Historical Clinical Trials Research Articles

Conventional Vaccine to Prevent AIDS A Paradigm or A Paradox? A SWOT Analysis

AIDS as a disease afflicts mankind for more than 3 decades. HIV, the causative is not yet checked with a prophylactic vaccine. The plausibility of the prevention by conventional prophylactic strategies based on Jenner’s conventional method of inducing memory response is reviewed here. In order to find the right direction towards achieving this goal, a SWOT analysis is represented here with a Venn diagram. Our increasing awareness on the viral genome and the antiviral treatment with the sensitive diagnostic tools strengthen the efforts, while the viral nature privileges its replenishment by hampering the host immune memory. Though antiviral drugs promise a notable degree of control, they render selection pressure favoring viral escapism with perking quasispecies or circulating recombinant forms (CRF). Few historical clinical trials teach us to frame new opportunities for the conduct of such trials that assures safety. The knowledge has exponentially increased on the host immune response, human genetics, retrovirology, drug development, gene delivery system to understand that HIV is the only pathogen that had the greatest consumption of our time and resources. The technological advancements add to our strength. However, the virus with its biological features proves its intrinsic competency for survival. Though the antiviral therapy confers some hope, the resistant forms pose a threat to their continuation. It emphasizes the need for prevention and suggests novel, unconventional prophylaxis. Treatment as a means of prevention and the use of immunomodulators to decrease the disease progression can help us to win the belligerence against AIDS.

QOL-23ASSOCIATION BETWEEN QUALITY OF LIFE AND VESTIBULAR SCHWANNOMA VOLUME, WORD RECOGNITION SCORES, AND PATIENT- AND PHYSICIAN-REPORTED DISEASE SEVERITY IN A US POPULATION OF NF2 PATIENTS

BACKGROUND: Neurofibromatosis type 2 (NF2) is associated with histologically benign but morbid tumors. Patient-reported outcomes (PROs) are important measures of patient function for this neuro-oncologic syndrome which impacts quality of life (QOL) due to multiple chronic tumors. Hence, NF2 serves as a model for developing PROs in neuro-oncology trials. The NFTI-QOL is a validated disease-specific QOL-instrument developed in the United Kingdom which has not been compared against historical clinical trial endpoints in NF2 including total vestibular schwannoma (VS) volume and best word recognition score (WRS). METHODS: An IRB-approved prospective observational study was conducted enrolling adult NF2 patients at Johns Hopkins. Measures included: NFTI-QOL, SF-36; total volume of bilateral VS, best WRS, provider- and patient-reported disease severity (ProvSev, PatSev) by institutionally-derived multi-item (e.g. symptom burden, age-of-onset, fatality-risk) and single-item Likert (mild, moderate, severe) scales. RESULTS: Twenty patients were enrolled; mean age at testing 46 + 21 years and age at diagnosis 32 + 18 years; 35% male. Prior treatment included surgery (50%), radiotherapy (25%), and systemic therapy (40%). Mean best WRS was 71.8 + 37% (n = 20). Two patients had no functional hearing and 10 had unilateral hearing. Mean total VS volume was 5.8 + 7.4 cc (n = 15). Additional lesions included meningioma (75%) and ependymoma (20%). Mean NFTI-QOL score was 8.5 + 5.1 and correlated well with all physical dimensions of the SF-36 (all p < 0.002). NFTI-QOL correlated well with PatSev (r = 0.60, 95%CI 0.21-0.82, p < 0.005) and multi-item ProvSev (r = 0.66, 0.31-0.85, p = 0.002) but not single-item ProvSev (r = 0.33, -0.13-0.68, p = 0.15). A trend toward positive correlation was observed between PatSev and multi-item ProvSev (r = 0.41, -0.04-0.72, p = 0.07). NFTI-QOL scores did not correlate with VS volume (r = 0.10, -0.44-0.58, p = 0.73), or best WRS (r = -0.40, -0.71-0.05, p-0.08). CONCLUSION: NFTI-QOL scores did not correlate with hearing function or tumor volume, but did correlate with patient and provider-reported disease severity underscoring the importance of patient-focused measures in therapeutic outcome assessment in NF2.

Intravenous thrombolysis for acute stroke: current standards and future directions.

Intravenous thrombolysis with the recombinant tissue plasminogen activator alteplase is the standard of care for patients with acute ischaemic stroke presenting within 4.5h of symptom onset. The odds of independent survival decline steeply with longer time to treatment delivery, reflecting progressive ischaemic damage to the brain. Standards accordingly emphasise optimisation of patient pathways to minimise treatment delays. Observational data and international clinical guidelines support the safety and efficacy of alteplase in many patient groups currently excluded from treatment (e.g. seizure at onset, concomitant diabetes and previous stroke) on the basis of historical clinical trial criteria. Future evolution of thrombolysis will optimise dosing, apply advanced imaging to extend treatment to groups currently excluded and investigate novel drugs, and adjunctive drug and device therapies. To date, trials of novel therapeutic approaches that have been applied at later time points have failed to demonstrate benefit, suggesting that the future gains are likely to arise from applications within current time windows.

A Toll-Like Receptor 3-Agonist as Promising Candidate in Multiple Sclerosis Treatment

Perturbations in immune processes play an important role in multiple sclerosis (MS), an autoimmune disorder where specific innate immune pattern-recognition receptors (PRRs), such as Toll-like receptors (TLRs) have recently been shown to play a major role in the initiation disease, the triggering of relapses, and regulation of CNS damage. The abnormal immune response in MS has been shown to be dependent on genetic background, despite environmental factors, including pathogens capable of overstimulating innate immune response through TLRs, appear to contribute to the development of autoreactive T cells that in turn cause myelin damage. However, whereas the upregulation of most TLRs plays a detrimental role in MS pathogenesis, recent studies suggest an ameliorative role of TLR3 in the onset and progression of MS and experimental autoimmune encephalomyelitis (EAE), a murine model of MS. TLR3 activation appears to protect from the disease, mainly through induction of interferon (IFN)β. Therefore, TLR3 stimulation with synthetic immunomodulators could represent a potential alternative approach in MS therapy. Among the investigational compounds TLR3-targeting, the mismatched double-stranded RNA molecule Ampligen®, can offer promise in the treatment of relapsing MS patients. Ampligen® is currently in phase III clinical trial in the treatment of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), an illness that shows remarkable levels of similarity with MS. The aim of this paper is to provide a brief overview about Ampligen® historical development, clinical pharmacology, clinical trials, and safety data, and to discuss about its potential role in MS treatment in the context of existing therapeutic options.

Sample size calculation based on efficient unconditional tests for clinical trials with historical controls

ABSTRACTIn historical clinical trials, the sample size and the number of success in the control group are often considered as given. The traditional method for sample size calculation is based on an asymptotic approach developed by Makuch and Simon (1980). Exact unconditional approaches may be considered as alternative to control for the type I error rate where the asymptotic approach may fail to do so. We provide the sample size calculation using an efficient exact unconditional testing procedure based on estimation and maximization. The sample size using the exact unconditional approach based on estimation and maximization is generally smaller than those based on the other approaches.

A Phase II Clinical Trial Of Lenalidomide and Prednisone In Low and Intermediate-1 IPSS Risk, Non-Del (5q) MDS Patients

IntroductionAnemia remains the most common management challenge for patients (pts) with lower risk MDS (Low and int-1 International prognostic Scoring System (IPSS) groups). Lenalidomide (LEN) is the treatment of choice for lower risk MDS pts with chromosome 5 deletion (del5q) where 67% of pts on MDS-003 study became red blood cell transfusion independence (RBC-TI). The MDS-002 study reported 26% RBC TI rate in non-del5q MDS pts. Strategies to optimize LEN responses in non-del5q include identifying predictive biomarkers or combination strategies to potentiate erythropoietin receptor signaling.Dexamethasone increases the proliferation of immature erythroid progenitors and in vitro increases erythroid progenitor sensitivity to LEN by enhancing erythropoietin (EPO)-transcriptional response and colony forming capacity (BL Ebert, un-published data).We hypothesize that combination treatment with LEN and prednisone will yield a higher erythroid response rate in patients with non-del (5q) lower risk MDS compared to the historical clinical trial experience with LEN monotherapy (MT). MethodsThe study was an investigator initiated two- step phase II design. In the first step 25 eligible patients were to be registered. If fewer than 4 of these 25 achieved erythroid hematological response (HI-E), then the study will be terminated early with the conclusion that the regimen does not warrant further investigation. Key eligibility criteria included confirmed MDS diagnosis, low or int-1 IPSS, RBC transfusion-dependent anemia defined as having received ≥4 transfusions of RBCs for Hgb ≤ 9.0 g/dl within 56 days or symptomatic anemia (Hgb ≤ 9.0 g/dl), erythroid stimulating agents failure or endogenous serum epo > 500 mU/ml., absolute neutrophil count (ANC) ≥ 500 /mm≥, platelet count ≥ 50,000 /mm≥, and creatinine Clearance ≥ 30 mL/min. The planned dose of LEN for subjects with a baseline CrCl >60ml/min was 10 mg/day. Prednisone dose was 30 mg po daily cycle 1 tapered by 10 mg after each cycle to 5 mg po every other day for responders beyond cycle 6. The primary objective was best response (HI-E) by IWG 2006 criteria within 24 weeks. ResultsTwenty five pts were enrolled. Baseline characteristics are summarized in table-1. The HI-E rate was 20% (5/25), and 22% (5/23) of evaluable patients. All responders became RBC TI (5 out of 23). The median time to response was 57 days. The median duration of response was 80 days (95% CI 69-91). Three out of 5 responders did not have hypomethylating agent (HMA) while 14 out of 20 non-responders received prior HMA. No patient transformed to acute myeloid leukemia. At a median follow up of 25 months the median OS was not reached (2 deaths).The most common adverse events deemed related to study drug (>10% of pts) included, neutropenia 54%, thrombocytopenia 40%, anemia 32%, diarrhea 27%, myalgia 20%, edema 24%, rash 20%, infection 12%, fever 12%, and fatigue 12%. Grade III/IV events included anemia (n=8), neutropenia (n=4), thrombocytopenia (n=3), and Cerebrovascular event (n=1). The most common causes for study discontinuation were no response (10 pts), loss of response (4pts), infection (4pts) and rash (4pts).Table 1n=25Agemedian72GenderMale17 (68%)RaceWhite23 (92%)ECOG PS08 (32%)116 (64%)21 (4%)RBC TDYes23 (92%)WHORA3 (12%)RARS6 (24%)RCMD13 (52%)RAEB-I2 (8%)MDS-U1 (4%)IPSSLow15 (60%)Int-110 (40%)Revised IPSSVery low1 (4%)Low19 (76%)intermediate5 (20%)LR-MDPSS15 (20%)214 (56%)34 (16%)Prior TherapyAzacitidine16 (64%)Decitabine3 (12%)ESA19 (76%) ConclusionCombination treatment with LEN and prednisone did not yield a higher erythroid response rate in patients with non-del (5q) lower risk MDS compared to the historical LEN MT. HI-E rates are less in pts who received HMA compared to MDS-002 study. Toxicity profile was similar to LEN (MT). Disclosures:Komrokji:Celgene: Research Funding, Speakers Bureau. Off Label Use: use of lenalidomide in non del 5q. Lancet:Celgene: Research Funding. List:Celgene: Research Funding.

Bayesian approach to the design and analysis of non‐inferiority trials for anti‐infective products

In the absence of placebo-controlled trials, determining the non-inferiority (NI) margin for comparing an experimental treatment with an active comparator is based on carefully selected well-controlled historical clinical trials. With this approach, information on the effect of the active comparator from other sources including observational studies and early phase trials is usually ignored because of the need to maintain active comparator effect across trials. This may lead to conservative estimates of the margin that translate into larger sample-size requirements for the design and subsequent frequentist analysis, longer trial durations, and higher drug development costs. In this article, we provide methodological approaches to determine NI margins that can utilize all relevant historical data through a novel power adjusted Bayesian meta-analysis, with Dirichlet process priors, that puts ordered weights on the amount of information a set of data contributes. We also provide a Bayesian decision rule for the non-inferiority analysis that is based on a broader use of available prior information and a sample-size determination that is based on this Bayesian decision rule. Finally, the methodology is illustrated through several examples.

AB0302 Results from the rate-ra study: a multicenter, open-label, single-arm study to evaluate the safety of administering rituximab at a more rapid infusion rate in patients with rheumatoid arthritis

BackgroundThe labelled dose of rituximab (RTX) in rheumatoid arthritis (RA) is 2 × 1000 mg IV infusions given 2 weeks apart (1 course), with recommended times of 4.25 hours (h)...

Abstract 3500: Analysis of the prevalence and prognostic significance of 92 endpoints using high throughput multiplexed qPCR In archival tissue from multiple NSCLC trials.

Abstract Over one third of all cancer related deaths worldwide are caused by non-small cell lung cancer (NSCLC). Until recently, tumor histology was rarely a factor in treatment decisions. However, this paradigm is shifting with the recent emergence of molecularly targeted therapies and next-generation chemotherapies. To better define the molecular sub-types of NSCLC that associate with active therapies and to evaluate their prognostic significance in historical clinical trials, we developed a microfluidics-based multiplexed PCR platform that enables analyses of 96 gene transcripts in 96 samples using material from as little as a single biopsy slide. The multiplexed assay panel consists of Taqman assays for markers of histology, chemo-resistance, prognosis, oncogenic pathway activity, epithelial vs. mesenchymal biology, as well as NSCLC drug targets. We report here on the development and validation of this 96-gene transcript-profiling panel. Using titrations of several lung biopsy formalin-fixed paraffin embedded (FFPE) tissues, we show that as little as 10 ng of FFPE RNA is feasible and yields robust gene expression data across all assays of the profiling panel. Using this technology, we tested archival lung biopsy samples from multiple Phase II and III studies to assess the prevalence and potential prognostic significance of 92 endpoints in parallel. We identified several markers that were strongly associated with histology as defined by TTF1 or p63 expression. In addition, several of the these markers were also associated with longer survival regardless of therapy, and will be discussed. These data suggest that retrospective analyses of clinical trial samples using Fluidigm-based expression analysis can be used to better inform future trial design in NSCLC. Citation Format: An D. Do, Teiko Sumiyoshi, Yulei Wang, Erica Schleifman, Yuanyuan Xiao, Barbara Klughammer, Cheryl V. Wong, Ilma Abbas, Ling Fu, Lukas C. Amler, Rajiv Raja, David S. Shames. Analysis of the prevalence and prognostic significance of 92 endpoints using high throughput multiplexed qPCR In archival tissue from multiple NSCLC trials. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3500. doi:10.1158/1538-7445.AM2013-3500

Meta-Analysis of Trials Comparing Oral Anticoagulation and Aspirin versus Dual Antiplatelet Therapy after Coronary Stenting

The combination of oral anticoagulation (OAC) and aspirin was the antithrombotic treatment initially adopted after coronary stenting (PCI-S). Although dual antiplatelet therapy with aspirin and a thienopyridine subsequently proved safer and more effective, OAC and aspirin combination is still used in patients with an indication for long-term OAC undergoing PCI-S. The absolute (AR) and relative (RR) risk of cardiac events and hemorrhagic/vascular complications of OAC and aspirin versus antiplatelet therapy were evaluated in a meta-analysis of four historical clinical trials. In 2,436 patients, the RR of a 30-day primary composite endpoint of death, myocardial infarction and the need for revascularization was significantly reduced by antiplatelet therapy (RR 0.41; 95% CI 0.25–0.69), whereas the RR of stent thrombosis (RR 0.26; 95% CI 0.06–1.14) and major bleeding (RR 0.36; 95% CI 0.14–1.02) was not statistically different. The 30-day AR of death, myocardial infarction, need for revascularization, major bleedings and vascular complications with OAC and aspirin were 0.65, 3.8, 4.2, 6.4 and 6.6%, respectively. In conclusion, due to the low AR of adverse events, the combination of OAC and aspirin appears an acceptable treatment after PCI-S in patients in whom long-term OAC is deemed mandatory.

Hypotheses and Type I Error in Active-Control Noninferiority Trials#

A fundamental assumption in the design and analysis of an active-control noninferiority trial is that the active control is truly effective. If this assumption does not hold, i.e., the active control is not effective, a harmful drug may be approved based on the result of a noninferiority trial. The assessment of the assumption is usually based on statistically significant results of historical randomized clinical trials on the active control, in which the conclusion may be falsely positive. This false positive rate, however, is not taken into consideration in current noninferiority trial test procedures. In this paper, various possible hypotheses for noninferiority trials are presented. The noninferiority hypotheses correctly associated with the objective of noninferiority trials are suggested. However, since there are no data collected for placebo in a noninferiority trial, this hypothesis cannot be directly tested by using data from noninferiority studies alone. The claim of noninferiority is based on the significant test for the control effect in historical trials and the significant test for noninferiority in a current noninferiority trial with a given fraction retention or margin. The false positive rate associated with such noninferiority test procedure is defined in this paper. The simulation result demonstrates the magnitude of the false positive rate inflation associated with the noninferiority test procedure.

The Ethics of Randomized Clinical Trials

Randomized clinical trials pose a number of fundamental ethical problems to which morally sensitive investigators must give careful consideration. The randomized double-blind clinical trial is ethically justified and the preferred method of demonstrating therapeutic effectiveness and safety. Alternate methods such as crossover and self-controlled designs, the use of historical controls, observational methods, and practitioner's clinical trials also exist and have their place in certain circumstances. The use of randomized double-blind clinical trials must assure adequate explanation of the research plan to the patient, the documentation of informed consent, adequate consideration of safety, and an acceptably low risk/benefit ratio.

Comparison of extracorporeal shock-wave lithotripsy and surgical lithotomy regarding patient satisfaction

A series of 19 patients who underwent extracorporeal shock-wave lithotripsy (ESWL) for urolithiasis was compared with 26 patients who were treated with surgical lithotomy (SL). A historical clinical trial was conducted using hospital chart records and telephone interviews to determine differences in outcome between the two groups. The ESWL group had significantly (p < 0.05) shorter duration of post-procedural pain, fewer requirements for pain medications, and decreased anxiety toward repetition of the procedure than did the SL group. In addition, the ESWL group had significantly (p < 0.05) shorter hospital stays, faster return to work on discharge from the hospital, and less physical limitation after the procedure. There was no appreciable difference in the occurrence of post-procedure urinary tract infections or in the patient's perception of the effectiveness of the procedure. These findings support the conclusion that treatment of urolithiasis by ESWL, is preferable to open flank SL.