Drug Efficacy Trials Research Articles

Comparison of several testing strategies for combination drug efficacy trials based on the closure principle

The author discusses three multiple testing procedures for identifying the minimum efficacious doses in a balanced factorial combination drug trial. All of these procedures utilize the closed testing principle, and hence strongly control the overall error rate and satisfy the coherence property, that is, if a hypothesis is retained then any hypothesis implied by it is also retained. While coherence is an essential requirement for any multiple testing procedure, consonance is a highly desirable characteristic. In the considered settings if a testing procedure is consonant then it always provides a set of all minimum efficacious combinations as a result, otherwise, it may lead to ambiguity. Although the coherence property is satisfied for any closed testing procedure and thus, does not depend on the test used for an individual hypothesis, whether the considered procedures satisfy the consonance property depends entirely on the nature of the test statistic. The author identifies the consonant and non-consonant procedures among the presented procedures and discusses possible drawbacks of non-consonant procedures with respect to combination drug efficacy trials. Additional properties of these procedures are assessed by simulations.

The New Anecdotes

This article deals with the interpretation and clinical implications of findings from randomized controlled trials (RCTs) of antidepressant drug efficacy. It will also deal with a related issue, namely the differential response of journals to articles reporting individual clinical case outcomes compared with articles reporting controlled trial outcomes.

World Antimalarial Resistance Network (WARN) III: Molecular markers for drug resistant malaria

Molecular markers for drug resistant malaria represent public health tools of great but mostly unrealized potential value. A key reason for the failure of molecular resistance markers to live up to their potential is that data on the their prevalence is scattered in disparate databases with no linkage to the clinical, in vitro and pharmacokinetic data that are needed to relate the genetic data to relevant phenotypes. The ongoing replacement of older monotherapies for malaria by new, more effective combination therapies presents an opportunity to create an open access database that brings together standardized data on molecular markers of drug resistant malaria from around the world. This paper presents a rationale for creating a global database of molecular markers for drug resistant malaria and for linking it to similar databases containing results from clinical trials of drug efficacy, in vitro studies of drug susceptibility, and pharmacokinetic studies of antimalarial drugs, in a World Antimalarial Resistance Network (WARN). This database will be a global resource, guiding the selection of first line drugs for treating uncomplicated malaria, for preventing malaria in travelers and for intermittent preventive treatment of malaria in pregnant women, infants and other vulnerable groups. Perhaps most important, a global database for molecular markers of drug resistant malaria will accelerate the identification and validation of markers for resistance to artemisinin-based combination therapies and, thereby, potentially prolong the useful therapeutic lives of these important new drugs.

Clinico-Pathological Observations on the Pathogenesis of Severe Thrombocytopenia and Anemia Induced by Plasmodium vivax Infections During Antimalarial Drug Efficacy Trials in Aotus Monkeys

During routine antimalarial drug efficacy trials, we observed, for the first time, severe thrombocytopenia developing in Aotus monkeys infected with Plasmodium vivax. Data obtained from 26 Aotus infected with the AMRU-1 strain showed that 77% developed severe thrombocytopenia, whereas only 15% had severe anemia, with hemorrhagic diathesis ensuing in 31%. In general, thrombocytopenic monkeys either failed primary treatment with experimental antimalarial drugs or were found to have higher-density parasitemias, longer patency duration, and lower hematocrits. In these monkeys, severe thrombocytopenia inversely correlated to parasitemia (R = -1.0), and animals that received a blood transfusion had significantly higher platelet counts (P < 0.05) by day 38 after inoculation. In conclusion, the AMRU-1 strain of P. vivax, was considered to be highly pathogenic to Aotus monkeys, and thrombocytopenia rather than anemia should be regarded an early indicator of drug treatment failure with this strain.

Molecular genotyping in a malaria treatment trial in Uganda – unexpected high rate of new infections within 2 weeks after treatment

Polymerase chain reaction (PCR) genotyping of malaria parasites in drug efficacy trials helps differentiate reinfections from recrudescences. A combination therapy trial of one (n = 115) or three (n = 117) days artesunate (1AS, 3AS 4 mg/kg/day) plus sulphadoxine-pyrimethamine (SP) vs. SP alone (n = 153) was conducted in Mbarara, a mesoendemic area of western Uganda. All paired recurrent Plasmodium falciparum parasitaemias on days 7, 14, 21 and 28 post-treatment were genotyped by PCR amplification and analysis of glutamate-rich protein (glurp) and merozoite surface proteins (msp) 1 and 2 genes to distinguish recrudescent from new infections. A total of 156 (1AS = 61, 3AS = 35, SP alone = 60) of 199 paired recurrent samples were successfully analysed and were resolved as 79 recrudescences (1AS = 32, 3AS = 8, SP = 39) and 77 as new infections (1AS = 29, 3AS = 27, SP = 21). The ratios of proportions of new to recrudescent infections were 0.2, 0.9, 1.4 and 1.9 on days 7, 14, 21 and 28, respectively (P < 0.001, chi(2) test for linear trend). Unexpected high new infection rates were observed early in follow-up on days 7 [5/26 (19.2%)] and 14 [24/51 (47.1%)]. These results impact significantly on resistance monitoring and point to the value of genotyping all recurrent infections in antimalarial trials.

VALIDATION OF MICROSATELLITE MARKERS FOR USE IN GENOTYPING POLYCLONAL PLASMODIUM FALCIPARUM INFECTIONS

Genotyping methods for Plasmodium falciparum drug efficacy trials have not been standardized and may fail to accurately distinguish recrudescence from new infection, especially in high transmission areas where polyclonal infections are common. We developed a simple method for genotyping using previously identified microsatellites and capillary electrophoresis, validated this method using mixtures of laboratory clones, and applied the method to field samples. Two microsatellite markers produced accurate results for single-clone but not polyclonal samples. Four other microsatellite markers were as sensitive as, and more specific than, commonly used genotyping techniques based on merozoite surface proteins 1 and 2. When applied to samples from 15 patients in Burkina Faso with recurrent parasitemia after treatment with sulphadoxine-pyrimethamine, the addition of these four microsatellite markers to msp1 and msp2 genotyping resulted in a reclassification of outcomes that strengthened the association between dhfr 59R, an anti-folate resistance mutation, and recrudescence (P = 0.31 versus P = 0.03). Four microsatellite markers performed well on polyclonal samples and may provide a valuable addition to genotyping for clinical drug efficacy studies in high transmission areas.

Comparison of microsatellite and antigen-coding loci for differentiating recrudescing Plasmodium falciparum infections from reinfections in Kenya

We have compared the ability of five Plasmodium falciparum microsatellites and three antigen-coding loci to differentiate recrudescence from reinfection. We used 133 pairs of P. falciparum-infected blood samples collected during in vivo drug efficacy trials from three sites in Kenya with different malaria endemicities. There were no significant differences between the marker subsets in their ability to discriminate recrudescences from new infections across the three sites. Overall, microsatellite loci revealed significantly higher expected heterozygosity and multiplicity of infection levels than antigen-coding loci. The mean expected heterozygosity across all loci in the three populations was significantly higher with microsatellites (0.70, 0.78 and 0.79) than antigen-coding loci (0.53, 0.60 and 0.62) for Mwea, Tiwi and Bondo areas, respectively. These observations can be explained by three non-exclusive hypotheses: (i) microsatellites are more polymorphic than antigenic loci; (ii) partially immune hosts remove certain parasites from infections on the basis of their antigenic alleles; and/or (iii) recombination occurs in vitro or in vivo with microsatellites.

Enhancing the Development and Approval of Acute Stroke Therapies

Previous Stroke Therapy Academic Industry Roundtable (STAIR) meetings focused on preclinical evidence of drug efficacy and enhancing acute stroke trial design and performance. A fourth (STAIR-IV) was held to discuss relevant issues related to acute stroke drug development and regulatory approval. The STAIR-IV meeting had 3 main focus areas. The first topic was novel approaches to statistical design of acute stroke trials and appropriate outcome measures. The second focus was the need for better cooperation among participants in stroke therapy development that may be addressed through a national consortium of stroke trial centers in the United States and elsewhere. Lastly, regulatory issues related to the approval of novel mono and multiple acute stroke therapies were discussed. The development of additional acute stroke therapies represents a large unmet need with many remaining challenges and also opportunities to incorporate novel approaches to clinical trial design that will lead to regulatory approval. The STAIR-IV meeting explored new concepts of trial methodology and data analysis, initiatives for implementing a US clinical trialist consortium, and pertinent regulatory issues to expedite approval of novel therapies.

PLASMODIUM FALCIPARUM GENOTYPING BY MICROSATELLITES AS A METHOD TO DISTINGUISH BETWEEN RECRUDESCENT AND NEW INFECTIONS

In vivo tests for susceptibility to antimalarial drugs require molecular methods to distinguish recrudescence from new infection. The most commonly used DNA markers (merozoite surface proteins [MSPs]) are under immune selective pressure, which might lead to misclassification. We evaluated immunologically neutral microsatellite markers in blood samples collected during a drug efficacy trial in Rwanda. Fifty percent of the infections classified as recrudescent by MSP were classified as new by microsatellite markers. Reciprocally, 23.3% of infections classified as recrudescent by microsatellite markers were identified as new by MSP. In drug efficacy studies, microsatellite markers should complement MSP genotyping to distinguish a recrudescence from a new infection.

New paradigms in the treatment of restless legs syndrome

Restless legs syndrome (RLS) is a common neurologic disorder occurring in 3% to 15% of the general population, which contributes to poor quality of life. Many patients go undiagnosed for years after onset of symptoms, which delays or prevents effective treatment. Extensive research over the past decade has led to a better understanding of RLS and effective treatment options. This review encompasses the most recently published pathophysiology, epidemiology, criteria for diagnosis, and clinical drug efficacy trials to provide clinicians with the information to effectively manage RLS. A comprehensive review of the medical literature was conducted and original research articles pertaining to RLS were evaluated. The pathophysiology of primary RLS is associated with dopaminergic dysfunction and abnormal brain iron metabolism. Secondary RLS is most often a consequence of iron deficiency. The prevalence of primary RLS is twofold greater in women and increases with age in men and women, although onset of symptoms may occur in up to 45% of patients before age 20 years. Patients may present with a variety of complaints including sleep disruption. Several studies have demonstrated the efficacy of low-dose levodopa and dopamine agonists. Ropinirole is the most widely studied. Other drugs that may help control symptoms include gabapentin, opioids, and clonazepam. Clinicians must be aware of the high prevalence of RLS, the potential for onset before age 20, and the various clinical presentations. Dopamine agonists are first-line therapy and provide symptom relief in 70% to 100% of patients.

Practical PCR genotyping protocols for Plasmodium vivax using Pvcs and Pvmsp1.

BackgroundPlasmodium vivax is the second most prevalent malaria parasite affecting more than 75 million people each year, mostly in South America and Asia. In addition to major morbidity this parasite is associated with relapses and a reduction in birthweight. The emergence and spread of drug resistance in Plasmodium falciparum is a major factor in the resurgence of this parasite. P. vivax resistance to drugs has more recently emerged and monitoring the situation would be helped, as for P. falciparum, by molecular methods that can be used to characterize parasites in field studies and drug efficacy trials.MethodsPractical PCR genotyping protocols based on polymorphic loci present in two P. vivax genetic markers, Pvcs and Pvmsp1, were developed. The methodology was evaluated using 100 P. vivax isolates collected in Thailand.Results and DiscussionAnalysis revealed that P. vivax populations in Thailand are highly diverse genetically, with mixed genotype infections found in 26 % of the samples (average multiplicity of infection = 1.29). A large number of distinguishable alleles were found for the two markers, 23 for Pvcs and 36 for Pvmsp1. These were generally randomly distributed amongst the isolates. A total of 68 distinct genotypes could be enumerated in the 74 isolates with a multiplicity of infection of 1.ConclusionThese results indicate that the genotyping protocols presented can be useful in the assessment of in vivo drug efficacy clinical trials conducted in endemic areas and for epidemiological studies of P. vivax infections.

ASSOCIATION OF PLASMODIUM FALCIPARUM ISOLATES ENCODING THE P. FALCIPARUM CHLOROQUINE RESISTANCE TRANSPORTER GENE K76T POLYMORPHISM WITH ANEMIA AND SPLENOMEGALY, BUT NOT WITH MULTIPLE INFECTIONS

The aim of the study was to assess whether infections with Plasmodium falciparum isolates encoding the P. falciparum chloroquine resistance transporter (pfcrt) gene K76T polymorphism, a molecular marker for chloroquine resistance, are associated with multiple infections, age, or clinical signs of malaria in a semi-immune population in a holoendemic area of Burkina Faso. The parameters of interest were investigated in 210 P. falciparum-positive inhabitants. Logistic regression analysis showed that pfcrt K76T-carrying isolates are significantly more likely to cause anemia and splenomegaly. Furthermore, we found that infections with P. falciparum isolates encoding pfcrt K76T are dependent on age rather than multiple infections. Our findings suggest that pfcrt K76T might serve as a valuable marker for assessing the long-term clinical effect of chronic infections with chloroquine-resistant P. falciparum isolates in populations, without the need of drug efficacy trials.

Current trends in the cardiovascular clinical trial arena (I).

The existence of effective therapies for most cardiovascular disease states, coupled with increased requirements that potential benefits of new drugs be evaluated on clinical rather than surrogate endpoints, makes it increasingly difficult to substantiate any incremental improvements in efficacy that these new drugs might offer. Compounding the problem is the highly controversial issue of comparing new agents with placebos rather than active pharmaceuticals in drug efficacy trials. Despite the recent consensus that placebos may be used ethically in well-defined, justifiable circumstances, the problem persists, in part because of increased scrutiny by ethics committees but also because of considerable lingering disagreement regarding the propriety and scientific value of placebo-controlled trials (and trials of antihypertensive drugs in particular).The disagreement also substantially affects the most viable alternative to placebo-controlled trials: actively controlled equivalence/noninferiority trials. To a great extent, this situation was prompted by numerous previous trials of this type that were marked by fundamental methodological flaws and consequent false claims, inconsistencies, and potential harm to patients.As the development and use of generic drugs continue to escalate, along with concurrent pressure to control medical costs by substituting less-expensive therapies for established ones, any claim that a new drug, intervention, or therapy is "equivalent" to another should not be accepted without close scrutiny. Adherence to proper methods in conducting studies of equivalence will help investigators to avoid false claims and inconsistencies. These matters will be addressed in the third article of this three-part series.

CHLOROQUINE-RESISTANT PLASMODIUM VIVAX MALARIA IN PERU

Reports from several sites in South America suggest the presence of isolated cases of chloroquine-resistant Plasmodium vivax malaria. To investigate the possibility of chloroquine-resistant P. vivax in Peru, we conducted 28-day in vivo drug efficacy trials at three sites in the Amazon region and one site on the northern Pacific Coast between 1998 and 2001. A total of 242 patients between the ages of 2 and 60 years were enrolled (177 from the Amazon region and 65 from the northern coast). All subjects received directly observed therapy with chloroquine, 25 mg/kg, over a three-day period. On enrollment, 49% had a documented fever and 96% had a history of fever; their geometric mean parasite density was 5,129 parasites/microL. A total of 212 (88%) of the 242 subjects completed their 28-day follow-up. Four of the 177 patients from the Amazon region had a recurrence of P. vivax parasitemia on days 21 and 28 after treatment was initiated. Two of these patients had chloroquine-resistant infections, based on polymerase chain reaction-single-stranded conformational polymorphism genotyping and chloroquine-desethylchloroquine blood levels, which were > or = 97 ng/mL at the time of the reappearance of parasitemia. None of the subjects studied on the northern Pacific Coast had recurrent parasitemia.

Encyclopedia of Alzheimer's disease: with directories of research, treatment and care facilities

The first and largest section of this encyclopedia offers such entries as disease pathology (genetic influences, disease stages and diagnosis), brain anatomy and physiology (cellular and biochemical cholinergic changes, the nervous system and plaque formation), disease process (stages and subtypes of Alzheimer's, coexisting illnesses and associated disorders), research and treatment (therapeutic options, drug efficacy and clinical trials), care and caregivers (memory aids, caregiver burdens and respite care) and government programs (laws, research centers, and federal insurance programs). Section Two is a directory, by state, of the National Institute of Aging's Alzheimer's Disease Centers, and government, clinical and university affiliated treatment and research centers. Section Three is a directory of home care providers and assisted living, adult day care and long-term residential facilities, noting location, special accommodations, certifications, number of beds, accreditations, insurance information, and URL if available.

Gender, ethnicity and genetics in cardiovascular disease: part 1: Basic principles.

Prior to 1993, most drug efficacy and safety trials were conducted in white males, although gender and racial differences in pharmacodynamics and pharmacokinetics have been documented since the early 1900s. Over the last 2 decades, supported by the FDA and legislation, attempts to include more women and minorities in clinical drug trials have been made, with limited success. Yet, there are important differences in pathophysiology and pharmacogenetics, as well as pharmacotherapeutic effectiveness. This is the first of 2 articles that review the basic scientific principles of such differences. In particular, genetic polymorphisms of cardiovascular candidate genes and drug metabolism are described. The pharmacodynamic and pharmacokinetic variations among genders and ethnicities are summarized.

DISTINGUISHING RECRUDESCENCE FROM REINFECTION IN A LONGITUDINAL ANTIMALARIAL DRUG EFFICACY STUDY: COMPARISON OF RESULTS BASED ON GENOTYPING OF MSP-1, MSP-2, AND GLURP

Genotyping frequently is used to distinguish recrudescent from new infections in antimalarial drug efficacy trials, but methodology and interpretation of results have not been standardized. We compared the utility of polymorphisms within 3 Plasmodium falciparum genes during a longitudinal trial in Kampala, Uganda. Merozoite surface protein-1 (msp-1) and merozoite surface protein-2 (msp-2) revealed greater diversity than glutamate-rich protein. Genotypes based on msp-1, msp-2, and all 3 genes combined were compared for 394 initial and subsequent isolates. Classification of most episodes as due to recrudescence or reinfection was straightforward. In 24% (msp-1), 16% (msp-2), and 62% (3 genes combined) of samples, subsequent episodes contained identical and new alleles, however. Our analysis suggested that such episodes should be classified as reinfections and not recrudescence. Comparing the 3 studied genes, msp-2 results were most accurate, and analysis of this single gene effectively distinguished recrudescence from reinfection in our study population.

Matrix metalloproteinase inhibitors (MMPIs): the beginning of phase I or the termination of phase III clinical trials.

The decade of the 1990s was ripe with enthusiasm for the use of MMPIs to treat cancer. Limitations to new cytotoxic chemotherapy approaches to treat solid cancers and a better understanding of tumor biology provided a strong impetus for alternative drug development. It is estimated that the pharmaceutical industry invested at least a billion dollars in this effort. Because MMPIs represent an entirely different therapeutic modality from proven anti-cancer agents, many of the therapeutic trials designed to test MMPIs in human patients with cancer bypassed traditional approaches to evaluate drug efficiency. The concept of systematic progression from small phase I (dose escalation to toxicity to examine drug safety), to phase II (drug treatment of patients with cancer types considered to be good candidates for the selected drug), to phase III (randomized trial of new drug versus best available therapy to determine drug efficacy) trials was modified. Much to the chagrin of everyone involved in these studies, the randomized trials of MMPIs in advanced cancer have, pretty much, flopped. This review article will attempt to dissect out aspects of previous human and animal studies that may be helpful in making decisions about the future of MMPI drug development for the treatment of cancer. The important questions to be addressed in this report are: What are the lessons that we have learned from preclinical (animal models) and clinical studies of MMPIs in cancer? Are we ready to abandon MMPIs as a therapeutic modality in cancer (termination of phase III trials) or do we need to have a better understanding of the myriad effects of MMPs in cancer before we proceed to develop different types of drugs that alter MMP activity in patients with cancer (beginning of new phase I trials)?

Advances with analgesics and NSAIDs for the treatment of spinal disorders.

One of the major developments with regard to chronic non-malignant pain in these last few years has been a better understanding of the mechanisms that act to maintain pain, while inferences about the pathophysiology have facilitated therapeutic decision-making. This chapter reviews the strength of evidence for the therapeutic effect of pharmacological symptomatic approaches using non-steroidal anti-inflammatory agents, opioids and co-analgesics in acute and chronic back pain with an emphasis on the results of randomized controlled trials as well as on the need for long-term comparative trials of drug efficacy, toxicity and compliance.

Reliability of a Rating Scale to Assess Post‐stroke Psychiatric Symptoms

Background: Various rating scales for post‐stroke psychiatric symptoms such as cognitive impairment have long been used in drug efficacy trials in Japan. However, their reliability has not been established. The purpose of the present study was to examine the inter‐rater and intra‐rater reliability of a rating scale, which has been conventionally used in Japan. Methods: The most frequent symptoms, including apathy, emotional and cognitive impairment, found in post‐stroke patients were assessed using a rating scale comprising 17 items and 4 global assessment scales. Semi‐structured interviews of 18 patients with symptoms with various degrees of severity were videotaped. Twelve physicians who were not interviewers independently assessed the severity of symptoms in the 18 patients by replaying the videotapes. This procedure was repeated twice with an interval of two months to examine inter‐rater and test‐retest reliability. Results: The results revealed almost satisfactory reliability. Intraclass correlation coefficients were over 0.6 in the inter‐rater analysis for most items and the concordance correlation coefficients were over 0.7 in the intra‐rater analysis. The rating scale was considered to be reliable, although some items showed relatively low agreement. Conclusion: The conventional rating scale to assess post‐stroke psychiatric symptoms showed satisfactory inter‐rater and intra‐rater reliability by the videotape method. The validity study should be further investigated.