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At least 73 records · Page 4Linked to original sources
PubMed2003

Fondaparinux, the first selective factor Xa inhibitor.

Fondaparinux (Arixtra, Sanofi-Synthelabo, Paris, France) is a pentasaccharide that selectively inhibits factor Xa; it is the first of a new class of synthetic antithrombotic agents. Fondaparinux has a linear pharmacokinetic profile allowing once-daily subcutaneous administration. Absence of metabolism, complete bioavailability, and lack of nonspecific binding in plasma contribute to the predictability of its effect. Fondaparinux has been approved for use in the prophylaxis of venous thromboembolism following orthopedic surgery. In this setting, it was found to reduce VTE risk by more than 50% in comparison with the low molecular weight heparin enoxaparin, with an incidence of clinically important bleeding not significantly different from that of standard low molecular weight heparin regimens. Furthermore, 4 weeks of prophylaxis with fondaparinux after hip fracture surgery was shown to reduce the risk of venous thromboembolism by 96% compared with 1-week prophylaxis. Finally, the efficacy and safety of fondaparinux in the treatment of venous thromboembolism and acute coronary syndromes appears promising.

Acute Disease↗
PubMed2005

Applying a phase II futility study design to therapeutic stroke trials.

BACKGROUND AND PURPOSE: Most large, randomized phase III efficacy trials of therapeutic agents in ischemic stroke have failed to find treatment benefit. We determined whether some phase III studies could have been avoided if preceded by smaller single-arm phase II studies to evaluate the futility of proceeding to phase III. METHODS: To provide examples of the application of phase II methodology, we obtained primary outcome data for the active treatment group of 6 phase III ischemic stroke therapy trials. For each study, we estimated the sample size number required for a multistage single-arm study using parameters specified in the original study. We evaluated outcome data for the first number of subjects in the phase III study treatment arm ordered by enrollment dates. We compared the proportion of favorable outcomes to prespecified stopping criteria derived from a single-arm phase II futility design. If the observed proportion of favorable outcomes was less than the stopping criterion, we declared the treatment not sufficiently effective to warrant further evaluation in phase III. RESULTS: We identified 3 trials as futile in phase II; none of 3 showed treatment efficacy in phase III. In the 3 remaining phase II trials in which we did not show futility, one showed efficacy in phase III. CONCLUSIONS: Single-arm phase II futility studies have been underused in stroke research, but provide a strategy for discarding treatments likely to be ineffective in phase III trials.

Clinical Trials as Topic↗
PubMed1994

[How to assess the size of a clinical trial?].

The interpretation of the results of a clinical trial, an experimental method now recognised as the agreed technique for studying new therapeutic modes of treatment in man, is based on a statistical study of data collected on a sample of patients enrolled in the study and treated till its fulfillment. This interpretation is often made using statistical inference techniques based on the construction of a decision rule associated with a statistical hypothesis test; this hypothesis test serves to formalize a research question in a precise manner, and allows the null hypothesis H0 to be tested against an alternative hypothesis H1. The decision rule will be constructed using a probability distribution, which assumes control against type I error, and consists of falsely rejecting the null hypothesis. However, the control of the risk of type II error, made error where one mistakenly takes a decision not to reject the null hypothesis, can only be achieved using a sufficiently large sample. The correct evaluation of the sample size is thus paramount if one does not wish to be doomed to the failure of a study, by including an insufficient number of patients to achieve the aimed objective. The aim of this report is to review how this evaluation can be due, in a practical manner without proof, in the context of simple situations which are used when Phase II or III clinical trials are put into action.

Clinical Trials as Topic↗
PubMedDate not supplied

Some practical aspects of the interim monitoring of clinical trials.

The decision to stop accrual early to a clinical trial is often difficult and multifaceted. Interim monitoring boundaries have been found useful in U.S. oncology trials for such decisions for reasons described here. This paper also discusses rationale that lead to more conservative approaches to early stopping decisions than are currently employed. A recent initiative of the National Cancer Institute to achieve the objectives of independent data monitoring committees in the phase III clinical trials which it sponsors is also described.

Bias↗
PubMed2001

Pentasaccharide Org31540/SR90107A clinical trials update: lessons for practice.

BACKGROUND: Patients undergoing orthopedic surgery are at particularly high risk for venous thromboembolism (VTE) and as such often receive prophylactic low-molecular-weight heparin (LMWH) or warfarin. However, efficacy and safety limitations of these agents have prompted a search for alternative antithrombotic drugs. METHODS: A new pentasaccharide, Org31540/SR90107A, the first of a class of synthetic and highly selective Factor Xa inhibitors, was investigated in a phase II double-blind, dose-ranging study for the prevention of deep vein thrombosis in 933 patients undergoing elective total hip replacement. The assessor-blind, comparative control was the LMWH enoxaparin. Patients were randomly assigned to 1 of 5 Org31540/SR90107A treatment groups (0.75, 1.5, 3, 6, or 8 mg/d subcutaneously) or to 30 mg enoxaparin subcutaneously every 12 hours. Treatment was started after surgery and continued for 5 to 10 days. Principal outcomes, determined on the basis of standard criteria, included venographically detected deep vein thrombosis and major bleeding. The 6.0- and 8.0-mg groups were discontinued early, in accordance with a protocol-defined safety rule. RESULTS: This phase II study showed improved dose-related efficacy and safety for Org31540/SR90107A versus enoxaparin and led to selection of 2.5 mg once daily as the optimal Org31540/SR90107A dose for large phase III trials in the prevention of VTE after total hip replacement, total knee replacement, and surgery for fractured hip. These studies have now been completed. CONCLUSIONS: Org31540/SR90107A is a new synthetic antithrombotic agent that has demonstrated a significant efficacy and safety dose effect in VTE prophylaxis after orthopedic surgery.

Antithrombin III↗
PubMed2004

Gaboxadol. Lundbeck/Merck.

H Lundbeck A/S, in collaboration with Merck & Co Inc, is developing gaboxadol, a GABAA agonist, for the potential treatment of sleep disorders. The compound is currently undergoing phase III clinical trials.

Animals↗
PubMed2003

Scientific and ethical considerations in trial design for investigational agents for the treatment of human immunodeficiency virus infection.

The design of clinical trials for new antiretroviral agents poses unique challenges, given the availability of highly active antiretroviral therapy (HAART). These challenges include the selection of appropriate populations, the methods used to partition the effects of the study drug under observation from those of the other concurrently administered medications in early studies, performance of dose-ranging studies for disease states in which suboptimal drug exposure may lead to the development of viral resistance that limits future treatment options, and the need to fulfill the obligations of international regulatory agencies. Throughout, science and ethics are tightly woven elements in study designs for antiretroviral drug trials. Fast-track drug approval status and successful lobbying by advocates for patients with acquired immunodeficiency syndrome aimed at the US Food and Drug Administration, the National Institutes of Health, the Centers for Disease Control and Prevention, university teaching centers, pharmaceutical companies, and members of Congress undoubtedly contributed to the development and swift regulatory approvals of the 17 antiretroviral medications now available in the United States for the treatment of human immunodeficiency virus infection.

Anti-HIV Agents↗
PubMed2002

Fondaparinux sodium.

black triangle Fondaparinux sodium, a selective factor Xa inhibitor, is the first in a new class of antithrombotics. It binds selectively with high affinity to antithrombin III and specifically catalyses the inactivation of factor Xa. The elimination half-life of fondaparinux sodium permits once daily treatment. black triangle A randomised, double-blind, parallel-group, dose-ranging, multicentre phase IIb study in 933 eligible patients established that a subcutaneous dose of between 1.5 and 3mg of fondaparinux sodium has the optimum efficacy and safety profile for prophylaxis of venous thromboembolism in patients undergoing major orthopaedic surgery. black triangle Fondaparinux sodium, given to more than 3600 patients undergoing major orthopaedic surgery who participated in prospective, randomised, double-blind, multicentre phase III clinical trials, significantly reduced the incidence of venous thromboembolism, with an overall risk reduction of 55.2% compared with enoxaparin. black triangle Fondaparinux sodium was well tolerated by patients undergoing major orthopaedic surgery, and at the recommended clinical dose of 2.5mg has a similar tolerability profile, including bleeding events, to standard enoxaparin regimens. Fondaparinux sodium has not been reported to cause antibody-induced thrombocytopenia.

Animals↗
PubMed1995

Trials with mitomycin, ifosfamide and cisplatin in non-small cell lung cancer.

In 1988, we reported a Phase II study of mitomycin, ifosfamide and cisplatin (MIC) in inoperable non-small cell lung cancer. The overall objective response rate was 56% in 66 evaluable cases. An improvement in performance status was observed in responding patients and toxicity was acceptable. Consequently we then embarked upon two major, multicentre randomised trials to test this regimen in cases with localised disease (MIC 1--chemotherapy plus radical radiotherapy versus radical radiotherapy alone) and advanced disease (MIC 2--chemotherapy plus palliative care versus palliative care alone). These trials are still in progress with targets of 500 and 300 randomised cases, respectively. The present interim analysis is based on 317 cases randomised in MIC 1 and 193 in MIC 2. The overall response rate (CR + PR) in the MIC 1 trial is 52% with 10% CRs and in the MIC 2 trial is 42% with 5% CRs. Formal symptomatic assessments are monitored in both trials and the present interim analysis indicates symptom improvement in cases randomised to chemotherapy, including patients who fail to achieve an objective PR or CR. Other Phase II studies employing MIC are also reviewed.

Adult↗
PubMed2003

RG-1068 RepliGen.

RG-1068 is a synthetic form of the natural human hormone secretin under development by RepliGen for the potential treatment of autism. RG-1068 received Fast Track designation for the treatment of pediatric autism in September 2001, and in February 2002, it entered phase III clinical trials.

Animals↗
PubMed2003

A model to select regimens for phase III trials for patients with advanced-stage non-small cell lung cancer.

PURPOSE: Historical data from pilot, Phase II, and Phase III studies for patients with advanced-stage non-small cell lung cancer (NSCLC) were used to evaluate a statistical model developed to provide assistance in selecting regimens from pilot studies for subsequent use in larger Phase III randomized studies. EXPERIMENTAL DESIGN: Information from 33 Phase III trials for patients with advanced-stage NSCLC performed from 1973 and 1994 in the United States and Canada was collected. The data from antecedent pilot or Phase II and subsequent Phase III trials were analyzed using a predictive statistical model. This model uses the number of patients in the pilot/Phase II study, the median survival of patients in the pilot, and the number of deaths observed, to estimate the statistical likelihood that the pilot regimen will be shown superior to standard therapy in a subsequent Phase III trial. RESULTS: Ten pilot/Phase II studies were identified that preceded eleven subsequent Phase III studies. The three pilot regimens associated with Phase III trials, revealing statistically significant longer survival, had an expected power of 0.69, 0.85, and 0.94 respectively. The regimens from the seven other pilot studies for which the median power expected was 0.38 (range, 0.07-0.80) showed no difference when compared with standard treatment in a Phase III trial. CONCLUSION: The use of the expected power model provides an important enhancement to the screening of new therapies. Regimens with an expected power of >0.55 may be good candidates for testing in Phase III trials.

Carcinoma, Non-Small-Cell Lung↗
PubMed1997

Overview of the randomized phase III trials in non-small cell lung cancer in North America.

Lung cancer is the leading cause of deaths due to cancer in the United States. Although surgery can be curative for the small group of patients with early stage disease, the majority of patients present with advanced disease, for which treatment is ineffective, resulting in a 5-year overall survival rate of only 13%. Research to discover and evaluate new treatment strategies that will result in a meaningful survival benefit for patients with lung cancer is constantly ongoing. However, the process is cumbersome and requires stringent evaluation of the candidate treatment during each phase of testing. The final step in this long process is to validate the benefit of a new treatment by comparing it with the current standard treatment in the setting of a randomized phase III clinical trial. The new promising treatments for non-small cell lung cancer that are currently in phase III testing in North America are reviewed, and upcoming phase III trials are discussed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Role of antiprogestational therapy for meningiomas.

Epidemiological evidence, including the greater incidence of female patients, a positive association with pregnancy, and a positive association with breast cancer suggested a role for female sex hormones (and hormonal modulation) in regulating the growth of meningioma. The detection of hormone receptors on meningioma specimens provided a mechanism for this effect. However, unlike breast cancer, progesterone receptors (not oestrogen receptors) predominate in meningioma. Clinical trials with anti-oestrogens have shown little effect while trials with progesterone agonists have shown no effect or possible stimulation of meningioma growth. Three trials have now indicated an inhibitory activity of the antiprogestational agent mifepristone. In the largest of these trials, 28 patients received daily oral mifepristone for up to 62 months with a suggestion of response in eight patients. Long-term therapy has been well tolerated. Adverse events include fatigue, hot flushes, gynaecomastia/breast tenderness, skin rash, cessation of menses and decrease in libido. Increases in cortisol and thyroid-stimulating hormone are the most striking endocrine changes. A randomized double-blind placebo-controlled phase III trial is underway to confirm the activity of mifepristone in unresectable meningioma.

Buserelin↗
PubMed2004

Memantine hydrochloride: pharmacological and clinical profile.

Memantine (Axura, Merz Pharmaceuticals GmbH; Ebixa, H. Lundbeck A/S, Namenda, Forest Laboratories, Inc.) is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with low to moderate affinity for the (+)MK-801 binding site. It is characterized as a voltage-sensitive open-channel NMDA receptor blocker that antagonizes NMDA receptor-mediated inward currents in vitro with an IC50 of 1-3 microM. In animal models, memantine displays both neuroprotective (antiexcitotoxic) and cognition-enhancing properties at therapeutically relevant concentrations. The strong voltage dependency and rapid blocking/unblocking kinetics of memantine are thought to be the basis for its excellent clinical tolerability. Recently completed clinical studies demonstrate positive effects of memantine in Alzheimer's disease both as a monotherapy and in patients receiving continuous donepezil treatment. Memantine treatment also has demonstrated significant improvement of cognitive performance in patients suffering from vascular dementia. Furthermore, the safety and tolerability of memantine in clinical trials has been excellent, with the incidence of premature withdrawals due to adverse events no greater than placebo and overall low frequencies of total adverse events. In 2002, memantine was approved by the European Medicines Agency (EMEA) for the treatment of moderately severe to severe Alzheimer's disease. More recently, memantine was approved in the US for the treatment of moderate to severe Alzheimer's disease (October 2003). Here, we review the most recent pharmacological and clinical data in dementia patients that has emerged from the systematic evaluation of memantine.

Alzheimer Disease↗