scholarly journals A randomized open label trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis.

2019 ◽  
Vol 4 ◽  
pp. 8 ◽  
Author(s):  
Nguyen Thi Thuy Ngan ◽  
Nguyen Thi Hoang Mai ◽  
Nguyen Le Nhu Tung ◽  
Nguyen Phu Huong Lan ◽  
Luong Thi Hue Tai ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Cryptococcal Meningitis ◽  
Treatment Guidelines ◽  
Controlled Trial ◽  
Safety Data ◽  
Open Label ◽  
Receptor Modulator ◽  
Open Label Trial ◽  
Early Fungicidal Activity

Background: Cryptococcal meningitis is a leading cause of death in HIV-infected patients. International treatment guidelines recommend induction therapy with amphotericin B and flucytosine. This antifungal combination is most effective, but unfortunately flucytosine is expensive and unavailable where the burden of disease is greatest. Where unavailable, guidelines recommend treatment with amphotericin and fluconazole, but this is less effective, with mortality rates of 40-50%. Faster rates of clearance of yeast from cerebrospinal fluid (CSF) are associated with better outcomes - improving the potency of antifungal therapy is likely to be an effective strategy to improve survival. Tamoxifen, a selective estrogen receptor modulator used to treat breast cancer, has anti-cryptococcal activity, appearing synergistic when combined in vitro with amphotericin, and fungicidal when combined with fluconazole. It is concentrated in the brain and macrophages, off-patent, cheap and widely available. We designed a randomized trial to deliver initial efficacy and safety data for tamoxifen combined with amphotericin and fluconazole. Method: A phase II, open-label, randomized (1:1) controlled trial of tamoxifen (300mg/day) combined with amphotericin (1mg/kg/day) and fluconazole (800mg/day) for the first 2 weeks therapy for HIV infected or uninfected adults with cryptococcal meningitis. The study recruits at Cho Ray Hospital and the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. The primary end point is Early Fungicidal Activity (EFA-the rate of yeast clearance from CSF), over the first two weeks of treatment. 50 patients will be recruited providing ≈80% and 90% power to detect a difference in the EFA of -0.11 or -0.13 log10CFU/ml/day, respectively. Discussion: The results of the study will inform the decision to proceed to a larger trial powered to mortality. The size of effect detectable has previously been associated with reduced mortality from this devastating disease. Particular side effects of interest include QT prolongation. Trial registration: Clinicaltrials.gov NCT03112031 (11/04/2017)

scholarly journals An open label randomized controlled trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Nguyen Thi Thuy Ngan ◽  
Nhat Thanh Hoang Le ◽  
Nguyen Ngo Vi Vi ◽  
Ninh Thi Thanh Van ◽  
Nguyen Thi Hoang Mai ◽  
...  
Keyword(s):  
Randomized Controlled Trial ◽  
Cryptococcal Meningitis ◽  
Standard Care ◽  
Therapeutic Potential ◽  
Controlled Trial ◽  
High Dose ◽  
Open Label ◽  
Randomized Controlled ◽  
Cancer Agent

Background: Cryptococcal meningitis has high mortality. Flucytosine is a key treatment but is expensive and rarely available. The anti-cancer agent tamoxifen has synergistic anti-cryptococcal activity with amphotericin in vitro. It is off-patent, cheap, and widely available. We performed a trial to determine its therapeutic potential.Methods:Open label randomized controlled trial. Participants received standard care - amphotericin combined with fluconazole for the first two weeks - or standard care plus tamoxifen 300mg/day. The primary end point was Early Fungicidal Activity (EFA) - the rate of yeast clearance from cerebrospinal fluid (CSF). Trial registration https://clinicaltrials.gov/ct2/show/NCT03112031 .Results: 50 patients were enrolled, (median age 34 years, 35 male). Tamoxifen had no effect on EFA (- 0.48log10 colony-forming units/mL/CSF control arm versus -0.49 tamoxifen arm, difference - 0.005log10CFU/ml/day, 95%CI: -0.16, 0.15, P=0.95). Tamoxifen caused QTc prolongation.Conclusion: High dose tamoxifen does not increase the clearance rate of Cryptococcus from CSF. Novel, affordable therapies are needed.Funding:The trial was funded through the Wellcome Trust Asia Programme Vietnam Core Grant 106680 and a Wellcome Trust Intermediate Fellowship to JND grant number WT097147MA.

scholarly journals Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate)

2017 ◽  
Vol 77 (2) ◽  
pp. 212-220 ◽  
Author(s):  
Dinesh Khanna ◽  
Christopher P Denton ◽  
Celia J F Lin ◽  
Jacob M van Laar ◽  
Tracy M Frech ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Phase Ii ◽  
Controlled Trial ◽  
Safety Data ◽  
Open Label ◽  
Double Blind ◽  
Skin Score ◽  
Open Label Extension ◽  
Registration Number ◽  
Randomised Controlled

ObjectivesAssess the efficacy and safety of tocilizumab in patients with systemic sclerosis (SSc) in a phase II study.MethodsPatients with SSc were treated for 48 weeks in an open-label extension phase of the faSScinate study with weekly 162 mg subcutaneous tocilizumab. Exploratory end points included modified Rodnan Skin Score (mRSS) and per cent predicted forced vital capacity (%pFVC) through week 96.ResultsOverall, 24/44 (55%) placebo-tocilizumab and 27/43 (63%) continuous-tocilizumab patients completed week 96. Observed mean (SD (95% CI)) change from baseline in mRSS was –3.1 (6.3 (–5.4 to –0.9)) for placebo and –5.6 (9.1 (–8.9 to–2.4)) for tocilizumab at week 48 and –9.4 (5.6 (–8.9 to –2.4)) for placebo-tocilizumab and –9.1 (8.7 (–12.5 to –5.6)) for continuous-tocilizumab at week 96. Of patients who completed week 96, any decline in %pFVC was observed for 10/24 (42% (95% CI 22% to 63%)) placebo-tocilizumab and 12/26 (46% (95% CI 27% to 67%)) continuous-tocilizumab patients in the open-label period; no patients had >10% absolute decline in %pFVC. Serious infection rates/100 patient-years (95% CI) were 10.9 (3.0 to 27.9) with placebo and 34.8 (18.0 to 60.8) with tocilizumab during the double-blind period by week 48 and 19.6 (7.2 to 42.7) with placebo-tocilizumab and 0.0 (0.0 to 12.2) with continuous-tocilizumab during the open-label period.ConclusionsSkin score improvement and FVC stabilisation in the double-blind period were observed in placebo-treated patients who transitioned to tocilizumab and were maintained in the open-label period. Safety data indicated increased serious infections in patients with SSc but no new safety signals with tocilizumab.Trial registration numberNCT01532869; Results.

scholarly journals Cryptococcosis in pregnancy and the postpartum period: Case series and systematic review with recommendations for management

2019 ◽  
Vol 58 (3) ◽  
pp. 282-292
Author(s):  
Katelyn A Pastick ◽  
Elizabeth Nalintya ◽  
Lillian Tugume ◽  
Kenneth Ssebambulidde ◽  
Nicole Stephens ◽  
...  
Keyword(s):  
Survival Rate ◽  
Pregnant Women ◽  
Amphotericin B ◽  
Cryptococcal Meningitis ◽  
Treatment Guidelines ◽  
Case Reports ◽  
Case Series ◽  
First Trimester ◽  
Secondary Prophylaxis ◽  
Fetal Survival

Abstract Cryptococcal meningitis causes 15% of AIDS-related deaths. Optimal management and clinical outcomes of pregnant women with cryptococcosis are limited to case reports, as pregnant women are often excluded from research. Amongst pregnant women with asymptomatic cryptococcosis, no treatment guidelines exist. We prospectively identified HIV-infected women who were pregnant or recently pregnant with cryptococcosis, screened during a series of meningitis research studies in Uganda from 2012 to 2018. Among 571 women screened for cryptococcosis, 13 were pregnant, one was breastfeeding, three were within 14 days postpartum, and two had recently miscarried. Of these 19 women (3.3%), 12 had cryptococcal meningitis, six had cryptococcal antigenemia, and one had a history of cryptococcal meningitis and was receiving secondary prophylaxis. All women with meningitis received amphotericin B deoxycholate (0.7–1.0 mg/kg). Five were exposed to 200–800 mg fluconazole during pregnancy. Of these five, three delivered healthy babies with no gross physical abnormalities at birth, one succumbed to meningitis, and one outcome was unknown. Maternal meningitis survival rate at hospital discharge was 75% (9/12), and neonatal/fetal survival rate was 44% (4/9) for those mothers who survived. Miscarriages and stillbirths were common (n = 4). Of six women with cryptococcal antigenemia, two received fluconazole, one received weekly amphotericin B, and three had unknown treatment courses. All women with antigenemia survived, and none developed clinical meningitis. We report good maternal outcomes but poor fetal outcomes for cryptococcal meningitis using amphotericin B, without fluconazole in the first trimester, and weekly amphotericin B in place of fluconazole for cryptococcal antigenemia.

Fluconazole and Amphotericin B for Cryptococcal Meningitis

1996 ◽  
Vol 30 (12) ◽  
pp. 1408-1410 ◽  
Author(s):  
Amy B Clark ◽  
Bob L Lobo ◽  
Michael S Gelfand
Keyword(s):  
Clinical Trials ◽  
Amphotericin B ◽  
Cryptococcal Meningitis ◽  
Patient Population ◽  
Standard Therapy ◽  
Alternative Therapy ◽  
Poor Response ◽  
Case Summary

OBJECTIVE: To describe a patient with cryptococcal meningitis treated with the combination of amphotericin B and fluconazole. CASE SUMMARY: A 41-year-old woman with cryptococcal meningitis who was not infected with HIV was treated with a combination of amphotericin B and fluconazole because she did not respond to amphotericin B alone and could not tolerate amphotericin B with flucytosine. She improved clinically, but it is unclear whether the combination was beneficial. DISCUSSION: Standard therapy for cryptococcal meningitis is amphotericin B with or without flucytosine. Fluconazole is an alternative therapy, but its efficacy has not been documented in the patient population not infected with HIV. Theoretically, the combination of amphotericin B and fluconazole is antagonistic, but in vitro and in vivo data suggest that antagonism may not occur. The combination of amphotericin B and fluconazole in cryptococcal meningitis has not been evaluated in clinical trials, and its use is not recommended. CONCLUSIONS: A patient with cryptococcal meningitis was treated with the combination of amphotericin B and fluconazole because of a poor response to amphotericin B monotherapy and intolerance to flucytosine. It is unclear whether her clinical response was a result of the combination.

Preliminary report of an open-label, multicenter, phase I/II study of AT-101 in combination with docetaxel (D) and prednisone (P) in men with docetaxel refractory prostate cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5145-5145
Author(s):  
B. Poiesz ◽  
J. Reeves ◽  
W. McNulty ◽  
J. Maleski ◽  
J. Holmlund ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Single Agent ◽  
Safety Data ◽  
Additional Patient ◽  
Open Label ◽  
Potent Inducer ◽  
First Line Therapy ◽  
Measurable Disease

5145 Background: Antiapoptotic Bcl-2 family proteins are overexpressed in castrate resistant prostate cancer (CRPC) and contribute to resistance to therapy. AT-101 is a pan-Bcl-2 inhibitor (Bcl-2, Bcl-XL, Bcl-W, and Mcl-1) and potent inducer of proapoptotic proteins. AT-101 is active as a single agent and in combinations with standard therapies in in vitro and in vivo tumor models, as a single agent in a phase II trial in CRPC, and in combination with D/P as first-line therapy in CRPC, as demonstrated by declines in PSA and RECIST responses. Methods: Men ≥18 years of age with docetaxel-refractory CRPC were eligible. Patients (pts) must have PSA progression per the Bubley criteria or documented disease progression while receiving prior D/P therapy. Pts (n = 40) were treated with D (75 mg/m2 day 1), P (5mg b.i.d. on days 1–21) and AT-101 40mg b.i.d. on days 1–3 of each 21-day cycle. Safety (NCI CTCAE v3.0) and efficacy (Bubley Criteria for PSA) were assessed at 3-wk intervals. Radiological assessments were performed at 6-wk intervals for pts with soft tissue disease and bone scans were performed after cycle 6 and at the completion of therapy. Results: Efficacy data was available on 34 pts. Thirty-five percent (12/34) of pts treated had at least a 30% decrease in PSA level and 18% (6/34) of pts achieved a >50% PSA decline. Twenty one of 34 pts included in this analysis had measurable disease. Five pts (24%) with measurable disease had a PR or CR by RECIST criteria and one additional patient had tumor shrinkage of 29%. Two (2) RECIST PRs are unconfirmed. Thus far, 3 pts have been on therapy for 6 months or more and 15 pts remain on study. Safety data was available on 22 pts. The most common (>20%) adverse events (AEs) included fatigue (55%), anorexia, including weight decreased (45%), diarrhea and nausea (27%), vomiting and neutropenia (23%). The grade 3/4 AEs occurring in more than 1 pt were: neutropenia (5), anemia, anorexia, dyspnea and leukopenia (2 pts each). One partial small bowel obstruction was the only related, serious adverse event (SAE) reported to date. Conclusions: This data supports that AT-101 can be administered safely with D/P in pts with CRPC who are docetaxel-refractory. Durable PSA and RECIST responses were observed. [Table: see text]

scholarly journals Controlled Trial of a 5-Day Course of Telithromycin versus Doxycycline for Treatment of Mild to Moderate Scrub Typhus

2007 ◽  
Vol 51 (6) ◽  
pp. 2011-2015 ◽  
Author(s):  
Dong-Min Kim ◽  
Ki Dong Yu ◽  
Ji Hyun Lee ◽  
Hyun Kuk Kim ◽  
Seung-Hyun Lee
Keyword(s):  
Adverse Events ◽  
Scrub Typhus ◽  
Controlled Trial ◽  
Sensitivity Study ◽  
University Hospital ◽  
Efficacy And Safety ◽  
Open Label ◽  
Serious Adverse Events ◽  
New Antibiotics

ABSTRACT New antibiotics are required to have the antibacterial activity against doxycycline-resistant Orientia tsutsugamushi. An in vitro sensitivity study showed that telithromycin was more effective than erythromycin for Rickettsia, Bartonella, and Coxiella burnetii. In this prospective, open-label, randomized trial, we enrolled patients with mild-to-moderate scrub typhus. We compared the efficacy and safety of a 5-day telithromycin therapy with those of a 5-day doxycycline therapy at Chosun University Hospital or one of its two community-based affiliated hospitals (Jangheung Hospital and Cheomdan Hospital), which are all located in southwestern Korea, between September and December 2005. A total of 92 patients were randomly assigned to either the telithromycin group (n = 47) or the doxycycline group (n = 45). After the treatment, fever control time was 20.45 ± 12.9 h in the telithromycin group and 22.60 ± 21.44 h in the doxycycline group (P > 0.05). After the treatment, the cure rate was 100% in the telithromycin group and 97.8% in the doxycycline group (P > 0.05). Furthermore, there were no significant differences in time elapsed until such symptoms as headache, myalgia, and rash disappeared. No serious adverse events or death were noted following the treatment in both groups. There were no significant differences in adverse events. In conclusion, the efficacy and safety of a 5-day once-a-day regimen of 800 mg telithromycin were equivalent to those of a 5-day twice-a-day regimen of 100 mg doxycycline in patients with mild-to-moderate scrub typhus. Telithromycin could be considered a promising new antibacterial agent for patients with scrub typhus.

Interim safety results of a global early access protocol (EAP) of abiraterone acetate (AA) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) progressing after taxane-based chemotherapy.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5059-5059
Author(s):  
Daniel J. George ◽  
Tracy McGowan ◽  
Gedske Daugaard ◽  
Thomas W. Flaig ◽  
Lajos Geczi ◽  
...  
Keyword(s):  
Latin America ◽  
Disease Progression ◽  
Controlled Trial ◽  
Safety Data ◽  
Osteoporotic Fractures ◽  
Abiraterone Acetate ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Early Access ◽  
Grade 3

5059 Background: The COU-AA-301 phase 3 trial showed significantly longer overall survival for AA + prednisone (P) than P alone in mCRPC pts refractory to docetaxel. This global EAP was conducted in the same setting to collect additional safety data. Methods: Open-label EAP in pts with mCRPC who progressed after 1 - 2 chemotherapy regimens (≥ 1 taxane), resided in areas where AA was unavailable and were ineligible for ongoing clinical trials of AA. Pts received AA (1000 mg PO/d) plus P (5 mg bid) in 28 d cycles until disease progression. Only serious or clinically important adverse events (AEs) were to be reported by investigators. First interim results (clinical cut-off date: December 31, 2011), reported as part of regulatory submissions, are presented. Results: 1079 pts from 15 countries were included: N. America (47%), Europe (29%), Australia (13%), Latin America (7%), and Asia (3%). Median age: 70 years (range: 47 – 93); 89% of pts were White. Median treatment exposure, incl. pts still on treatment (285 pts), was ≈ 3 months. 620 pts (58%) received ≥ 4 treatment cycles, 58 pts (5%) received ≥ 8 cycles. 441 pts (41%) reported serious or clinically important AEs, which were treatment-related in 154 pts (14%). Most common grade 3-4 AEs: ↑ALP (6%), anemia (3%), hypertension (3%), back pain (2%), and fatigue (2%). Grade 3-4 AEs of special interest were infrequent: LFT abnormalities (8%), hypertension (3%), cardiac disorders (2%), hypokalemia (< 1%), fluid retention/edema (< 1%), osteoporotic fractures (< 1%). Main reason for discontinuation (795 pts): disease progression, in 335 pts (31%). 253 pts (23%) discontinued after marketing authorization. Discontinuations due to treatment-emergent AEs, death, or withdrawal of consent were < 6% each. Conclusions: The safety profile observed in these EAP interim results was consistent with that in the COU-AA-301 randomized, placebo controlled trial conducted in the same clinical setting. No new safety signals with AA plus P were detected in this expanded patient population, which included pts from Latin America and Asia, i.e. regions that did not participate in COU-AA-301. Clinical trial information: NCT01217697.

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