be randomised to one of two doses of the study drug, while 24 control group patients will receive no drug and will be followed during their hospitalisation. The control group will receive all standard treatments mandated by the institutional sepsis alert protocol. The phase II study will employ a permuted blocked randomisation technique, and the primary endpoint will be change in serum total cholesterol level (48 hours − enrolment). Secondary endpoints include change in cholesterol level from enrolment to 7 days, change in Sequential Organ Failure Assessment score over the first 48 hours and 7 days, in-hospital and 28-day mortality, lipid oxidation status, inflammatory biomarkers, and high-density lipoprotein function.Ethics and disseminationInvestigators are trained and follow good clinical practices, and each phase of the study was reviewed and approved by the institutional review boards of each institution. Results of each phase will be disseminated through presentations at national meetings and publication in peer-reviewed journals. If promising, data from the pilot study will be used for a larger, multicentre, phase II clinical trial.Trial registration numberNCT03405870.

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A phase II study of anti-PD1 monoclonal antibody (Nivolumab) administered in combination with anti-LAG3 monoclonal antibody (Relatlimab) in patients with metastatic melanoma naive to prior immunotherapy in the metastatic setting.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.tps10085 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. TPS10085-TPS10085

Author(s):

Anjali Rohatgi ◽

Ryan Campbell Massa ◽

William E. Gooding ◽

Tullia C. Bruno ◽

Dario Vignali ◽

...

Keyword(s):

Clinical Trial ◽

Monoclonal Antibody ◽

T Cells ◽

T Cell ◽

Metastatic Melanoma ◽

Phase Ii ◽

Primary Endpoint ◽

Disease Assessment ◽

Survival Duration ◽

Metastatic Setting

TPS10085 Background: Novel checkpoint inhibitors are a promising treatment for advanced melanoma, as only a fraction of patients have durable responses to current FDA-approved immunotherapy. Lymphocyte activation gene 3 (LAG3) is an inhibitory checkpoint receptor on CD4+ and CD8+ T cells, where engagement results in suppression of T cell activation and proliferation. LAG3 and PD1 are co-expressed on T cells during T cell receptor signaling and are down-regulated after antigen clearance. Persistent stimulation leads to prolonged LAG3 and PD1 expression and to T cell exhaustion, a possible mechanism of resistance to immunotherapy. Both LAG3 and PD1 are expressed on tumor-infiltrating T cells in melanoma. Murine tumors treated with both anti-LAG3 and anti-PD1 have demonstrated increased tumor regression than tumors in mice treated with either single agent. Further, a phase I trial has demonstrated safety of combined anti-LAG3 monoclonal antibody, relatlimab and anti-PD1 monoclonal antibody, nivolumab. Methods: This phase II, single-center clinical trial is designed to enroll treatment naive patients with unresectable or metastatic melanoma to ultimately receive combined relatlimab and nivolumab after a lead-in arm where patients are randomized to receive relatlimab, nivolumab, or the combination for the first 4 week cycle. For the lead-in phase, patients will have baseline and post-treatment blood and tumor sampling. Disease assessment by imaging will occur after the lead-in phase at 4 weeks. After completion of the lead-in phase, all patients proceed to combination therapy with disease assessment at 12-week intervals. The primary endpoint for the lead-in phase is to evaluate changes in immune cell populations in peripheral blood and tumor with the single agents and combination treatment. The primary endpoint for the combination phase is best overall anti-tumor response. Secondary clinical endpoints include progression-free survival, overall survival, duration of response and toxicity. Exploratory endpoints are to determine the mechanistic effects of anti-LAG3 and anti-PD1 on the blood and tumor microenvironment, cytokine signatures, and correlation of these with clinical response. The study is currently accruing with enrollment of 9 out of 42 patients. Clinical trial information: NCT03743766.

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Safety and efficacy of hydroxychloroquine for treatment of non-severe COVID-19 among adults in Uganda: a randomized open label phase II clinical trial

BMC Infectious Diseases ◽

10.1186/s12879-021-06897-9 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Pauline Byakika-Kibwika ◽

Christine Sekaggya-Wiltshire ◽

Jerome Roy Semakula ◽

Jane Nakibuuka ◽

Joseph Musaazi ◽

...

Keyword(s):

Clinical Trial ◽

Viral Load ◽

Adverse Events ◽

Phase Ii ◽

Intervention Group ◽

Viral Clearance ◽

Control Group ◽

Rt Pcr ◽

Open Label ◽

Open Label Phase

Abstract Background Several repurposed drugs such as hydroxychloroquine (HCQ) have been investigated for treatment of COVID-19, but none was confirmed to be efficacious. While in vitro studies have demonstrated antiviral properties of HCQ, data from clinical trials were conflicting regarding its benefit for COVID-19 treatment. Drugs that limit viral replication may be beneficial in the earlier course of the disease thus slowing progression to severe and critical illness. Design We conducted a randomized open label Phase II clinical trial from October–December 2020. Methods Patients diagnosed with COVID-19 using RT-PCR were included in the study if they were 18 years and above and had a diagnosis of COVID-19 made in the last 3 days. Patients were randomized in blocks, to receive either HCQ 400 mg twice a day for the first day followed by 200 mg twice daily for the next 4 days plus standard of care (SOC) treatment or SOC treatment alone. SARS COV-2 viral load (CT values) from RT-PCR testing of samples collected using nasal/orapharyngeal swabs was performed at baseline, day 2, 4, 6, 8 and 10. The primary outcome was median time from randomization to SARS COV-2 viral clearance by day 6. Results Of the 105 participants enrolled, 55 were assigned to the intervention group (HCQ plus SOC) and 50 to the control group (SOC only). Baseline characteristics were similar across treatment arms. Viral clearance did not differ by treatment arm, 20 and 19 participants respectively had SARS COV-2 viral load clearance by day 6 with no significant difference, median (IQR) number of days to viral load clearance between the two groups was 4(3–4) vs 4(2–4): p = 0.457. There were no significant differences in secondary outcomes (symptom resolution and adverse events) between the intervention group and the control group. There were no significant differences in specific adverse events such as elevated alkaline phosphatase, prolonged QTc interval on ECG, among patients in the intervention group as compared to the control group. Conclusion Our results show that HCQ 400 mg twice a day for the first day followed by 200 mg twice daily for the next 4 days was safe but not associated with reduction in viral clearance or symptom resolution among adults with COVID-19 in Uganda. Trial registration: NCT04860284.

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