Prophylactic treatment of irinotecan-induced diarrhea with neomycin (a randomized, placebo-controlled, double-blind study)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3626-3626
Author(s):  
R. H. Mathijssen ◽  
F. A. De Jong ◽  
D. F. Kehrer ◽  
R. H. Van Schaik ◽  
J. Verweij ◽  
...  
Keyword(s):  
Prophylactic Treatment ◽  
Plasma Concentrations ◽  
Aminoglycoside Antibiotic ◽  
Concomitant Administration ◽  
Patient Characteristics ◽  
Common Side Effect ◽  
Double Blind Study ◽  
Double Blind ◽  
Severe Diarrhea ◽  
Grade 3

3626 Background: Delayed-type diarrhea is a common side-effect of irinotecan, and is associated with a bacterial-mediated formation of the active irinotecan metabolite SN-38 from its glucuronide conjugate in the intestines. We hypothesized that concomitant administration of the aminoglycoside antibiotic neomycin would diminish exposure of the gut to SN-38, ameliorating the incidence of diarrhea. Methods: Patients were treated with irinotecan in a randomized, placebo-controlled, double-blind trial. In arm A, patients received irinotecan (350 mg/m2 i.v. for 90 minutes once every 3 weeks) combined with neomycin (660 mg orally 3 times daily for 3 consecutive days, starting 2 days before chemotherapy). In arm B, patients received the same irinotecan regimen with placebo. To detect a 50% reduction to less than grade 2 diarrhea (power=.80; P=.05), 60 patients had to be studied. Blood samples for additional pharmacokinetic and pharmacogenetic analyses were obtained after separate informed consent. Results: Sixty-two patients were evaluable for toxicity analysis. Relevant baseline patient characteristics (P>.06), SN-38 plasma concentrations (P=.80; N=43), and UGT1A1*28 genotype status (P=.58; N=52) were similar in both arms. Distribution, severity, and duration of diarrhea did not differ significantly between both arms (P>.32), although grade 3 diarrhea tended to be less frequent in the neomycin arm (45% reduction; P=.19). Grade 2 nausea was more common in this arm (39% vs. 9%; P<.01). The presence of at least one UGT1A1*28 allele was strongly related to the incidence of grade 2–3 diarrhea (69% vs. 34%; P=.01). Conclusions: Our results do not suggest a role for neomycin in the prophylactic treatment of irinotecan-induced diarrhea. In addition, neomycin does not influence systemic SN-38 pharmacokinetics. Also, it is suggested that each patient’s UGT1A1*28 genotype status could be used as a prospective screening tool to prevent severe diarrhea. No significant financial relationships to disclose.

Unexpected Reduction in Migraine and Psychogenic Headaches Following rTMS Treatment for Major Depression: A Report of Two Cases

CNS Spectrums ◽  
2007 ◽  
Vol 12 (12) ◽  
pp. 921-925 ◽  
Author(s):  
John P. O'Reardon ◽  
Jeisson F. Fontecha ◽  
Mario A. Cristancho ◽  
Suzanne Newman
Keyword(s):  
Antidepressant Treatment ◽  
Repetitive Transcranial Magnetic Stimulation ◽  
Common Side Effect ◽  
Double Blind Study ◽  
Double Blind ◽  
Positive Effects ◽  
Diagnostic And Statistical Manual ◽  
Headache Pain ◽  
Psychogenic Headaches ◽  
Maintenance Intervention

ABSTRACTOur objective is to report a coincident reduction in headache pain in patients treated with repetitive transcranial magnetic stimulation (rTMS) for major depressive disorder (MDD). Two patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of MDD, non-responsive to prior antidepressant treatment who were enrolled in a sham-controlled, double-blind study of rTMS for MDD. After the study, it was revealed that both were in the active-treatment arm. Both patients suffered from near daily headaches and kept logs of headache frequency and severity before, during, and after the study. Headache pain was significantly reduced under double-blind conditions with rTMS treatment, but returned to baseline following cessation of rTMS treatment. Ultimately, when receiving rTMS post-study as a maintenance intervention for MDD (~2 rTMS sessions/week), the positive effects on headache amelioration were sustained. Headache pain is frequently comorbid with mood disorders and has been reported as the most common side effect with rTMS. In these subjects, rTMS was, in fact, associated with relief of depressive symptoms and preexisting headache pain. This indicates that rTMS may be beneficial for both disorders in some patients.

Final results from ClarIDHy, a global, phase 3, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4069-4069
Author(s):  
Ghassan K. Abou-Alfa ◽  
Teresa Macarulla ◽  
Milind M. Javle ◽  
Robin Kate Kelley ◽  
Sam Joseph Lubner ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Primary Endpoint ◽  
Failure Time ◽  
Objective Response ◽  
Idh1 Mutation ◽  
High Rate ◽  
Double Blind Study ◽  
Double Blind ◽  
Grade 3

4069 Background: CCA is a rare cancer for which there are limited effective therapies. IDH1 mutations occur in ̃20% of intrahepatic CCAs, resulting in production of the oncometabolite D-2-hydroxyglutarate, which promotes oncogenesis. IVO (AG-120) is a first-in-class, oral, small-molecule inhibitor of mutant IDH1 (mIDH1). ClarIDHy aimed to demonstrate the efficacy of IVO vs PBO in pts with unresectable or metastatic m IDH1 CCA. The primary endpoint was met with significant improvement in progression-free survival (PFS) by independent radiology center (IRC) with IVO vs PBO (hazard ratio [HR] = 0.37, p < 0.0001). Objective response rate (ORR) and stable disease for IVO were 2.4% (3 partial responses) and 50.8% (n = 63) vs 0% and 27.9% (n = 17) for PBO. IVO pts experienced significantly less decline in physical and emotional functioning domains of quality of life at cycle 2 day 1 vs PBO pts (nominal p < 0.05). Methods: Pts with m IDH1 CCA were randomized 2:1 to IVO (500 mg PO QD) or matched PBO and stratified by prior systemic therapies (1 or 2). Key eligibility: unresectable or metastatic m IDH1 CCA based on central testing; ECOG PS 0–1; measurable disease (RECIST v1.1). Crossover from PBO to IVO was permitted at radiographic progression. Primary endpoint: PFS by IRC. Secondary endpoints included overall survival (OS; by intent-to-treat), ORR, PFS (by investigator), safety, and quality of life. The planned crossover-adjusted OS was derived using the rank-preserving structural failure time (RPSFT) model. Results: As of 31 May 2020, ̃780 pts were prescreened for an IDH1 mutation and 187 were randomized to IVO (n = 126) or PBO (n = 61); 13 remain on IVO. Median age 62 y; M/F 68/119; 91% intrahepatic CCA; 93% metastatic disease; 47% had 2 prior therapies. 70% of PBO pts crossed over to IVO. OS data were mature, with 79% OS events in IVO arm and 82% in PBO. Median OS (mOS) was 10.3 months for IVO and 7.5 months for PBO (HR = 0.79; 95% CI 0.56–1.12; one-sided p = 0.093). The RPSFT-adjusted mOS was 5.1 months for PBO (HR = 0.49; 95% CI 0.34–0.70; p < 0.0001). Common all-grade treatment emergent adverse events (TEAEs, ≥ 15%) in the IVO arm: nausea 41%, diarrhea 35%, fatigue 31%, cough 25%, abdominal pain 24%, decreased appetite 24%, ascites 23%, vomiting 23%, anemia 18%, and constipation 15%. Grade ≥ 3 TEAEs were reported in 50% of IVO pts vs 37% of PBO pts, with grade ≥ 3 treatment-related AEs in 7% of IVO pts vs 0% in PBO. 7% of IVO pts experienced an AE leading to treatment discontinuation vs 9% of PBO pts. There were no treatment-related deaths. Conclusions: IVO was well tolerated and resulted in a favorable OS trend vs PBO despite a high rate of crossover. These data – coupled with statistical improvement in PFS, supportive quality of life data, and favorable safety profile – demonstrate the clinical benefit of IVO in advanced m IDH1 CCA. Clinical trial information: NCT02989857.

scholarly journals Effect of Clarithromycin on Inflammatory Markers in Patients with Atherosclerosis

2003 ◽  
Vol 10 (4) ◽  
pp. 525-528 ◽  
Author(s):  
Hans F. Berg ◽  
Boulos Maraha ◽  
Gert-Jan Scheffer ◽  
Marcel F. Peeters ◽  
Jan A. J. W. Kluytmans
Keyword(s):  
Inflammatory Markers ◽  
Interleukin 2 ◽  
Patient Characteristics ◽  
Double Blind Study ◽  
Double Blind ◽  
Necrosis Factor Alpha ◽  
Treatment Groups ◽  
Reactive Protein ◽  
Factor Alpha ◽  
Artery Disease

ABSTRACT Atherosclerosis can to a certain extent be regarded as an inflammatory disease. Also, inflammatory markers may provide information about cardiovascular risk. Whether macrolide antibiotics, especially clarithromycin, have an anti-inflammatory effect in patients with atherosclerosis is not exactly known. To study this phenomenon, a placebo-controlled, randomized, double-blind study was performed. A total of 231 patients with documented coronary artery disease received a daily dose of either 500 mg of slow-release clarithromycin or placebo until the day of surgery. Levels of inflammatory markers (C-reactive protein, interleukin-2 receptor [IL-2R], IL-6, IL-8, and tumor necrosis factor alpha) were assessed during the preoperative outpatient visit, on the day of surgery, and 8 weeks after surgery. Also, changes in the levels of inflammatory markers between visits were determined by delta calculations. Baseline patient characteristics were balanced between the two treatment groups: the average age was 66 years (standard deviation [SD] = 9.0), 79% of the patients were male, and the average number of tablets used was 16 (SD = 9.3). The inflammatory markers of the groups as well as the delta calculations were not significantly changed. Treatment with clarithromycin did not influence the inflammatory markers in patients with atherosclerosis.

scholarly journals 2712. Safety and Immunogenicity of two Doses of ExPEC4V Vaccine Against Extraintestinal Pathogenic Escherichia coli Disease in Healthy Adult Participants

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S954-S954
Author(s):  
William B Smith ◽  
Darren Abbanat ◽  
Bart Spiessens ◽  
Oscar Go ◽  
Wouter Haazen ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Immune Responses ◽  
Geometric Mean ◽  
Protein A ◽  
Fold Increase ◽  
Vaccine Safety ◽  
Double Blind Study ◽  
Double Blind ◽  
Grade 3 ◽  
O Antigens

Abstract Background The ExPEC4V vaccine contains 4 Escherichia coli O-antigens (O1A, O2, O6A, O25B) conjugated to exotoxin protein A and is being studied for prevention of Invasive Extraintestinal pathogenic E. coli (ExPEC) Disease (IED). This phase-2 double-blind study assessed safety and immunogenicity of ExPEC4V Clinical Trial Material (CTM), manufactured via a redesigned process (optimized O1A strain). Methods Participants (≥18 years) in stable health were randomized (3:1) to receive ExPEC4V dose 4:4:4:8 μg PS/serotype or placebo on Day 1 and second vaccination on Day 181 (6 months after first vaccination). Participants will be followed for safety until end of study at Day 360. Reactogenicity and immunogenicity (by ELISA, opsonophagocytic killing [OPA] assays) were evaluated pre-vaccination, and 15 days after first and second vaccinations (Day 195). Results Of 100 participants randomized (mean age 56, 48% males) and vaccinated (ExPEC4V, n = 75; placebo, n = 25), 97 completed Day 30. Solicited local AEs were higher for ExPEC4V (38.7%) than placebo (20%); most frequent was pain/tenderness (38.7% vs 20%). Solicited systemic AEs were higher in ExPEC4V (49.3%) than placebo (20%); most frequent was fatigue (32% vs. 12%). No serious or grade 3 solicited local AEs were reported. One participant in ExPEC4V experienced a grade 3 solicited systemic fatigue considered vaccine-related by investigator. ExPEC4V demonstrated immune responses against all serotypes at Day 15. Geometric mean titer effective concentration rank by serotypes was O2 > O1A > O6 > O25B (Figures 1 and 2). At Day 15, ≥ 82% of participants in ExPEC4V and none in placebo had ≥2-fold increase from baseline of ELISA titer for all serotypes. In ExPEC4V, ≥47% had ≥2-fold increase from baseline of OPA titer for all serotypes, while 8% in placebo had ≥2-fold increase only for O6A. Good correlation was observed between ELISA and OPA across serotypes (r ≥ 0.76). Conclusion ExPEC4V elicited robust and functional immune responses across all serotypes and was well tolerated with no vaccine safety findings. This study supports the development of future multivalent ExPEC vaccine to prevent IED. Disclosures All authors: No reported disclosures.

Temelastine, a New H1-Receptor Antagonist

1986 ◽  
Vol 14 (4) ◽  
pp. 200-204 ◽  
Author(s):  
Fred Alexander ◽  
Robert M Stote ◽  
Nancy Allison ◽  
Robert G Familiar ◽  
Dianne Tatoian ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Plasma Concentrations ◽  
Controlled Study ◽  
Blood Levels ◽  
Double Blind Study ◽  
Double Blind ◽  
The Central Nervous System ◽  
H1 Receptor Antagonist ◽  
Oral Doses ◽  
Wheal Size

Temelastine is a selective, competitive histamine H1-receptor antagonist which does not penetrate the central nervous system. The effect of varying doses of temelastine was compared in a randomized, double-blind, controlled study by measuring the inhibition of cutaneous histamine wheals. In twelve subjects single oral doses of 50, 100 and 200 mg of temelastine produced dose-dependent reductions in wheal areas. The inhibition of wheal size was maximal by 2 hr after dosing and was present at 8 hr. At 2 hr the 50, 100, and 200 mg doses reduced the wheal size by 53, 64, and 78%, respectively. Chlorpheniramine, 4 mg, reduced wheal size by 32% at the same period. The ability of temelastine to antagonize the histamine-induced skin reaction over 20 hr was evaluated in a second randomized, double-blind study. Eight subjects participated. Temelastine, 100 mg, produced reductions of 64, 49, 56 and 51% in histamine wheal area at 8, 12, 16 and 20 hr, respectively. Plasma concentrations at these times were 4.04, 2.77, 1.88, and 1.44 μmol/l, respectively. These data suggest that blood levels as low as 1.44 μmol/l may be sufficient to produce an antihistaminic effect, and that daily or twice daily dosing with 100 mg may be adequate to control allergic symptoms.

Celiac disease and chemotherapy

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 19561-19561
Author(s):  
S. I. Robinson ◽  
J. Murray ◽  
R. R. McWilliams
Keyword(s):  
Celiac Disease ◽  
Retrospective Chart Review ◽  
Uterine Sarcoma ◽  
Gluten Free Diet ◽  
Common Side Effect ◽  
Gluten Free ◽  
Severe Diarrhea ◽  
High Incidence ◽  
Grade 3 ◽  
Severe Grade

19561 Background: Diarrhea is a common side effect of chemotherapy (CT). At times, often unpredictably, patients develop profound diarrhea during CT. Though the clinical diagnosis of celiac disease (CD) is relatively rare, (1/ 2000), the serologic prevalence is much higher (1/ 133), suggesting a large number of undiagnosed cases. Latent CD may be unmasked by stressors, such as CT. We hypothesized that undiagnosed CD may account for some cases of severe diarrhea from CT. Methods: We performed a retrospective chart review at the Mayo Clinic (1980–2006) for patients with diagnoses of cancer and CD that received CT at our center. CD cases were confirmed by biopsy (n= 25) or serologic studies. Data analyzed included severe (grade ≥ 3,) diarrhea while on CT, site of primary cancer, diagnosis of CD prior to or after CT, and specific CT agents received. Results: We identified 27 patients with CD and cancer (12 lymphoma, 6 gastrointestinal, 2 leukemia, 2 breast, 1 brain, bladder, lung, uterine, sarcoma) who received CT at our center. Fifteen were diagnosed with CD prior to receiving CT and 12 after, with the former group presumably on a gluten-free diet. One patient was excluded for lack of clinical data. Five of remaining 14 patients (35%) managed for their CD prior to CT had diarrhea, though 4 of these 5 had only mild diarrhea (gr. 1). One patient suffered gr. 3 diarrhea, though was reported to be poorly compliant with his diet. Three patients received treatment with 5- fluorouracil (5FU), and 2 had gr. 1 diarrhea. Five of the 12 patients (42%) with celiac disease undiagnosed prior to CT were reported to have diarrhea during treatment (3 gr. 4; 2 gr. 1). Of those receiving 5FU, 3 out of 4 had severe (gr. 4) diarrhea. The small numbers of patients precluded meaningful statistical analysis. Conclusion: Patients with known CD compliant with a gluten-free diet tolerated CT well. However, in a subset of undiagnosed patients, severe diarrhea developed during CT, most notably with 5FU-based regimens. We propose that when patients have diarrhea disproportionate to other effects, CD should be considered. Also, in malignancies with a high incidence of CD such as lymphoma and small bowel cancer, underlying CD should be considered before CT is given. No significant financial relationships to disclose.

Efficacy and tolerability of bevacizumab (BEV) plus capecitabine and cisplatin (XP) in Chinese patients (pts) with locally advanced or metastatic gastric/gastroesophageal junction cancer (AGC): Results from the AVATAR study.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 73-73 ◽  
Author(s):  
Lin Shen ◽  
Jin Li ◽  
Jian-Ming Xu ◽  
Hong-Ming Pan ◽  
Guanghai Dai ◽  
...  
Keyword(s):  
Gastroesophageal Junction ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Chinese Patients ◽  
Double Blind Study ◽  
Double Blind ◽  
Gastroesophageal Junction Cancer ◽  
The Difference ◽  
Grade 3

73 Background: In the AVAGAST study, chemotherapy (fluoropyrimidine and cisplatin) + BEV did not significantly improve overall survival (OS) vs. chemotherapy + placebo. Geographic differences in efficacy were observed, but only 12 Chinese pts were included. AVATAR, a study similar in design to AVAGAST, is a randomized double-blind study conducted exclusively in China in pts with AGC. Methods: Pts aged >18 years with gastric adenocarcinoma were randomized 1:1 to XP + BEV 7.5 mg/kg or placebo + XP. The primary objective was OS; secondary objectives included progression-free survival (PFS) and safety. Results: Baseline characteristics of the 202 pts were well balanced. The primary efficacy endpoint of improved OS in the BEV arm was not met (HR 1.11, 95% CI 0.79–1.56; p=0.5567; see table ). BEV + XP was well tolerated. Grade 3–5 adverse events (AEs) and serious AEs were 60% and 19% for BEV and 68% vs. 21% for placebo, respectively. Grade 3–5 AEs of special interest with BEV occurred in 8% of BEV pts and 15% of placebo pts; the difference was mainly due to grade 3–5 haemorrhage (BEV 4%, placebo 12%). Conclusions: Addition of BEV to XP in Chinese pts with AGC did not significantly improve outcomes in AVATAR. The results from AVATAR are consistent with the findings seen in the Asian sub-population of the previous AVAGAST study. [Table: see text]

Improved survival outcomes in clinically relevant patient subgroups from COU-AA-301, a phase III study of abiraterone acetate (AA) plus prednisone (P) in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel-based chemotherapy.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 4-4 ◽  
Author(s):  
H. I. Scher ◽  
C. Logothetis ◽  
A. Molina ◽  
O. B. Goodman ◽  
C. N. Sternberg ◽  
...  
Keyword(s):  
Abiraterone Acetate ◽  
Phase Iii ◽  
Double Blind Study ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Androgen Synthesis ◽  
Phase Iii Study ◽  
Study Population ◽  
Grade 3 ◽  
Patient Subgroups

4 Background: AA is a selective androgen biosynthesis inhibitor that blocks the action of CYP17. Preclinical and early clinical studies suggest that AA potently inhibits persistent androgen synthesis from adrenal and intratumoral sources, thus suppressing an important growth stimulus for mCRPC. Methods: COU-AA-301 ( NCT00638690 ) is an international, randomized, double blind study of AA (1,000 mg + P 5 mg po BID) vs placebo + P administered to men with mCRPC progressing after docetaxel-based chemo. OS is the primary endpoint. Patients treated with previous ketoconazole or > 2 prior chemo regimens were excluded. Results: Data are drawn from a planned, stratified interim analysis, unblinded in August 2010, based on significant OS improvement in the AA + P treatment group compared to the placebo + P group [median OS 14.8 vs.10.9 months; HR = 0.646 (0.54-0.77), P < 0.0001]. A subgroup analysis for OS is presented in the table. Mineralocorticoid- related AEs were more common in the AA arm vs placebo: fluid retention 30.5% vs 22.3%, hypokalemia 17.1% vs 8.4%; but grade 3/4 hypokalemia (3.8% vs 0.8%), and grade 3/4 hypertension (1.3% vs 0.3%) were infrequent. LFT abnormalities were observed in 10.4% AA vs 8.1% placebo; and cardiac disorders were observed in 13.3% AA vs 10.4% placebo. Conclusions: AA significantly prolongs OS in patients with mCRPC who have progressed after docetaxel-based chemo. AA's favorable treatment effect on OS, observed across multiple patient subgroups (HR range 0.59 – 0.74 vs placebo + P), was consistent with the survival benefit for the overall study population. [Table: see text] [Table: see text]

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