Abstract
Background
Recurrent Clostridioides difficile infection (rCDI) is associated with loss of microbial diversity and microbe-derived secondary bile acids, which inhibit C. difficile germination ...and growth. SER-109, an investigational microbiome drug of donor-derived, purified spores, reduced recurrence in a dose-ranging, phase (P) 1 study in subjects with multiple rCDIs.
Methods
In a P2 double-blind trial, subjects with clinical resolution on standard-of-care antibiotics were stratified by age (< or ≥65 years) and randomized 2:1 to single-dose SER-109 or placebo. Subjects were diagnosed at study entry by PCR or toxin testing. Safety, C. difficile–positive diarrhea through week 8, SER-109 engraftment, and bile acid changes were assessed.
Results
89 subjects enrolled (67% female; 80.9% diagnosed by PCR). rCDI rates were lower in the SER-109 arm than placebo (44.1% vs 53.3%) but did not meet statistical significance. In a preplanned analysis, rates were reduced among subjects ≥65 years (45.2% vs 80%, respectively; RR, 1.77; 95% CI, 1.11–2.81), while the <65 group showed no benefit. Early engraftment of SER-109 was associated with nonrecurrence (P < .05) and increased secondary bile acid concentrations (P < .0001). Whole-metagenomic sequencing from this study and the P1 study revealed previously unappreciated dose-dependent engraftment kinetics and confirmed an association between early engraftment and nonrecurrence. Engraftment kinetics suggest that P2 dosing was suboptimal. Adverse events were generally mild to moderate in severity.
Conclusions
Early SER-109 engraftment was associated with reduced CDI recurrence and favorable safety was observed. A higher dose of SER-109 and requirements for toxin testing were implemented in the current P3 trial.
Clinical Trials Registration
NCT02437487, https://clinicaltrials.gov/ct2/show/NCT02437487?term=SER-109&draw= 2&rank=4.
In a phase 2 trial, SER-109, an investigational microbiome drug, did not reduce rates of recurrent CDI, despite a previously successful open-label study. Key contributing factors, which led to a redesign of the currently enrolling phase 3 trial, are highlighted.
Firmicutes bacteria produce metabolites that maintain the intestinal barrier and mucosal immunity. Firmicutes are reduced in the intestinal microbiota of patients with ulcerative colitis (UC). In a ...phase 1b trial of patients with UC, we evaluated the safety and efficacy of SER-287, an oral formulation of Firmicutes spores, and the effects of vancomycin preconditioning on expansion (engraftment) of SER-287 species in the colon.
We conducted a double-blind trial of SER-287 in 58 adults with active mild-to-moderate UC (modified Mayo scores 4–10, endoscopic subscores ≥1). Participants received 6 days of preconditioning with oral vancomycin (125 mg, 4 times daily) or placebo followed by 8 weeks of oral SER-287 or placebo. Patients were randomly assigned (2:3:3:3) to groups that received placebo followed by either placebo or SER-287 once weekly, or vancomycin followed by SER-287 once weekly, or SER-287 once daily. Clinical end points included safety and clinical remission (modified Mayo score ≤2; endoscopic subscores 0 or 1). Microbiome end points included SER-287 engraftment (dose species detected in stool after but not before SER-287 administration). Engraftment of SER-287 and changes in microbiome composition and associated metabolites were measured by analyses of stool specimens collected at baseline, after preconditioning, and during and 4 weeks after administration of SER-287 or placebo.
Proportions of patients with adverse events did not differ significantly among groups. A higher proportion of patients in the vancomycin/SER-287 daily group (40%) achieved clinical remission at week 8 than patients in the placebo/placebo group (0%), placebo/SER-287 weekly group (13.3%), or vancomycin/SER-287 weekly group (17.7%) (P = .024 for vancomycin/SER-287 daily vs placebo/placebo). By day 7, higher numbers of SER-287 dose species were detected in stool samples from all SER-287 groups compared with the placebo group (P < .05), but this difference was not maintained beyond day 7 in the placebo/SER-287 weekly group. In the vancomycin groups, a greater number of dose species were detected in stool collected on day 10 and all subsequent time points through 4 weeks post dosing compared with the placebo group (P < .05). A higher number of SER-287 dose species were detected in stool samples on days 7 and 10 from subjects who received daily vs weekly SER-287 doses (P < .05). Changes in fecal microbiome composition and metabolites were associated with both vancomycin/SER-287 groups.
In this small phase 1b trial of limited duration, the safety and tolerability of SER-287 were similar to placebo. SER-287 after vancomycin was significantly more effective than placebo for induction of remission in patients with active mild to moderate UC. Engraftment of dose species was facilitated by vancomycin preconditioning and daily dosing of SER-287. ClinicalTrials.gov ID NCT02618187.
Display omitted
Between February 1993 and September 1995, 739 patients with metastatic breast cancer were entered on an Intergroup trial (E1193) comparing doxorubicin (60 mg/m(2)), paclitaxel (175 mg/m(2)/24 h), and ...the combination of doxorubicin and paclitaxel (AT, 50 mg/m(2) and 150 mg/m(2)/24 h, plus granulocyte colony-stimulating factor 5 mg/kg) as first-line therapy. Patients receiving single-agent doxorubicin or paclitaxel were crossed over to the other agent at time of progression.
Patients were well balanced for on-study characteristics.
Responses (complete response and partial response) were seen in 36% of doxorubicin, 34% of paclitaxel, and 47% of AT patients (P =.84 for doxorubicin v paclitaxel, P =.007 for v AT, P =.004 for paclitaxel v AT). Median time to treatment failure (TTF) is 5.8, 6.0, and 8.0 months for doxorubicin, paclitaxel, and AT, respectively (P =.68 for doxorubicin v paclitaxel, P =.003 for doxorubicin v AT, P =.009 for paclitaxel v AT). Median survivals are 18.9 months for patients taking doxorubicin, 22.2 months for patients taking paclitaxel, and 22.0 months for patients taking AT (P = not significant). Responses were seen in 20% of patients crossing from doxorubicin --> paclitaxel and 22% of patients crossing from paclitaxel --> doxorubicin (P = not significant). Changes in global quality-of-life measurements from on-study to week 16 were similar in all three groups.
(1) doxorubicin and paclitaxel, in the doses used here, have equivalent activity; (2) the combination of AT results in superior overall response rates and time to TTF; and (3) despite these results, combination therapy with AT did not improve either survival or quality of life compared to sequential single-agent therapy.
The excess risk of second malignancy after Hodgkin disease is an increasing problem. In light of the long-term data, guidelines for follow-up of survivors of Hodgkin disease need to be redefined. In ...this study we attempt to analyze the long-term risks and temporal trends, identify patient- and treatment-related risk factors, and determine the prognosis of patients who develop a second malignancy after radiation treatment with or without chemotherapy for Hodgkin disease. Among 1319 patients with clinical stage I-IV Hodgkin disease, 181 second malignancies and 18 third malignancies were observed. With a median follow-up of 12 years, the relative risk (RR) and absolute excess risk of second malignancy were 4.6 and 89.3/10 000 person-years. The RR was significantly higher with combined chemotherapy and radiation therapy (6.1) than with radiation therapy alone (4.0, P = .015). The risk increased with increasing radiation field size (P = .03) in patients who received combined modality therapy, and with time after Hodgkin disease. After 15 and 20 years, there was a 2.3% and 4.0% excess risk of second malignancy per person per year. The 5-year survival after development of a second malignancy was 38.1%, with the worst prognosis seen after acute leukemia and lung cancer. The excess risk of second malignancy after Hodgkin disease continues to be increased after 15 to 20 years, and there does not appear to be a plateau. Our analysis suggests that the risk may be reduced with smaller radiation fields, as are used in current trials of abbreviated chemotherapy and limited-field radiation therapy.
To analyze the long-term survival and the pattern and timing of excess mortality in patients with early-stage Hodgkin's disease.
Between 1969 and 1997, 1,080 patients age 50 or younger were treated ...for clinical stage IA to IIB Hodgkin's disease. Overall survival was determined, and prognostic factors were assessed. Relative risk and absolute excess risk (AR) of mortality were calculated for the entire cohort and by prognostic groups (on the basis of B symptoms, mediastinal status, and number of sites, modified from the European Organization for Research and Treatment of Cancer).
The median follow-up was 12 years. The 15- and 20-year Kaplan-Meier survival estimates were 84% and 78%, respectively. Cox proportional hazards models showed that number of involved sites (P =.006), mediastinal status (P =.02), and histology (P =.02) were independent predictors of death from all causes. The AR of mortality in patients with a favorable prognosis increased over time, whereas for those with an unfavorable prognosis, the AR peaked in the first 5 years, predominantly from Hodgkin's disease. The relative risk of mortality from all causes, causes other than Hodgkin's disease, second tumors, and cardiac disease remained significantly elevated more than 20 years after treatment.
Patients treated for early-stage Hodgkin's disease have a sustained excess mortality risk despite good control of the disease. Treatment reduction efforts in patients with early-stage, favorable-prognosis disease should continue, but for patients with an unfavorable prognosis, modified treatment may not be advisable. The excess mortality noted beyond two decades underscores the importance of long-term follow-up care in patients treated for Hodgkin's disease.
Objective. We sought to compare daptomycin with ceftriaxone for the treatment of patients with community-acquired pneumonia (CAP). Methods. Two phase-3 randomized, double-blind trials that enrolled ...adult patients hospitalized with CAP were conducted. Patients received intravenous daptomycin (4 mg/kg) or ceftriaxone (2 g) once daily for 5–14 days. Aztreonam could be added for patients with gram-negative infections. Clinical responses at the test-of-cure visit among patients in the intent-to-treat and clinically evaluable populations were the primary efficacy end points. Results. After combining data from the trials, the intent-to-treat population included 413 daptomycin-treated patients and 421 ceftriaxone-treated patients, and the clinically evaluable population included 369 daptomycin-treated patients and 371 ceftriaxone-treated patients. In the intent-to-treat population, the clinical cure rate among daptomycin-treated patients with CAP was 70.9%, compared with 77.4% among ceftriaxone-treated patients (95% confidence interval for the difference between cure rates, −12.4% to −0.6%). In the clinically evaluable population, the clinical cure rate was lower among daptomycin-treated patients (79.4%) than among ceftriaxone-treated patients (87.9%; 95% confidence interval for the difference between cure rates, −13.8% to −3.2%). A posthoc analysis revealed that, among those who had received up to 24 h of prior effective therapy, cure rates were similar among daptomycin-treated (90.7%) and ceftriaxone-treated patients (88.0%; 95% confidence interval for the difference between cure rates, −6.1% to 11.5%). Conclusions. Daptomycin is not effective for the treatment of CAP, including infections caused by Streptococcus pneumoniae and Staphylococcus aureus. The observation that as little as 24 h of prior effective therapy may impact clinical outcome suggests that trials to evaluate CAP treatment may need to exclude patients who have received any potentially effective therapy before enrollment.
To determine whether a matrix metalloproteinase inhibitor improves progression-free survival (PFS) in patients with metastatic breast cancer who have responding or stable disease after first-line ...chemotherapy.
One hundred seventy-nine eligible patients were randomly assigned to receive oral marimastat (10 mg bid; n = 114) or a placebo (n = 65) within 3 to 6 weeks of completing six to eight cycles of first-line doxorubicin- and/or taxane-containing chemotherapy for metastatic disease. Patients were evaluated every 3 months until disease progression.
When comparing placebo with marimastat, there was no significant difference in PFS (median, 3.1 months v 4.7 months, respectively; hazard ratio, 1.26; 95% CI, 0.91 to 1.74; P = .16) or overall survival (median, 26.6 months v 24.7 months, respectively; hazard ratio, 1.03; 95% CI, 0.73 to 1.46; P = .86). Patients treated with marimastat were more likely to develop grade 2 or 3 musculoskeletal toxicity (MST), a known complication of the drug indicative of achieving a biologic effect, compared with patients administered placebo (63% v 22%, respectively; P < .0001). Patients with grade 2 or 3 MST had significantly inferior survival compared with patients who had grade 0 or 1 MST (median, 22.5 months v 28.2 months; P = .04). In addition, patients who had a marimastat plasma concentration of at least 10 ng/mL at month 1 and/or 3 were significantly more likely to have grade 2 to 3 MST (P < .0001).
Marimastat does not prolong PFS when used after first-line chemotherapy for metastatic breast cancer. Patients with higher marimastat levels exhibited MST, and MST was associated with inferior survival.
Key Clinical Message
Spindle epithelial tumor with thymus‐like element should be included in the differential diagnosis of thyroid gland cancers, particularly in medullary carcinoma, younger patients ...and indolent clinical presentation, because it may influence treatment and prognosis.
Nitrate and nitrites are used to give the characteristic color to cured meat products and to preserve them. According to the scientific knowledge available at the moment, these compounds are approved ...as food additives based on a detailed ponderation between the potential risks and benefits. The controversy over nitrites has increased with the release of an IARC Monograph suggesting an association between colorectal cancer and dietary nitrite in processed meats. The trend in "clean label" products reinforced the concern of consumers about nitrates and nitrites in meat products. This review aims to explain the role of nitrates and nitrites used in meat products. The potential chemical hazards and health risks linked to the consumption of cured meat products are described. Different strategies aiming to replace synthetic nitrate and nitrite and obtain green-label meat products are summarized, discussing their impact on various potential hazards. In the light of the present knowledge, the use or not of nitrite is highly dependent on the ponderation of two main risks-the eventual formation of nitrosamines or the eventual out-growth of severe pathogens. It is evident that synthetic nitrite and nitrate alternatives must be researched, but always considering the equilibrium that is the safety of a meat product.
PDF
