scholarly journals Pharmacokinetics and Tolerability of a Higher Rifampin Dose versus the Standard Dose in Pulmonary Tuberculosis Patients

2007 ◽  
Vol 51 (7) ◽  
pp. 2546-2551 ◽  
Author(s):  
Rovina Ruslami ◽  
Hanneke M. J. Nijland ◽  
Bachti Alisjahbana ◽  
Ida Parwati ◽  
Reinout van Crevel ◽  
...  
Keyword(s):  
Dose Group ◽  
Standard Dose ◽  
High Dose ◽  
Double Blind ◽  
Time Curve ◽  
Tb Treatment ◽  
Randomized Phase Ii ◽  
Proportional Increase ◽  
To Receive

ABSTRACT Rifampin is a key drug for tuberculosis (TB) treatment. The available data suggest that the currently applied 10-mg/kg of body weight dose of rifampin may be too low and that increasing the dose may shorten the treatment duration. A double-blind randomized phase II clinical trial was performed to investigate the effect of a higher dose of rifampin in terms of pharmacokinetics and tolerability. Fifty newly diagnosed adult Indonesian TB patients were randomized to receive a standard (450-mg, i.e., 10-mg/kg in Indonesian patients) or higher (600-mg) dose of rifampin in addition to other TB drugs. A full pharmacokinetic curve for rifampin, pyrazinamide, and ethambutol was recorded after 6 weeks of daily TB treatment. Tolerability was assessed during the 6-month treatment period. The geometric means of exposure to rifampin (area under the concentration-time curve from 0 to 24 h [AUC0-24]) were increased by 65% (P < 0.001) in the higher-dose group (79.7 mg·h/liter) compared to the standard-dose group (48.5 mg·h/liter). Maximum rifampin concentrations (C max) were 15.6 mg/liter versus 10.5 mg/liter (49% increase; P < 0.001). The percentage of patients for whom the rifampin C max was ≥8 mg/liter was 96% versus 79% (P = 0.094). The pharmacokinetics of pyrazinamide and ethambutol were similar in both groups. Mild (grade 1 or 2) hepatotoxicity was more common in the higher-dose group (46 versus 20%; P = 0.054), but no patient developed severe hepatotoxicity. Increasing the rifampin dose was associated with a more than dose-proportional increase in the mean AUC0-24 and C max of rifampin without affecting the incidence of serious adverse effects. Follow-up studies are warranted to assess whether high-dose rifampin may enable shortening of TB treatment.

scholarly journals Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of the β-Lactamase Inhibitor Vaborbactam (RPX7009) in Healthy Adult Subjects

2016 ◽  
Vol 60 (10) ◽  
pp. 6326-6332 ◽  
Author(s):  
David C. Griffith ◽  
Jeffery S. Loutit ◽  
Elizabeth E. Morgan ◽  
Stephanie Durso ◽  
Michael N. Dudley
Keyword(s):  
Plasma Clearance ◽  
Healthy Adult ◽  
Phase 1 ◽  
High Dose ◽  
Double Blind ◽  
Time Curve ◽  
Content Type ◽  
Multiple Doses ◽  
To Receive ◽  
Lactamase Inhibitor

ABSTRACTVaborbactam (formerly RPX7009) is a member of a new class of β-lactamase inhibitor with pharmacokinetic properties similar to those of many β-lactams, including carbapenems. The pharmacokinetics and safety of vaborbactam were evaluated in 80 healthy adult subjects in a first-in-human randomized, placebo-controlled, double-blind, sequential single- and multiple-ascending-dose study. A total of 10 dose cohorts were enrolled in the study, with 6 subjects randomized to receive 250 to 2,000 mg of vaborbactam and 2 subjects randomized to receive placebo in each cohort. Maximum concentrations for vaborbactam were achieved at the end of the 3-h infusion. Vaborbactam exposure (Cmaxand area under the concentration-time curve [AUC]) increased in a dose-proportional manner following multiple doses. There was no evidence of accumulation with multiple doses, consistent with the terminal half-life of ∼2 h. Both the volume of distribution (Vss) and plasma clearance were independent of dose. For the 2,000-mg dose, the plasma clearance was 0.17 ± 0.03 liters/h, the AUC from 0 h to infinity (AUC0–∞) was 144.00 ± 13.90 mg · h/liter, and theVsswas 21.80 ± 2.26 mg · h/liter. Urinary recovery was 80% or greater over 48 h across all dose groups. No subjects discontinued the study due to adverse events (AEs), and no serious AEs (SAEs) were observed. All AEs were mild to moderate and similar among the vaborbactam- and placebo-treated subjects, with mild lethargy as the only unique AE reported with the high dose of vaborbactam. Overall, this study revealed the safety, tolerability, and pharmacokinetic profile of vaborbactam and formed the basis for advancement into patient studies in combination with meropenem, including treatment of patients with carbapenem-resistantEnterobacteriaceae(CRE) infections. (This study is registered at ClinicalTrials.gov under identifier NCT01751269.)

scholarly journals Double-Blind, Randomized, Placebo-Controlled Phase II Dose-Finding Study To Evaluate High-Dose Rifampin for Tuberculous Meningitis

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
S. Dian ◽  
V. Yunivita ◽  
A. R. Ganiem ◽  
T. Pramaesya ◽  
L. Chaidir ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Tuberculous Meningitis ◽  
Standard Dose ◽  
Geometric Mean ◽  
Phase Iii ◽  
High Dose ◽  
Treatment Area ◽  
Double Blind ◽  
Time Curve

ABSTRACT High doses of rifampin may help patients with tuberculous meningitis (TBM) to survive. Pharmacokinetic pharmacodynamic evaluations suggested that rifampin doses higher than 13 mg/kg given intravenously or 20 mg/kg given orally (as previously studied) are warranted to maximize treatment response. In a double-blind, randomized, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg, or 1,350 mg (10, 20, and 30 mg/kg) oral rifampin combined with other TB drugs for 30 days. The endpoints included pharmacokinetic measures, adverse events, and survival. A double and triple dose of oral rifampin led to 3- and 5-fold higher geometric mean total exposures in plasma in the critical early days (2 ± 1) of treatment (area under the concentration-time curve from 0 to 24 h [AUC0–24], 53.5 mg · h/liter versus 170.6 mg · h/liter and 293.5 mg · h/liter, respectively; P < 0.001), with proportional increases in cerebrospinal fluid (CSF) concentrations and without an increase in the incidence of grade 3 or 4 adverse events. The 6-month mortality was 7/20 (35%), 9/20 (45%), and 3/20 (15%) in the 10-, 20-, and 30-mg/kg groups, respectively (P = 0.12). A tripling of the standard dose caused a large increase in rifampin exposure in plasma and CSF and was safe. The survival benefit with this dose should now be evaluated in a larger phase III clinical trial. (This study has been registered at ClinicalTrials.gov under identifier NCT02169882.)

scholarly journals High-Dose Adrenaline in Adult In-Hospital Asystolic Cardiopulmonary Resuscitation: A Double-Blind Randomised Trial

1993 ◽  
Vol 21 (2) ◽  
pp. 192-196 ◽  
Author(s):  
J. Lipman ◽  
W. Wilson ◽  
S. Kobilski ◽  
J. Scribante ◽  
C. Lee ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Cardiac Arrest ◽  
Intensive Care ◽  
Side Effects ◽  
Cardiopulmonary Resuscitation ◽  
Standard Dose ◽  
Randomised Trial ◽  
High Dose ◽  
Double Blind ◽  
To Receive

Forty intensive care unit patients requiring cardiopulmonary resuscitation were randomised to receive either the standard dose of adrenaline (1 mg every five minutes) or high-dose adrenaline (10 mg every five minutes). In the majority of patients, overwhelming sepsis was the major contributing factor leading to cardiac arrest. In this group of patients no difference could be detected in response to high-dose adrenaline compared with the standard dose. Although no side-effects were noted with this high dose of adrenaline, more investigation is required prior to its routine use in cardiopulmonary resuscitation.

Combined Carbimazole-131I Treatment for Thyrotoxicosis

1972 ◽  
Vol 17 (2) ◽  
pp. 57-61 ◽  
Author(s):  
J. R. McDougall ◽  
W. R. Greig
Keyword(s):  
Dose Group ◽  
Low Dose ◽  
Radioactive Iodine ◽  
Standard Dose ◽  
Antithyroid Drugs ◽  
131I Treatment ◽  
Therapeutic Regime ◽  
The Individual ◽  
To Receive

A sequential therapeutic regime was prescribed for 74 thyrotoxic patients. Every patient received carbimazole in conventional doses for 20 weeks; the average time to obtain control was 10.2 weeks. The patients although older than those usually treated with antithyroid drugs (range 38–68 years) showed no difference in the expected rate of control or in the recognised incidence of side effects. Following the carbimazole therapy the patients were alternatively allotted to receive standard or low (50% of standard) doses of 131I, the individual doses being calculated from simple formulae. After the radio-iodine all of the patients were treated with carbimazole for a further 20 weeks. Review of the patients after completion of the trial and subsequent follow up without therapy shows that 42.1 per cent of the standard dose group remain euthyroid after one therapy dose of 131I, 36.8 per cent have relapsed and 21.1 per cent have become hypothyroid. In the low dose group 44.4 per cent are euthyroid, 47.2 per cent have had a recurrence and 8.4 per cent have become hypothyroid. The results are discussed in the light of current views about the treatment of thyrotoxicosis with drugs and with radioactive iodine.

scholarly journals DESTINATION: a phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the long-term safety and tolerability of tezepelumab in adults and adolescents with severe, uncontrolled asthma

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Andrew Menzies-Gow ◽  
Sandhia Ponnarambil ◽  
John Downie ◽  
Karin Bowen ◽  
Åsa Hellqvist ◽  
...  
Keyword(s):  
High Dose ◽  
Treatment Cessation ◽  
Uncontrolled Asthma ◽  
Phase 3 ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Long Term Treatment ◽  
To Receive

Abstract Background Tezepelumab is a human monoclonal antibody that blocks the activity of the epithelial cytokine thymic stromal lymphopoietin. The efficacy, safety and oral corticosteroid-sparing potential of tezepelumab are being investigated in two ongoing, phase 3, randomized, double-blind, placebo-controlled studies (NAVIGATOR [NCT03347279] and SOURCE [NCT03406078]). DESTINATION (NCT03706079) is a long-term extension (LTE) of these studies. Methods DESTINATION is a randomized, double-blind, placebo-controlled LTE study in adults (18–80 years old) and adolescents (12–17 years old) with severe, uncontrolled asthma who are receiving treatment with medium- or high-dose inhaled corticosteroids plus at least one additional controller medication with or without oral corticosteroids. The study population will comprise patients who complete the 52- and 48-week NAVIGATOR and SOURCE studies, respectively. Patients who were randomized to receive tezepelumab 210 mg every 4 weeks (Q4W) in either predecessor study will continue to receive this regimen for 1 year; those who were previously randomized to receive placebo will be re-randomized (1:1) to receive either tezepelumab 210 mg Q4W or placebo for 1 year. Patients will receive their prescribed controller medications throughout DESTINATION and study physicians will have the opportunity to down- or up-titrate dosage of these medications, if appropriate. The primary objective is to evaluate the long-term safety and tolerability of tezepelumab over 104 weeks (inclusive of the treatment period of either predecessor study). The secondary objective is to assess the long-term effect of tezepelumab on asthma exacerbations. Patients recruited from SOURCE will be followed up post-treatment for 12 weeks. Patients recruited from NAVIGATOR who complete 100 weeks of tezepelumab treatment will be eligible for either 12 weeks of follow-up or a 36-week extended follow-up during which the clinical benefit of tezepelumab after treatment cessation will be investigated. Discussion DESTINATION will evaluate the long-term safety, tolerability and efficacy of tezepelumab versus placebo with continued dosing for up to 2 years. DESTINATION will also evaluate the clinical effect of tezepelumab after treatment cessation. This LTE study aims to elucidate the long-term safety implications of receiving tezepelumab and to assess its potential long-term treatment benefits in patients with severe, uncontrolled asthma. Trial registration NCT03706079 (ClinicalTrials.gov). Registered 15 October 2018.

Randomized Phase II Study of High-Dose Paclitaxel With or Without Amifostine in Patients With Metastatic Breast Cancer

1999 ◽  
Vol 17 (10) ◽  
pp. 3038-3047 ◽  
Author(s):  
K. Gelmon ◽  
E. Eisenhauer ◽  
C. Bryce ◽  
A. Tolcher ◽  
L. Mayer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Metastatic Breast ◽  
Response Rates ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Vibration Sense ◽  
Randomized Phase Ii ◽  
To Receive

PURPOSE: To determine whether the neurotoxicity of paclitaxel 250 mg/m2 given over 3 hours every 3 weeks could be reduced by pretreatment with amifostine 910 mg/m2. Secondary objectives included comparing myelosuppression, myalgias, and response rates of the two groups. PATIENTS AND METHODS: Forty womenwith metastatic breast cancer were randomized to receive either paclitaxel alone (arm 1) or paclitaxel preceded by amifostine (arm 2). All were assessable for toxicity, and 37 were assessable for response. At baseline and after each cycle, all patients completed questionnaires for neurologic symptoms and had standardized neurologic examinations, including objective assessments of power and vibration sense. In addition, standard follow-up assessments for other toxicities and tumor response were undertaken. Changes from baseline after courses 1, 2, and 3 were assessed. The sample size was sufficient to detect a 50% improvement in the expected determination in sensory change. RESULTS: There were no differences observed in any of the measures of neurotoxicity. Other toxicity was similar in arms 1 and 2, including hair loss (95% v 90%), neurosensory changes (100% v 100%), fatigue/lethargy (85% v 90%), myalgia (95% v 90%), and grade 4 neutropenia (47% v 60%). Nausea, vomiting, dizziness, hypotension, and sneezing were more common in the amifostine arm. Response rates (22.2% v 36.8%) and paclitaxel pharmacokinetics were not significantly different. CONCLUSION: There was no protection from paclitaxel-related neurotoxicity or hematologic toxicity in this study. These results suggest that the mechanism of action of paclitaxel-related toxic effects is not amenable to the cytoprotective action of amifostine.

scholarly journals Safety and immunogenicity of a recombinant COVID-19 vaccine (Sf9 cells) in healthy population aged 18 years or older: two single-center, randomised, double-blind, placebo-controlled, phase 1 and phase 2 trials

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Fan-Yue Meng ◽  
Fan Gao ◽  
Si-Yue Jia ◽  
Xiang-Hong Wu ◽  
Jing-Xin Li ◽  
...  
Keyword(s):  
Dose Group ◽  
Low Dose ◽  
Phase 1 ◽  
High Dose ◽  
Healthy Population ◽  
Phase 2 ◽  
Double Blind ◽  
Double Blind Placebo ◽  
To Receive ◽  
Dose Vaccine

AbstractCOVID-19 vaccines from multiple manufacturers are needed to cope with the problem of insufficient supply. We did two single-center, randomised, double-blind, placebo-controlled phase 1 and phase 2 trials to assess the safety, tolerability and immunogenicity of a recombinant COVID-19 vaccine (Sf9 cells) in healthy population aged 18 years or older in China. Eligible participants were enrolled, the ratio of candidate vaccine and placebo within each dose group was 3:1 (phase 1) or 5:1 (phase 2). From August 28, 2020, 168 participants were sequentially enrolled and randomly assigned to receive the low dose vaccine, high dose vaccine or placebo with the schedule of 0, 28 days or 0, 14, 28 days in phase 1 trial. From November 18, 2020, 960 participants were randomly assigned to receive the low dose vaccine, high dose vaccine or placebo with the schedule of 0, 21 days or 0, 14, 28 days in phase 2 trial. The most common solicited injection site adverse reaction within 7 days in both trials was pain. The most common solicited systematic adverse reactions within 7 days were fatigue, cough, sore throat, fever and headache. ELISA antibodies and neutralising antibodies increased at 14 days, and peaked at 28 days (phase 1) or 30 days (phase 2) after the last dose vaccination. The GMTs of neutralising antibody against live SARS-CoV-2 at 28 days or 30 days after the last dose vaccination were highest in the adult high dose group (0, 14, 28 days), with 102.9 (95% CI 61.9–171.2) and 102.6 (95% CI 75.2–140.1) in phase 1 and phase 2 trials, respectively. Specific T-cell response peaked at 14 days after the last dose vaccination in phase 1 trial. This vaccine is safe, and induced significant immune responses after three doses of vaccination.

Comparable Survival in Newly Diagnosed Multiple Myeloma (MM) after VAD Induction with High Dose Therapy Using Melphalan 140mg/M2 + TBI 12 Gy (MEL+TBI) Versus Standard Therapy with VBMCP and No Benefit from Interferon (IFN) Maintenance: Final Clinical Results of Intergroup Trial S9321 in the Context of IFM 90 and MRC VII Trials.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 539-539 ◽  
Author(s):  
John Crowley ◽  
Rafael Fonseca ◽  
Phillip Greipp ◽  
McCoy Jason ◽  
Barlogie Bart
Keyword(s):  
Randomized Clinical Trials ◽  
Standard Dose ◽  
Dose Intensity ◽  
Clinical Results ◽  
High Dose ◽  
Newly Diagnosed ◽  
Dose Therapy ◽  
Meta Analyses ◽  
To Receive

Abstract ECOG, CALGB and SWOG (coordinating group) enrolled 899 patients with newly diagnosed MM to receive VAD x 4 (813 were considered eligible), followed by randomization to PBSC-supported MEL-TBI (n=261) versus VBMCP (n=255), using CTX 4.5g/m2 + G-CSF for PBSC mobilization in all patients. Responders to VBMCP or MEL-TBI were randomized to IFN (n=121) or no maintenance (n=121). With a median follow-up of alive patients of 60 mos, median EFS and OS from 1st randomization were 25 and 62 mos for MEL-TBI and 21 and 53 mos for VBMCP (p=.14 for EFS, p=.87 for OS). EFS and OS from IFN randomization were also identical at 23/59 mos for IFN versus 18/74 mos for observation (p=.2/.6). 87 VBMCP failures received salvage autotransplants, with a post-relapse median survival of 24 mos which was similar to the 27 mos observed among the remaining 83 VBMCP failures managed with standard salvage therapies. When examined in the context of 2 other randomized trials (IFM 90, MRC VII), OS from baseline of S932, limited to patients <60 yr (as in IFM 90 + MRC VII), is intermediate between the high dose arms of IFM 90/MRC VII and the standard dose arms of these two trials (randomization at baseline) (Figure 1). OS from the time of randomization to high or standard dose therapy on S9321 (again restricted to age <60 yr) was similar to OS timed from transplant for the high dose arms of IFM 90 and MRC VII. (Figure 2). Figure Figure The comparable outcome after high- versus standard-dose therapies on S9321, interpreted in the context of 2 other published randomized clinical trials, may relate to (1) higher dose intensity with VBMCP than with other standard regimens or (2) a detrimental effect of TBI in S9321. We conclude that with the current follow-up MEL-TBI is no better than VAD/VBMCP with the option of salvage transplant and that IFN maintenance is of no benefit in this maintenance setting. Data from this trial will be provided to MRC to be included in their on-going meta-analyses of high-dose therapies and IFN maintenance.

scholarly journals Pharmacokinetics, Tolerability, and Bacteriological Response of Rifampin Administered at 600, 900, and 1,200 Milligrams Daily in Patients with Pulmonary Tuberculosis

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
R. E. Aarnoutse ◽  
G. S. Kibiki ◽  
K. Reither ◽  
H. H. Semvua ◽  
F. Haraka ◽  
...  
Keyword(s):  
Geometric Mean ◽  
Double Blind ◽  
Time Curve ◽  
Bacteriological Response ◽  
Solid Media ◽  
Dose Ranging ◽  
Proportional Increase ◽  
Grade 3 ◽  
Higher Doses

ABSTRACT In a multiple-dose-ranging trial, we previously evaluated higher doses of rifampin in patients for 2 weeks. The objectives of the current study were to administer higher doses of rifampin for a longer period to compare the pharmacokinetics, safety/tolerability, and bacteriological activity of such regimens. In a double-blind, randomized, placebo-controlled, phase II clinical trial, 150 Tanzanian patients with tuberculosis (TB) were randomized to receive either 600 mg (approximately 10 mg/kg of body weight), 900 mg, or 1,200 mg rifampin combined with standard doses of isoniazid, pyrazinamide, and ethambutol administered daily for 2 months. Intensive pharmacokinetic sampling occurred in 63 patients after 6 weeks of treatment, and safety/tolerability was assessed. The bacteriological response was assessed by culture conversion in liquid and solid media. Geometric mean total exposures (area under the concentration-versus-time curve up to 24 h after the dose) were 24.6, 50.8, and 76.1 mg · h/liter in the 600-mg, 900-mg, and 1,200-mg groups, respectively, reflecting a nonlinear increase in exposure with the dose (P < 0.001). Grade 3 adverse events occurred in only 2 patients in the 600-mg arm, 4 patients in the 900-mg arm, and 5 patients in the 1,200-mg arm. No significant differences in the bacteriological response were observed. Higher daily doses of rifampin (900 and 1,200 mg) resulted in a more than proportional increase in rifampin exposure in plasma and were safe and well tolerated when combined with other first-line anti-TB drugs for 2 months, but they did not result in improved bacteriological responses in patients with pulmonary TB. These findings have warranted evaluation of even higher doses of rifampin in follow-up trials. (This study has been registered at ClinicalTrials.gov under identifier NCT00760149.)

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