Factorial designs in clinical trials: options for combination treatment studies.

2005 ◽  
pp. 24-32 ◽  
Author(s):  
David J Couper ◽  
James D Hosking ◽  
Ron A Cisler ◽  
David R Gastfriend ◽  
Daniel R Kivlahan
Keyword(s):  
Clinical Trials ◽  
Combination Treatment ◽  
Factorial Designs

scholarly journals Comparison of Repeated Doses of Ivermectin Versus Ivermectin Plus Albendazole for the Treatment of Onchocerciasis: A Randomized, Open-label, Clinical Trial

2019 ◽  
Vol 71 (4) ◽  
pp. 933-943 ◽  
Author(s):  
Linda Batsa Debrah ◽  
Ute Klarmann-Schulz ◽  
Jubin Osei-Mensah ◽  
Bettina Dubben ◽  
Kerstin Fischer ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Single Dose ◽  
Combination Treatment ◽  
Primary Outcome ◽  
Onchocerca Volvulus ◽  
Open Label ◽  
Annual Treatment ◽  
Repeated Doses ◽  
Better Than

Abstract Background Improved treatment for onchocerciasis is needed to accelerate onchocerciasis elimination in Africa. Aiming to better exploit registered drugs, this study was undertaken to determine whether annual or semiannual treatment with ivermectin (IVM; 200 µg/kg) plus albendazole (ALB; 800 mg single dose) is superior to IVM alone. Methods This trial was performed in Ghana and included 272 participants with microfilariae (MF), who were randomly assigned to 4 treatment arms: (1) IVM annually at 0, 12, and 24 months; (2) IVM semiannually at 0, 6, 12, 18, and 24 months; (3) IVM+ALB annually; or (4) IVM+ALB semiannually. Microfiladermia was determined pretreatment and at 6, 18, and 36 months. The primary outcome was the proportion of fertile and viable female worms in onchocercomata excised at 36 months. Results Posttreatment nodule histology showed that 15/135 (11.1%), 22/155 (14.2%), 35/154 (22.7%), and 20/125 (16.0%) living female worms had normal embryogenesis in the IVM annual, IVM semiannual, IVM+ALB annual, and IVM+ALB semiannual groups, respectively (P = .1229). Proportions of dead worms also did not differ between the 4 groups (P = .9198). Proportions of patients without MF at 36 months (1 year after the last treatment) were 35/56 (63%) after annual IVM, 42/59 (71%) after semiannual IVM, 39/64 (61%) after annual IVM+ALB, and 43/53 (81%) after semiannual IVM+ALB. Conclusions The combination treatment of IVM plus ALB was no better than IVM alone for sterilizing, killing adult worms, or achieving sustained MF clearance. However, semiannual treatment was superior to annual treatment for achieving sustained clearance of Onchocerca volvulus MF from the skin (P = .024). Clinical Trials Registration ISRCTN50035143

scholarly journals The efficacy of mirabegron in the treatment of urgency and the potential utility of combination therapy

2018 ◽  
Vol 10 (8) ◽  
pp. 243-256 ◽  
Author(s):  
Karl-Erik Andersson ◽  
Nurul Choudhury ◽  
Jean-Nicolas Cornu ◽  
Moses Huang ◽  
Cees Korstanje ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Combination Therapy ◽  
Combination Treatment ◽  
Primary Objective ◽  
Antimuscarinic Agent ◽  
Antimuscarinic Agents ◽  
Related Quality ◽  
Health Related ◽  
Bothersome Symptom ◽  
Clinical Benefits

Urgency is the prevalent and most bothersome symptom of overactive bladder (OAB) and the treatment of urgency is the primary objective in the management of OAB. Urgency has a major impact on other symptoms of OAB and culminates in an increased frequency of micturition and reduced volume voided, which may contribute to shorter intervals between the need to void. Antimuscarinic agents and mirabegron, a β3-adrenoceptor agonist, constitute the main oral pharmacotherapeutic options for the treatment of urgency and other OAB symptoms. The reduction of urgency and other OAB symptoms significantly improve health-related quality of life. This review will explore the distinct mechanisms of action and effects of antimuscarinic agents and mirabegron, in relation to their effect on the pathophysiology of urgency. The review will also provide an overview of the various validated measurements of urgency and the numerous clinical trials regarding antimuscarinic agent monotherapy, mirabegron monotherapy, or combination treatment with mirabegron added on to the antimuscarinic agent solifenacin. A narrative review of the literature relating to pathophysiology of urgency, the validated measurements of urgency, and clinical trials relating to the pharmacological treatment of urgency. Antimuscarinic agent monotherapy, mirabegron monotherapy, or combination treatment with mirabegron added on to the antimuscarinic agent solifenacin statistically significantly reduce the symptoms of urgency compared with placebo. Combination therapy with mirabegron added on to solifenacin also statistically significantly reduces the symptoms of severe urgency compared with antimuscarinic agent monotherapy. A critique of the clinical benefits of combination therapy is also provided. Combination therapy provides an alternative treatment in patients with OAB that includes urgency who respond poorly to first-line monotherapy and who may otherwise often move on to more invasive treatments.

scholarly journals Factorial designs: an overview with applications to orthodontic clinical trials

2013 ◽  
Vol 36 (3) ◽  
pp. 314-320 ◽  
Author(s):  
N. Pandis ◽  
T. Walsh ◽  
A. Polychronopoulou ◽  
C. Katsaros ◽  
T. Eliades
Keyword(s):  
Clinical Trials ◽  
Factorial Designs

scholarly journals Toxicity Profile of Combining PD-1/PD-L1 Inhibitors and Thoracic Radiotherapy in Non-Small Cell Lung Cancer: A Systematic Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Butuo Li ◽  
Chao Jiang ◽  
Linlin Pang ◽  
Bing Zou ◽  
Mingjun Ding ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Systematic Review ◽  
Clinical Trials ◽  
Cell Death ◽  
Combination Treatment ◽  
Small Cell ◽  
High Grade ◽  
Thoracic Radiotherapy ◽  
Small Cell Lung ◽  
Significant Difference

BackgroundThe combination of immune checkpoint inhibitors (ICIs) and thoracic radiotherapy (TRT) has shown significant clinical activity in patients with non-small cell lung cancer (NSCLC). However, the currently available data on adverse events (AEs) were derived from a small subset of patients included in prospective clinical trials or retrospective studies. Thus, we conducted this systematic review to determine the AEs associated with this combination treatment.MethodsAn electronic literature search was performed in databases and conference proceedings of prospective clinical trials assessing the combination of ICIs and TRT for patients with NSCLC. The systematic analysis was conducted to determine the profile and incidence of AEs of combination treatment. We further performed the comparison of AEs between programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors, and sequential and concurrent administration of ICIs and TRT to help identify high risk patients. The systematic analyses were conducted with the Review Manager (version 5.3; The Cochrane Collaboration, Oxford, United Kingdom) and Stata version 12.0 (StataCorp, College Station, TX, USA) software.ResultsEleven clinical trials involving 1,113 patients with NSCLC were eligible for analysis. The incidence of all-grade AEs was 95.5%; that of high-grade AEs (grade ≥3) was 30.2%. The most frequent all-grade AE was fatigue (49.7%), while pneumonitis was the most common high-grade AE (3.8%) and grade 5 AE (0.6%). Notably, the toxicity profiles of PD-1 and PD-L1 inhibitors were similar. Concurrent treatment was associated with a higher incidence of higher-grade AEs (41.6% vs 24.8%, P=0.17) and pneumonitis (7.1% vs 3.9%, P=0.14) compared to sequential treatment, but no significant difference was observed.ConclusionMost AEs of this combination treatment are tolerable; as the most common high-grade AE, pneumonitis deserves the utmost attention of physicians. The toxicity profiles of patients receiving PD-1 or PD-L1 were similar, and no significant difference was observed between concurrent and sequential treatment.

scholarly journals Early combination treatment with existing HIV antivirals: an effective treatment for COVID-19? 

2020 ◽  
Author(s):  
Roberto Nico Dallocchio ◽  
Alessandro Dessì ◽  
Andrea De Vito ◽  
Giovanna Delogu ◽  
Pier Andrea ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Molecular Docking ◽  
Severe Acute Respiratory Syndrome ◽  
Rna Polymerase ◽  
Protease Inhibitor ◽  
Combination Treatment ◽  
Binding Sites ◽  
Nucleoside Analogues ◽  
Rna Dependent Rna Polymerase ◽  
Protein Pocket

Abstract Since no effective therapy exists, we aimed to test existing HIV antivirals for combination treatment of Coronavirus disease 19 (COVID-19). Our molecular docking findings suggest that lopinavir, ritonavir, darunavir, and atazanavir activated interactions with the key binding sites of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) protease with a better Ki for lopinavir, ritonavir, and darunavir. Furthermore, we evidenced the ability of remdesivir, tenofovir, emtricitabine, and lamivudine to be incorporated in SARS-CoV-2 RNA-dependent RNA polymerase in the same protein pocket where poses the corresponding natural nucleoside substrates with comparable Ki and activating similar interactions. In principle, the four antiviral nucleotides might be used effectively against SARS-CoV-2. The combination of a protease inhibitor and two nucleoside analogues should be evaluated in clinical trials for the treatment of COVID-19.

Anti-Myeloma Effects of Carfilzomib with Cyclophosphamide (CY) or Bendamustine (Ben).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2952-2952
Author(s):  
Eric Sanchez ◽  
Mingjie Li ◽  
Cathy Wang ◽  
Haiming Chen ◽  
James R. Berenson
Keyword(s):  
Clinical Trials ◽  
Tumor Growth ◽  
Treatment Regimen ◽  
Combination Treatment ◽  
Tumor Size ◽  
Tumor Volume ◽  
Single Agent ◽  
Lower Percentage ◽  
Vehicle Group ◽  
Combination Regimen

Abstract Abstract 2952 Introduction: Carfilzomib (Onyx Pharmaceuticals, South San Francisco, CA, USA) is an irreversible proteasome inhibitor (PI) that has shown preclinical and clinical efficacy against multiple myeloma (MM). It has shown clinical benefit as a single agent and with steroids in early clinical trials, even among patients resistant to prior bortezomib treatment. We determined the anti-MM effects of carfilzomib in combination with cyclophosphamide (CY) or bendamustine (Ben) in vivo using our xenograft model of human MM, LAGk-1A. Methods: Each SCID mouse received a 20 – 40 mm3 MM tumor piece surgically implanted into the hind limb. Seven days post-implantation mice were bled, human IgG levels were measured by ELISA and mice randomized into groups. Carfilzomib stock solution (2 mg/ml) was diluted to 3 mg/kg using 10% capsitol and administered twice weekly via intravenous (i.v.) injection. Cyclophosphamide (Baxter, Deerfield, IL, USA) stock solution (20 mg/ml) was diluted in sodium chloride and administered via oral gavage once weekly at 10 mg/kg. Bendamustine (Teva Pharmaceuticals, North Wales, PA, USA) stock solution (5 mg/ml) was diluted to 5 mg/kg in sterile water and administered via intraperitoneal (i.p.) once weekly. Mice (n = 8) were bled to determine hIgG levels and the tumors were measured using standard calipers. Data was analyzed as the mean ± SEM. Results: LAGk-1A-bearing mice treated with single agent carfilzomib or CY did not show a reduction in tumor growth compared to vehicle-treated mice. In contrast, the combination of carfilzomib plus CY resulted in a statistically significant decrease in tumor size and IgG levels when compared to vehicle-treated mice on days 35, 42, 49, and 56 (tumor volume; P = 0.0007, P = 0.0003, P = 0.0008 and P = 0.0001: IgG levels; P = 0.0023, P = 0.0327, P = 0.0219 and P = 0.0190, respectively). Toxicity was minimal as seven of eight mice survived this combination regimen. Furthermore, tumor growth delay (TGD) to a volume of 1,125 mm3 was delayed by 53.6% (22 days, day 41 for control compared to day 63 for the carfilzomib + CY group) among animals receiving this combination treatment regimen when compared to vehicle-treated animals. In contrast, shorter TGDs were obtained when mice were dosed with single agents. When mice were dosed with carfilzomib alone, a TGD of 12.1% (5 days, day 41 for control compared to day 46 for the carfilzomib group) was obtained. When mice were dosed with CY alone, a TGD of 26.8% (11 days, day 41 for control compared to day 52 for the CY group) was obtained. Percentage inhibition of tumor growth (T/C) is represented as the median tumor volume of the test drug group over the median tumor volume of the vehicle group. A T/C ratio of ≤42% is indicative of drug efficacy. At day 56 post tumor implantation, mice receiving single agent treatment with carfilzomib or CY had T/C's of 88% and 67%, respectively. In contrast, at the same time point, mice receiving the cafilzomib plus CY regimen resulted in a lower percentage T/C of 29%. We also evaluated the combination of carfilzomib plus Ben in LAGk-1A-bearing mice. Animals treated with single agents did not result in a reduction in tumor volume compared to vehicle-treated mice. In contrast, the combination of carflzomib and Ben resulted in a decrease in tumor size compared to vehicle-treated mice on days 35, 42, 49, and 56 (P = 0.0184, P < 0.0001, P = 0.0035, and P = 0.0026, respectively). Additionally, this combination resulted in a reduction in IgG levels compared to vehicle-treated mice on days 42, 49 and 56 (P = 0.0426, P = 0.0257 and P = 0.0204, respectively). Furthermore, six of eight mice survived this treatment regimen. Compared to vehicle-treated mice, animals treated with the combination treatment showed a TGD to 1,250 mm3 of 38% (16 days, day 42 for control compared to day 58 for the carfilzomib + Ben). When compared to vehicle-treated mice, carfilzomib-treated animals showed a TGD of only 14.3% (6 days, day 42 for control compared to day 48 for the carfilzomib), and there was no TGD for mice treated with Ben alone. Conclusions: We have shown that the combination of carfilzomib plus CY or Ben shows marked anti-MM effects using our xenograft MM model LAGk-1A. The results from these preclinical studies provide the basis for clinical trials evaluating the combination of carfilzomib with CY or Ben for patients with MM. Disclosures: Berenson: Onyx: Consultancy, Honoraria, Speakers Bureau.

Clinical trials versus clinical practice in colorectal cancer: Equivalent populations?

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 802-802
Author(s):  
Alejandra Magdaleno Cremades ◽  
María del Carmen Ors Castaño ◽  
María Ballester Espinosa ◽  
Marta Llopis Cuquerella ◽  
María del Rocío Ramirez Belloch ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Clinical Trials ◽  
Clinical Practice ◽  
Adjuvant Treatment ◽  
Combination Treatment ◽  
Primary Tumor ◽  
Stage Iv ◽  
Stage Iii ◽  
Stage Iii Colon Cancer

802 Background: Clinical trials are criticized due to inclusion of selected populations. The aim of this analysis is to compare populations included in clinical trials which justify treatment recommendations in stage III and IV colorectal cancer (CRC) to patient populations in our area. Methods: Data related to age, sex, primary tumor and stage of CRC patients consecutively diagnosed in Vega Baja Hospital and Elche University General Hospital were collected. Also data regarding the same variables were collected from the publications of clinical trials which justify adjuvant treatment in stage III colon cancer and combination treatment with chemotherapy and targeted therapies in stage IV CRC. Results: We analyzed 249 patients with stage III colon cancer and 237 patients with stage IV CRC from our area. In our experience, 56.6% of stage III colon cancer were males, and median age was 66.2 years (23 - 91), with 41.8% ≥ 70 years. In clinical trials supporting adjuvant treatment 54 - 56.1% of patients were males, and median age was 59 - 61 years (19-83), with 14 - 21.7% ≥ 70 years. In our experience 64.4% of stage IV CRC patients were males, and median age was 67.2 years (38-89), 76.4% primary tumor in colon. In clinical trials supporting combination treatment with chemotherapy and targeted therapies 60-67% of patients were males, and median age was 59.2 – 62 years, primary tumor in colon 57.9 – 81% (Table). Conclusions: Patient populations included in clinical trials which support standard treatment in CRC are younger to those in our area. This fact, added to the restrictions based on inclusion and exclusion criteria of clinical trials, justify the qualification of “selected” to these populations not being representative of our clinical practice. [Table: see text]

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