scholarly journals Time to abandon placebo control in pivotal phase III trials?

2015 ◽  
Vol 14 (3) ◽  
pp. 306-307 ◽  
Author(s):  
John R. Geddes ◽  
Andrea Cipriani
Keyword(s):  
Phase Iii ◽  
Placebo Control ◽  
Pivotal Phase ◽  
Phase Iii Trials

scholarly journals Genetic epidemiology of dengue viruses in phase III trials of the CYD tetravalent dengue vaccine and implications for efficacy

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Maia A Rabaa ◽  
Yves Girerd-Chambaz ◽  
Kien Duong Thi Hue ◽  
Trung Vu Tuan ◽  
Bridget Wills ◽  
...  
Keyword(s):  
Genetic Epidemiology ◽  
Phase Iii ◽  
Envelope Gene ◽  
Dengue Vaccine ◽  
Virus Genotype ◽  
Pivotal Phase ◽  
Dengue Viruses ◽  
High Amino Acid ◽  
Phase Iii Trials ◽  
Trial Participants

This study defined the genetic epidemiology of dengue viruses (DENV) in two pivotal phase III trials of the tetravalent dengue vaccine, CYD-TDV, and thereby enabled virus genotype-specific estimates of vaccine efficacy (VE). Envelope gene sequences (n = 661) from 11 DENV genotypes in 10 endemic countries provided a contemporaneous global snapshot of DENV population genetics and revealed high amino acid identity between the E genes of vaccine strains and wild-type viruses from trial participants, including at epitope sites targeted by virus neutralising human monoclonal antibodies. Post-hoc analysis of all CYD14/15 trial participants revealed a statistically significant genotype-level VE association within DENV-4, where efficacy was lowest against genotype I. In subgroup analysis of trial participants age 9–16 years, VE estimates appeared more balanced within each serotype, suggesting that genotype-level heterogeneity may be limited in older children. Post-licensure surveillance is needed to monitor vaccine performance against the backdrop of DENV sequence diversity and evolution.

Pimavanserin: A Novel Antipsychotic for Parkinson’s Disease Psychosis

2017 ◽  
Vol 51 (6) ◽  
pp. 479-487 ◽  
Author(s):  
Kevin M. Bozymski ◽  
Denise K. Lowe ◽  
Kiersten M. Pasternak ◽  
Travis L. Gatesman ◽  
Ericka L. Crouse
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Practice ◽  
Phase Ii ◽  
English Language ◽  
Phase Iii ◽  
Pivotal Phase ◽  
Phase Iii Trials ◽  
Tract Infections ◽  
Motor Effects

Objective: To review the pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of pimavanserin for the treatment of hallucinations and delusions of Parkinson’s disease psychosis (PDP). Data Sources: A comprehensive PubMed search (1966 to January 2017) was conducted using the search terms Parkinson’s disease psychosis, hallucinations, delusions, pimavanserin, and ACP-103. Additional data were obtained from references of identified articles, governmental sources, manufacturer product labeling and website, and Clinicaltrials.gov. Study Selection and Data Extraction: All English-language trials evaluating pimavanserin in PDP were included. Data from review articles were included if relevant to clinical practice. One phase II and 3 phase III trials are discussed. Data Synthesis: Pimavanserin was approved in April 2016 for the treatment of delusions and hallucinations of PDP. One phase II and 2 phase III trials reported no difference for primary outcomes when pimavanserin was compared with placebo. The pivotal phase III ACP-103-020 trial adapted a scale to target more specific symptoms prevalent in PDP and showed that least-squares mean differences of the total PD-adapted Scale for the Assessment of Positive Symptoms score were significantly improved for pimavanserin-treated patients as compared with placebo-treated patients (difference = −3.06; 95% CI [−4.91 to −1.20]; P = 0.0014]). Pimavanserin’s adverse effect profile includes urinary tract infections, falls, peripheral edema, hallucinations, confusion, nausea, and headaches. Conclusion: Pimavanserin is a novel 5-HT2A inverse agonist that has shown promising results for managing hallucinations and delusions in patients with PDP without worsening motor effects or orthostasis. Yet its high cost and specialty pharmacy access may limit use in clinical practice.

scholarly journals Direct Oral Anticoagulants in Patients with Obesity and Atrial Fibrillation: Position Paper of Italian National Association of Hospital Cardiologists (ANMCO)

2021 ◽  
Vol 10 (18) ◽  
pp. 4185
Author(s):  
David Mocini ◽  
Stefania Angela Di Fusco ◽  
Edoardo Mocini ◽  
Lorenzo Maria Donini ◽  
Carlo Lavalle ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
High Body Mass Index ◽  
Normal Weight ◽  
Phase Iii ◽  
Fixed Dose ◽  
Pivotal Phase ◽  
Phase Iii Trials

The use of the direct oral anticoagulants dabigatran, rivaroxaban, apixaban and edoxaban (DOACs) offers some major advantages over warfarin and other vitamin K antagonists (VKAs). One advantage is the possibility to use a fixed dose in normal-weight patients, overweight patients and patients with obesity. However, the “one size fits all” strategy raised a concern regarding the possibility to undertreat patients with a high body mass index. No randomized controlled trials (RCTs) have ever compared VKAs and DOACs in this population. We analyzed data from the literature on DOAC pharmacokinetics and pharmacodynamics, results from the four pivotal phase III trials on non-valvular atrial fibrillation, retrospective observational studies and metanalyses. While we are aware of the limitation imposed by the absence of specific RCTs, we propose the position of the Italian Association of Hospital Cardiologists (ANMCO) on the use of DOACs in patients with obesity based on the existing evidence.

scholarly journals The role of golimumab in inflammatory arthritis. A review of the evidence

2018 ◽  
Vol 10 (9) ◽  
pp. 181-194
Author(s):  
Zunera Tahir ◽  
Arthur Kavanaugh
Keyword(s):  
Inflammatory Arthritis ◽  
Tumor Necrosis Factor Inhibitor ◽  
Phase Iii ◽  
Pivotal Phase ◽  
Double Blind ◽  
Pubmed Central ◽  
Factor Inhibitor ◽  
Phase Iii Trials ◽  
Necrosis Factor

Background: Golimumab (GOL) is a tumor necrosis factor inhibitor that is used for various types of inflammatory arthritis such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). This article is a systematic review of the evidence for the efficacy and safety of golimumab in inflammatory arthritides, specifically RA, PsA and AS. Methods: We conducted a search of randomized controlled trails in MEDLINE [PubMed], CENTRAL, Embase, and Current Controlled Trials databases (ClinicalTrials.gov) through 2017 for studies that evaluated golimumab in inflammatory arthritides. We focused on pivotal, phase III trials for this review of the safety and efficacy of the drug. However, as some important information is not available in detail in publications from the phase III studies, additional individual studies pertaining to antidrug antibodies were also included. Results: A total of 12, randomized, double-blind, placebo-controlled studies were included in this review of literature. Two trials focused on the GOL response in the PsA population, four trials focused on the GOL response in the AS population, and five trials focused on the GOL response in the RA population. Additional studies that evaluated autodrug antibodies produced in patients using GOL were also included. Conclusion: Golimumab was found to be clinically effective and also have a good safety profile in the treatment of RA, PsA, and AS based on data available from large studies.

scholarly journals Incorporating CDK4/6 Inhibitors in the Treatment of Advanced Luminal Breast Cancer

Breast Care ◽  
2017 ◽  
Vol 12 (5) ◽  
pp. 296-302 ◽  
Author(s):  
Isabel Echavarria ◽  
Yolanda Jerez ◽  
Miguel Martin ◽  
Sara López-Tarruella
Keyword(s):  
Breast Cancer ◽  
Endocrine Resistance ◽  
Safety Data ◽  
Predictive Biomarkers ◽  
Resistance Mechanisms ◽  
Phase Iii ◽  
Luminal Breast Cancer ◽  
Pivotal Phase ◽  
Phase Iii Trials ◽  
Cell Cycle Deregulation

After optimizing endocrine monotherapy modalities in the setting of advanced luminal breast cancer (BC), dual endocrine/targeted therapy combinations have been tested with positive results, and are transforming this BC subtype treatment landscape. Cell cycle deregulation is a hallmark of cancer that has become a key druggable target in hormone receptor (HR)-positive BC due to its role in endocrine resistance mechanisms. Cyclin dependent kinase (CDK)4/6 inhibitors have experienced a fast development in combination with endocrine therapy and have already been commercialized in some countries. In this review, we will summarize the development of these CDK4/6 inhibitors in luminal BC, from the preclinical data to the pivotal phase III trials that led to their approval, focusing on the efficacy and safety data for each of the treatment settings. Moreover, we will consider the challenges CDK4/6 inhibitors face in their positioning in the algorithm of treatment for advanced luminal BC and the considerations physicians should take into account when selecting these therapies for their patients. However, we are still in need of reliable predictive biomarkers in order to identify patients who will derive the greatest benefit from these drug combinations that are not exempt from toxicity.

Rates of peripheral neuropathy (PN) in patients (Pts) with relapsed and refractory multiple myeloma (RRMM) treated with carfilzomib vs comparators in pivotal phase III trials.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 8041-8041 ◽  
Author(s):  
Ruben Niesvizky ◽  
Vania Hungria ◽  
Joy Ho ◽  
Aleksandr Suvorov ◽  
Darrell White ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Phase Iii ◽  
Pivotal Phase ◽  
Free Survival ◽  
Pain Subscale ◽  
Patient Reported ◽  
Phase Iii Trials ◽  
History Of ◽  
Recent Phase ◽  
Clinical Trial Information

8041 Background: PN is a dose-limiting toxicity for some anti-MM agents, such as the proteasome inhibitor (PI) bortezomib (V). Carfilzomib (K), a novel irreversible PI associated with low PN, was evaluated in 2 recent phase 3 studies in RRMM pts. Methods: This analysis evaluated PN rates in ASPIRE (K [27 mg/m2]-lenalidomide [R]-dexamethasone[d] [KRd] vs Rd in relapsed MM; Stewart 2015) and ENDEAVOR (Kd [K 56 mg/m2] vs Vd in RRMM; Dimopoulos 2016). We evaluated grade ≥2 PN during treatment, patient-reported outcomes (PROs; QLQ-C30 pain, FACT/GOG-neurotoxicity subscales), and progression-free survival (PFS) in pts with BL history of PN. Results: In ASPIRE, grade ≥2 PN rate was low (8.9% [KRd] vs 8.0% [Rd]; Table). Pain subscale scores were similar between arms. Median PFS was longer with KRd vs Rd for pts with BL grade ≥2 PN. In ENDEAVOR, grade ≥2 PN rate during the study (prespecified key secondary endpoint) was significantly lower with Kd vs Vd (6.0% vs 32.0%; Table). Pts had significantly improved pain and neurotoxicity subscale scores with Kd vs Vd. PFS improved with Kd vs Vd in pts with BL history of grade ≥2 PN (Table). Conclusions: In ENDEAVOR, Kd resulted in less PN vs Vd; in ASPIRE, PN rate was similar for KRd vs Rd. PFS was longer with KRd and Kd vs Rd and Vd, respectively, including in pts with BL grade ≥2 PN. Improved pain and neurotoxicity outcomes with K may be attributed to better disease control and/or lower PN rates. Clinical trial information: NCT01568866, NCT01080391. [Table: see text]

scholarly journals The potential of lasmiditan in migraine

2020 ◽  
Vol 13 ◽  
pp. 175628642096784
Author(s):  
Jasper Mecklenburg ◽  
Bianca Raffaelli ◽  
Lars Neeb ◽  
Margarita Sanchez del Rio ◽  
Uwe Reuter
Keyword(s):  
Side Effects ◽  
Placebo Treatment ◽  
Phase Iii ◽  
Moderate Intensity ◽  
Pivotal Phase ◽  
Significant Difference ◽  
The Us ◽  
Phase Iii Trials ◽  
Bothersome Symptom

Lasmiditan, a highly selective 5-hydroxytryptamine receptor 1F (5-HT1F) agonist, is the first drug in its class and is lacking triptan-like vasoactive properties. The US Food and Drug Administration (FDA) has recently approved lasmiditan for the acute treatment of migraine in adults based on positive results of two pivotal phase III trials, which showed a significant difference to placebo in the proportion of patients achieving total migraine freedom within 2 h. More patients with lasmiditan achieved headache freedom and, in addition, freedom from the most bothersome symptom, that is, photophobia, than with placebo. Treatment-related side effects seem to be related to the rapid penetration of the drug into the brain and include dizziness, paresthesia and drowsiness, mostly of mild to moderate intensity. Interim results from an ongoing long-term phase III trial suggest a decrease in the frequency of adverse events after multiple lasmiditan use. Lasmiditan is a promising acute anti-migraine therapy, in particular for patients with cardiovascular risk factors, contraindications, or unwanted side effects to triptans.

scholarly journals Liposomal Doxorubicin in Breast Cancer

2007 ◽  
Vol 3 (5) ◽  
pp. 557-569 ◽  
Author(s):  
M Shehata ◽  
A Mukherjee ◽  
R Sharma ◽  
S Chan
Keyword(s):  
Breast Cancer ◽  
Liposomal Doxorubicin ◽  
Pegylated Liposomal Doxorubicin ◽  
Cytotoxic Agents ◽  
Phase Iii ◽  
Toxicity Profile ◽  
Pivotal Phase ◽  
Liposomal Formulations ◽  
Phase Iii Trials ◽  
Relative Differences

Drug-delivery carriers represent an important step in the development of targeted therapy. Encapsulation of drug into liposomes represents such a carrier, and helps to minimize side effects of conventional doxorubicin by improving the tumor-specific biodistribution profile. We review the development of the two liposomal doxorubicin formulations, pegylated liposomal doxorubicin and liposomal-encapsulated doxorubicin citrate from reconstitution and comparative pharmacokinetics to pivotal Phase III trials, with special emphasis in breast cancer. The relative differences in the toxicity profile can be attributed to their differences in the liposomal formulations. Areas of special interest include the reduction in cardiac toxicities and the improved efficacy, such as in the treatment of ovarian cancer. These improvements have also increased the potential of these liposomal formulations of doxorubicin for combination and sequencing with other biological and cytotoxic agents for clinical benefit.

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