scholarly journals How radical is radical cure? Site-specific biases in phase-III clinical trials underestimate the effect of radical cure against Plasmodium vivax hypnozoites

2021 ◽  
Author(s):  
John H. Huber ◽  
Cristian Koepfli ◽  
Guido España ◽  
Narimane Nekkab ◽  
Michael T. White ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Vector Control ◽  
Plasmodium Vivax ◽  
Trial Data ◽  
Phase Iii ◽  
Transmission Model ◽  
Radical Cure ◽  
Major Barrier ◽  
Site Specific ◽  
Phase Iii Clinical Trials

ABSTRACTBackgroundPlasmodium vivax relapses caused by reactivating hypnozoites are a major barrier for elimination and control of this form of malaria. Radical cure is a form of therapy capable of addressing this problem. Recent clinical trials of radical cure have yielded efficacy estimates ranging from 65% to 94%, with substantial variation across trial sites. We performed an analysis of simulated trial data using a transmission model to demonstrate that variation in efficacy estimates across trial sites can arise from differences in the conditions under which trials are conducted.Methods and FindingsOur analysis revealed that differences in transmission intensity, heterogeneous exposure, and relapse rate can yield efficacy estimates ranging as wide as 11-82%, despite simulating trial data under the uniform assumption that treatment had a 75% chance of clearing hypnozoites. A longer duration of prophylaxis leads to a greater measured efficacy, particularly at higher transmission intensities, making the comparison of the protection of different radical cure treatment regimens against relapse more challenging. We show that vector control and parasite genotyping offer two potential means to yield more standardized efficacy estimates that better reflect protection against relapse.ConclusionsWe predict that site-specific biases are likely to contribute to variation in efficacy estimates both within and across phase-III clinical trials. Future clinical trials can reduce site-specific biases by conducting trials in low-transmission settings where reinfections from mosquito biting are less common, by preventing reinfections using vector control measures, or by identifying and excluding reinfections that occur during follow-up using parasite genotyping methods.

scholarly journals How radical is radical cure? Site-specific biases in clinical trials underestimate the effect of radical cure on Plasmodium vivax hypnozoites

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
John H. Huber ◽  
Cristian Koepfli ◽  
Guido España ◽  
Narimane Nekkab ◽  
Michael T. White ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Vector Control ◽  
Plasmodium Vivax ◽  
Trial Data ◽  
Control Measures ◽  
Transmission Model ◽  
Radical Cure ◽  
Major Barrier ◽  
Site Specific ◽  
Treatment Regimens

Abstract Background Plasmodium vivax blood-stage relapses originating from re-activating hypnozoites are a major barrier for control and elimination of this disease. Radical cure is a form of therapy capable of addressing this problem. Recent clinical trials of radical cure have yielded efficacy estimates ranging from 65 to 94%, with substantial variation across trial sites. Methods An analysis of simulated trial data using a transmission model was performed to demonstrate that variation in efficacy estimates across trial sites can arise from differences in the conditions under which trials are conducted. Results The analysis revealed that differences in transmission intensity, heterogeneous exposure and relapse rate can yield efficacy estimates ranging as widely as 12–78%, despite simulating trial data under the uniform assumption that treatment had a 75% chance of clearing hypnozoites. A longer duration of prophylaxis leads to a greater measured efficacy, particularly at higher transmission intensities, making the comparison between the protection of different radical cure treatment regimens against relapse more challenging. Simulations show that vector control and parasite genotyping offer two potential means to yield more standardized efficacy estimates that better reflect prevention of relapse. Conclusions Site-specific biases are likely to contribute to variation in efficacy estimates both within and across clinical trials. Future clinical trials can reduce site-specific biases by conducting trials in low-transmission settings where re-infections from mosquito bite are less common, by preventing re-infections using vector control measures, or by identifying and excluding likely re-infections that occur during follow-up, by using parasite genotyping methods.

Rome I versus Rome II; Overlap in patients enrolled in tegaserod phase III clinical trials for irritable bowel syndrome (IBS)

2001 ◽  
Vol 120 (5) ◽  
pp. A284-A284
Author(s):  
B NAULT ◽  
S SUE ◽  
J HEGGLAND ◽  
S GOHARI ◽  
G LIGOZIO ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Irritable Bowel Syndrome ◽  
Phase Iii ◽  
Phase Iii Clinical Trials ◽  
Irritable Bowel ◽  
Rome I

Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials

2001 ◽  
Vol 28 (6) ◽  
pp. 620-625 ◽  
Author(s):  
Pierre Falardeau ◽  
Pierre Champagne ◽  
Patrick Poyet ◽  
Claude Hariton ◽  
[Eacute]ric Dupont
Keyword(s):  
Clinical Trials ◽  
Phase Iii ◽  
Phase Iii Clinical Trials ◽  
Naturally Occurring ◽  
Antiangiogenic Drug

scholarly journals Animal and Human Vaccines against West Nile Virus

Pathogens ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1073
Author(s):  
Juan-Carlos Saiz
Keyword(s):  
Clinical Trials ◽  
West Nile Virus ◽  
Vaccine Development ◽  
Phase Iii ◽  
West Nile ◽  
Specific Therapy ◽  
Phase Iii Clinical Trials ◽  
Neuroinvasive Disease ◽  
The Us ◽  
The Status

West Nile virus (WNV) is a widely distributed enveloped flavivirus transmitted by mosquitoes, which main hosts are birds. The virus sporadically infects equids and humans with serious economic and health consequences, as infected individuals can develop a severe neuroinvasive disease that can even lead to death. Nowadays, no WNV-specific therapy is available and vaccines are only licensed for use in horses but not for humans. While several methodologies for WNV vaccine development have been successfully applied and have contributed to significantly reducing its incidence in horses in the US, none have progressed to phase III clinical trials in humans. This review addresses the status of WNV vaccines for horses, birds, and humans, summarizing and discussing the challenges they face for their clinical advance and their introduction to the market.

scholarly journals The role of future treatments in the management of neovascular age-related macular degeneration in Europe

2021 ◽  
pp. 112067212110183
Author(s):  
Laurent Kodjikian ◽  
Carl Joe Mehanna ◽  
Salomon-Yves Cohen ◽  
François Devin ◽  
Sam Razavi ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Macular Degeneration ◽  
Age Related Macular Degeneration ◽  
Phase Iii ◽  
Vascular Endothelial ◽  
Real World Data ◽  
Phase Iii Clinical Trials ◽  
Age Related ◽  
Injection Frequency ◽  
Endothelial Growth Factor

Anti-vascular endothelial growth factor (VEGF) agents have transformed the management of patients with neovascular age-related macular degeneration (nAMD) over the past two decades. However, as more long-term real-world data become available, it is clear that treatment outcomes are inferior to those reported in large, controlled clinical trials. This is largely driven by undertreatment, that is, not maintaining a consistent injection frequency to achieve sustained VEGF suppression, whether due to patient non-compliance, an important injection burden, or non/incomplete anatomical response. Newer therapeutic advances under evaluation hold promise in achieving more, for less. We review the latest drugs currently in or having successfully finished phase III clinical trials, and determine their potential place in the management of patients with nAMD in Europe.

scholarly journals Matching comparisons of therapeutic efficacy suggest better clinical outcomes for patients treated with peginterferon beta-1a than with glatiramer acetate

2021 ◽  
Vol 14 ◽  
pp. 175628642097591
Author(s):  
Thomas F. Scott ◽  
Ray Su ◽  
Kuangnan Xiong ◽  
Arman Altincatal ◽  
Carmen Castrillo-Viguera ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Propensity Score ◽  
Clinical Outcomes ◽  
Glatiramer Acetate ◽  
Therapeutic Efficacy ◽  
Individual Patient Data ◽  
Patient Data ◽  
Phase Iii ◽  
Lower Probability ◽  
Phase Iii Clinical Trials

Background: Peginterferon beta-1a and glatiramer acetate (GA) are approved first-line therapies for the treatment of relapsing forms of multiple sclerosis, but their therapeutic efficacy has not been compared directly. Methods: Clinical outcomes at 2 years, including no evidence of disease activity (NEDA), for patients receiving peginterferon beta-1a 125 mcg every 2 weeks (Q2W) or GA 20 mg/ml once daily (QD) were compared by propensity score matching analysis using individual patient data from ADVANCE and CONFIRM phase III clinical trials. In addition, clinical outcomes at 1–3 years for patients receiving peginterferon beta-1a Q2W or GA 40 mg/ml three times a week (TIW) were evaluated using a matching-adjusted comparison analysis of individual patient data from ADVANCE and the ADVANCE extension study, ATTAIN, and aggregate patient data from the phase III GALA and the GALA extension studies. Results: Propensity-score-matched peginterferon beta-1a patients ( n = 336) had a significantly lower annualized relapse rate [ARR (0.204 versus 0.282); rate ratio = 0.724; p = 0.045], a significantly lower probability of 12-week confirmed disability worsening (10.0% versus 14.6%; hazard ratio = 0.625; p = 0.048), and a significantly higher rate of NEDA (20.3% versus 11.5%; p = 0.047) compared with GA 20 mg/ml QD patients after 2 years of treatment. Matching-adjusted peginterferon beta-1a patients (effective n = 276) demonstrated a similar ARR at 1 year (0.278 versus 0.318; p = 0.375) and significantly lower ARR at 2 years (0.0901 versus 0.203; p = 0.032) and 3 years (0.109 versus 0.209; p = 0.047) compared with GA 40 mg/ml TIW patients ( n = 834). Conclusion: Results from separate matching comparisons of phase III clinical trials and extension studies suggest that peginterferon beta-1a 125 mcg Q2W may provide better clinical outcomes than GA (20 mg/ml QD or 40 mg/ml TIW).

558 Programmed death (PD)-1 and PD-ligand-1 inhibitors in the treatment of non-small cell lung cancer: a systematic review of their efficacy and safety

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A592-A592
Author(s):  
Melissa Lingohr-Smith ◽  
Chelsea Deitelzweig ◽  
Grace Lin ◽  
Jay Lin
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Patient Outcomes ◽  
Nsclc Patient ◽  
Response Rates ◽  
Phase Iii ◽  
Combination Therapies ◽  
Phase Iii Clinical Trials ◽  
Programmed Death ◽  
Grade 3

BackgroundTreatment advances have been made in non-small cell lung cancer (NSCLC) with the development and approval of programmed death (PD)-1 and PD-ligand 1 (PD-L1) inhibitors. PD-1 and PD-L1 inhibitors may be used as monotherapies or in combination with other agents and have been shown to improve NSCLC patient outcomes in clinical trials. We conducted a systematic search to compare the efficacy and safety of PD-1/PD-L1 inhibitors in the treatment of NSCLC.MethodsA systematic literature search of PubMed was conducted to identify phase III clinical trials in which the efficacy of PD-1/PD-L1 inhibitors in the treatment of NSCLC was evaluated. PD-1 inhibitors included nivolumab and pembrolizumab; PD-L1 inhibitors included atezolizumab, avelumab, and durvalumab. Patient characteristics and efficacy data were extracted.ResultsSixteen phase III clinical trials were identified (nivolumab=4; pembrolizumab=5; atezolizumab=5; avelumab=1; durvalumab=1). Across the 3 nivolumab monotherapy trials (n=638; median ages: 61–63 years), median progression-free survival (PFS) ranged 2.3–4.2 months; response rates ranged 19%-26%; grade 3/4 adverse events occurred in 7%-18% of patients. Nivolumab in combination with iplimumab (n=583; median age: 64 years) had a median PFS of 5.1 months and response rate of 33%; grade 3/4 adverse events occurred in 33% of patients. Across the 3 pembrolizumab monotherapy trials (n=1,481; median ages: 63–64 years), median PFS ranged 3.9–10.3 months; response rates ranged 18%-45%; grade ≥3 adverse events occurred in 13%-27% of patients. In the 2 pembrolizumab combination therapy trials (n=688; median ages: 65 years), median PFS ranged 6.4–8.8 months; response rates ranged 48%-58%; grade ≥3 adverse events occurred in 67%-70% of patients. In the 4 atezolizumab combination therapy trials (n=1,486; median ages: 63–64 years), median PFS ranged 6.3–8.3 months; response rates ranged 47%-63.5%; grade 3/4 adverse events occurred in 54%-73% of patients. In the 3 monotherapy trials of atezolizumab (n=613; median age: 63 years), avelumab (n=396; median age: 64 years), and durvalumab (n=476; median age: 64 years), the median months of PFS were 2.7, 2.8, and 17.2, respectively; response rates were 14%, 15%, and 30%, respectively; grade ≥3 adverse events occurred in 15%, 10%, and 30.5% of patients, respectively.ConclusionsAlthough treatment responses varied, most of the evaluated PD-1/PD-L1 inhibitors were associated with a clinical benefit for NSCLC trial patients. Generally, treatment efficacy was greater with combination therapies, but adverse events occurred more frequently. Innovations in the targeting/personalization of PD-1/PD-L1 combination therapies will likely lead to improved NSCLC patient outcomes and further research is needed in this regard.

scholarly journals Immunological Backbone of Uveal Melanoma: Is There a Rationale for Immunotherapy?

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1055 ◽  
Author(s):  
Ernesto Rossi ◽  
Giovanni Schinzari ◽  
Ilaria Grazia Zizzari ◽  
Brigida Anna Maiorano ◽  
Monica Maria Pagliara ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Uveal Melanoma ◽  
Clinical Benefit ◽  
Standard Treatment ◽  
Checkpoint Inhibitors ◽  
Phase Iii ◽  
Phase Iii Clinical Trials

No standard treatment has been established for metastatic uveal melanoma (mUM). Immunotherapy is commonly used for this disease even though UM has not been included in phase III clinical trials with checkpoint inhibitors. Unfortunately, only a minority of patients obtain a clinical benefit with immunotherapy. The immunological features of mUM were reviewed in order to understand if immunotherapy could still play a role for this disease.

What are the reciprocal influences of randomized clinical trials and the patient–psychiatrist relationship?

1999 ◽  
Vol 14 (2) ◽  
pp. 93-100
Author(s):  
J. Catteau ◽  
C. Cyran ◽  
R. Bordet ◽  
C.E. Thomas ◽  
B.A. Dupuis
Keyword(s):  
Clinical Trials ◽  
Depressive Disorders ◽  
Randomized Clinical Trials ◽  
Antidepressant Drugs ◽  
Antidepressant Medication ◽  
Study Data ◽  
Phase Iii ◽  
Double Blind ◽  
Phase Iii Clinical Trials ◽  
Reciprocal Influences

SummaryThe goal of this prospective investigation was to study the course and the quality of patient-psychiatrist relationships during phase II / phase III clinical trials of antidepressant medication prescribed for depressive disorders. All patients who participated in the clinical trials (and subsequently in this survey) signed written informed consent statements and were subject to random double blind treatment assignment. Retrospective analysis of 118 investigations was carried out, and the patients involved were questioned concerning their experiences and impressions during and after the study. Data show that the outcome of clinical trials of antidepressant drugs are not a function of pre-existing good patient-psychiatrist relationships. On the other hand, no effects on the patient-psychiatrist relationship were found as a result of the experimental procedure, and it can be concluded that no detrimental effects on future patient-psychiatrist relationships were incurred.

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