Betrixaban: A Novel Oral Anticoagulant With a New Niche

Objective: To evaluate the efficacy, safety, and clinical implication of betrixaban for prophylaxis of venous thromboembolism (VTE) in patients with acute medical illness. Data Sources: A search for clinical trials was performed from January 2006 to January 2017 in English language using Clinicaltrials.gov and PubMed/MEDLINE. The following search terms were used: betrixaban, pharmacokinetics, pharmacology, and drug safety. Study Selection: The following limits were used to access the clinical trials: controlled clinical trial, randomized clinical trial, clinical trial, clinical trial phase II, and clinical trial phase III. The search was narrowed to include only humans. Data Extraction: The search criteria resulted in 6 clinical trials assessing the safety and efficacy of betrixaban. Additionally, references from publications assessing the safety and efficacy of betrixaban in atrial fibrillation, treatment and prevention of VTE, and extended duration VTE prophylaxis were assessed. Data Synthesis: Prior to 2017, no anticoagulant therapy had been approved for extended VTE prophylaxis in acutely ill medical patients. Betrixaban is the first direct oral anticoagulant approved for VTE prophylaxis in adult, acutely ill patients at risk for thromboembolisms. Based on the APEX trial, betrixaban 80 mg administered daily for 35 to 42 days was compared to enoxaparin administered daily for 6 to 14 days. In 7441 patients, fewer VTEs were seen in the betrixaban compared to enoxaparin with no significant difference in adverse reactions. Conclusion: Based on clinical trials, betrixaban appears to be safe and effective in preventing VTE in acutely ill patients who are at risk of developing VTE.

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EVALUASI KHASIAT DAN KEAMANAN OBAT (UJI KLINIK)

Majalah Kedokteran Andalas ◽

10.22338/mka.v34.i1.p31-38.2010 ◽

2015 ◽

Vol 34 (1) ◽

pp. 31

Author(s):

Rahmatini Rahmatini

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Phase I ◽

Phase Ii ◽

Phase Ii Clinical Trial ◽

Phase I Clinical Trial ◽

Phase Iii ◽

Phase Iii Clinical Trials ◽

Trial Phase

AbstrakUji klinik adalah suatu pengujian khasiat obat baru pada manusia, dimana sebelumnya diawali oleh pengujian pada binatang atau uji pra klinik. Pada dasarnya uji klinik memastikan efektivitas, keamanan dan gambaran efek samping yang sering timbul pada manusia akibat pemberian suatu obat. Bila uji klinik tidak dilakukan maka dapat terjadi malapetaka pada banyak orang bila langsung dipakai secara umum seperti pernah terjadi dengan talidomid (1959-1962) dan obat kontrasepsi pria (gosipol) di Cina. Setiap obat yang ditemukan melalui eksperimen in vitro atau hewan coba tidak terjamin bahwa khasiatnya benar-benar akan terlihat pada penderita. Pengujian pada manusia sendirilah yang dapat “menjamin” apakah hasil in vitro atau hewan sama dengan manusia.Uji klinik terdiri dari 4 fase, yaitu uji klinik fase I.Uji klinik fase II, uji klinik fase III dan uji klinik fase IV. Uji klinik fase I dilakukan pada manusia sehat, bertujuan untuk menentukan dosis tunggal yang dapat diterima, Uji klinik fase II, dilakukan pada 100-200 orang penderita untuk melihat apakah efek farmakologik yang tampak pada fase I berguna atau tidak untuk pengobatan. Uji klinik fase III dilakukan pada sekitar 500 penderita yang bertujuan untuk memastikan bahwa suatu obat baru benar-benar berkhasiat. Uji klinik fase IV merupakan pengamatan terhadap obat yang telah dipasarkan. Fase ini bertujuan menentukan pola penggunaan obat di masyarakat serta pola efektifitas dan keamanannya pada penggunaan yang sebenarnya.Uji klinik yang baik dilakukan dengan prosedur yang sudah digariskan dan komponen- komponennya disiapkan dengan matang sehingga hasilnya betul- betul dapat dimanfaatkan sebagai acuan pengobatan.Kata kunci : Khasiat- keamanan- uji klinikAbstractClinical trials is a new drug efficacy testing in humans, which previously preceded by testing on animals or pre-clinical testing. Basically, clinical trials confirm description of effectiveness, safety and side effects that often arise in humans because given of a drug. If clinical trials are not done then it can be evil in many people when directly used in general as once happened with thalidomide (1959-1962) and male contraceptive drugs (gossypol) in China. Any drug that is found through experiments in vitro or animal is not guaranteed that the propertiesTINJAUAN PUSTAKA32will actually be seen in patients. Tests on humans themselves who can "guarantee" if the results of in vitro or animal similar to humans.Clinical trial consisted of 4 phases, namely phase I clinical trial, phase II clinical trial, phase III clinical trials, and phase IV clinical trial. Phase I clinical trial, performed on healthy humans, aims to determine an acceptable single-dose, phase II clinical trial, performed on 100-200 patiens to see whether the pharmacologic effects seen in Phase I is useful or not for treatment. Phase III clinical trials conducted on about 500 patients which aims to ensure that a new drug is really efficacy. Phase IV clinical trial is an observation of the drug has been marketed. This phase aims to determine patterns of drug use in society and patterns of effectiveness and safety in actual use.Good clinical trials conducted with procedures that have been outlined and its components prepared and thus the results can actually be used as a reference treatment. Key words : Efficacy – Safety - Clinical trial

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The case for introducing pre-registered confirmatory pharmacological pre-clinical studies

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x18760109 ◽

2018 ◽

Vol 38 (5) ◽

pp. 749-754 ◽

Cited By ~ 1

Author(s):

Olivia Kiwanuka ◽

Bo-Michael Bellander ◽

Anders Hånell

Keyword(s):

Clinical Trial ◽

Traumatic Brain Injury ◽

Clinical Trials ◽

Brain Injury ◽

Network Analysis ◽

Clinical Studies ◽

Phase Iii ◽

Phase Iii Clinical Trial ◽

Phase Iii Clinical Trials ◽

Experimental Drugs

When evaluating the design of pre-clinical studies in the field of traumatic brain injury, we found substantial differences compared to phase III clinical trials, which in part may explain the difficulties in translating promising experimental drugs into approved treatments. By using network analysis, we also found cases where a large proportion of the studies evaluating a pre-clinical treatment was performed by inter-related researchers, which is potentially problematic. Subjecting all pre-clinical trials to the rigor of a phase III clinical trial is, however, likely not practically achievable. Instead, we repeat the call for a distinction to be made between exploratory and confirmatory pre-clinical studies.

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A Review of Phase III Clinical Trials of Prostate Cancer Chemoprevention

Annals of The Royal College of Surgeons of England ◽

10.1308/003588407x179125 ◽

2007 ◽

Vol 89 (3) ◽

pp. 207-211 ◽

Cited By ~ 18

Author(s):

JF Thorpe ◽

S Jain ◽

TH Marczylo ◽

AJ Gescher ◽

WP Steward ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Trial ◽

Clinical Trials ◽

Cancer Prevention ◽

Age Of Onset ◽

Cancer Chemoprevention ◽

Phase Iii ◽

Phase Iii Clinical Trials ◽

Prostate Cancer Prevention ◽

Phase Iii Trials

INTRODUCTION Prostate cancer is an excellent target for chemoprevention strategies; given its late age of onset, any delay in carcinogenesis would lead to a reduction in its incidence. This article reviews all the completed and on-going phase III trials in prostate cancer chemoprevention. PATIENTS AND METHODS All phase III trials of prostate cancer chemoprevention were identified within a Medline search using the keywords ‘clinical trial, prostate cancer, chemoprevention’. RESULTS In 2003, the Prostate Cancer Prevention Trial (PCPT) became the first phase III clinical trial of prostate cancer prevention. This landmark study was terminated early due to the 24.8% reduction of prostate cancer prevalence over a 7-year period in those men taking the 5α-reductase inhibitor, finasteride. This article reviews the PCPT and the interpretation of the excess high-grade prostate cancer (HGPC) cases in the finasteride group. The lack of relationship between cumulative dose and the HGPC cases, and the possible sampling error of biopsies due to gland volume reduction in the finasteride group refutes the suggestion that this is a genuine increase in HGPC cases. The other on-going phase III clinical trials of prostate cancer chemoprevention – the REDUCE study using dutasteride, and the SELECT study using vitamin E and selenium – are also reviewed. CONCLUSIONS At present, finasteride remains the only intervention shown in long-term prospective phase III clinical trials to reduce the incidence of prostate cancer. Until we have the results of trials using alternative agents including the on-going REDUCE and SELECT trials, the advice given to men interested in prostate cancer prevention must include discussion of the results of the PCPT. The increased rate of HGPC in the finasteride group continues to generate debate; however, finasteride may still be suitable for prostate cancer prevention, particularly in men with lower urinary tract symptoms.

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Clinical Trial Regulations In India : Past, Present and Future

JMS SKIMS ◽

10.33883/jms.v20i1.305 ◽

2017 ◽

Vol 20 (1) ◽

pp. 5-17

Author(s):

Haroon Rashid

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Disease Burden ◽

International Standards ◽

New Drugs ◽

Safety And Efficacy ◽

Long Time ◽

Regulatory Bodies ◽

Guidance Documents ◽

Human Use

Clinical trials are the only way of establishing the safety and efficacy of any new drug before its introduction in the market for human use. Clinical trials (with safeguards) are necessary for introduction of new drugs for a country like India, considering its disease burden and emergence of new variants of disease.The regulatory bodies need to frame guidelines and regulatory approval processes on a par with international standards. Many of the new laws, guidance documents, notifications and initiatives for regulating pharmaceutical industry were in the charts for quite a long time. Indian regulatory authorities have started looking into speedy implementation and providing support in terms ofnecessary infrastructure and investment. JMS 2017; 20(1):5-17

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Safety and Efficacy of Anti-Bcma CAR-T Cells for Relapsed/Refractory Multiple Myeloma: A Systematic Review of Literature

Blood ◽

10.1182/blood-2020-134529 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 5-6

Author(s):

Israr Khan ◽

Abdul Rafae ◽

Anum Javaid ◽

Zahoor Ahmed ◽

Haifza Abeera Qadeer ◽

...

Keyword(s):

Clinical Trial ◽

Multiple Myeloma ◽

Clinical Trials ◽

T Cells ◽

Partial Response ◽

Residual Disease ◽

Safety And Efficacy ◽

Refractory Multiple Myeloma ◽

Car T Cells ◽

Car T

Background: Multiple myeloma (MM) is a plasma cell disorder and demonstrates overexpression of B cell maturation antigen (BCMA). Our objective is to evaluate the safety and efficacy of chimeric antigen receptor T cells (CAR-T) against BCMA in patients with relapsed/refractory multiple myeloma (RRMM). Methods: We conducted a systematic literature search using PubMed, Cochrane, Clinicaltrials.gov, and Embase databases. We also searched for data from society meetings. A total of 935 articles were identified, and 610 were screened for relevance. Results: Data from thirty-one original studies with a total of 871 patients (pts) were included based on defined eligibility criteria, see Table 1. Hu et al. reported an overall response rate (ORR) of 100% in 33 pts treated with BCMA CAR-T cells including 21 complete response (CR), 7 very good partial response (VGPR), 4 partial response (PR). Moreover, 32 pts achieved minimal residual disease (MRD) negative status. Chen et al. reported ORR of 88%, 14% CR, 6% VGPR, and 82% MRD negative status with BCMA CAR-T therapy in 17 RRMM pts. In another clinical trial by Han et al. BCMA CAR-T therapy demonstrated an ORR of 100% among 7 evaluable pts with 43% pts having ≥ CR and 14% VGPR. An ORR of 100% with 64% stringent CR (sCR) and 36% VGPR was reported with novel anti-BCMA CART cells (CT103A). Similarly, Li et al. reported ORR of 87.5%, sCR of 50%, VGPR 12.5%, and PR 25% in 16 pts. BCMA targeting agent, JNJ-4528, showed ORR of 91%, including 4sCR, 2CR, 10MRD, and 7VGPR. CAR-T- bb2121 demonstrated ORR of 85%, sCR 36%, CR 9%, VGPR 57%, and MRD negativity of 100% (among 16 responsive pts). GSK2857916, a BCMA targeting CAR-T cells yielded ORR of 60% in both clinical trials. Three studies utilizing bispecific CART cells targeting both BCMA & CD38 (LCARB38M) reported by Zhao et al., Wang et al., and Fan et al. showed ORR of 88%, 88%, & 100% respectively. Topp et al. reported ORR of 31% along with 5 ≥CR and 5 MRD negative status in 42 pts treated with Bi T-cells Engager BiTE® Ab BCMA targeting antigen (AMG420). One clinical trial presented AUTO2 CART cells therapy against BCMA with an ORR of 43%, VGPR of 14%, and PR of 28%. CT053CAR-BCMA showed 14sCR and 5CR with a collective ORR of 87.5% and MRD negative status of 85% in 24 and 20 evaluable pts, respectively. Likewise, Mikkilineni et al. reported an ORR of 83%, sCR of 16.7%, and VGPR & PR of 25% and 41% in 12 pts treated with FHVH-BCMA T cells. Similar results are also reported in other clinical trials of BCMA targeting CART therapy (Table 1). The most common adverse effects exhibited were grade 1-3 hematologic (cytopenia) and cytokine release syndrome (CRS) (mostly reversible with tocilizumab). Conclusion: Initial data from ongoing clinical trials using BCMA targeting CAR-T therapy have yielded promising results both in terms of improved outcome and tolerable toxicity profiles. Although two phase 3 trails are ongoing, additional data is warranted to further ensure the safety and efficacy of anti-BCMA CAR-T cells therapy in pts with RRMM for future use. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

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Ethical Issues and Barriers for Multi-National Paediatric Clinical Trials: The Challenging Experience of the DEEP Project

Blood ◽

10.1182/blood-2019-124689 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4820-4820

Author(s):

Viviana Giannuzzi ◽

Mariagrazia Felisi ◽

Hugo Devlieger ◽

Aurelio Maggio ◽

George Papanikolaou ◽

...

Keyword(s):

Clinical Trials ◽

Ethical Issues ◽

Descriptive Analysis ◽

National Level ◽

Comparative Trial ◽

Phase Iii ◽

Eu Countries ◽

Paediatric Trial ◽

Significant Difference ◽

The Eu

Introduction: The procedures and requirements for the clinical trial application (CTA) to Ethics Committees (ECs) and/or Competent Authorities (CAs) are not fully harmonised, and this is even more evident when non-EU countries are involved. This lack of harmonisation makes more difficult the approach in the case of 'small populations', such as children and patients affected by rare diseases. A phase III efficacy-safety comparative trial (DEEP-2) involving paediatric patients affected by transfusion dependent haemoglobinopathies from seven European and non-European countries (Albania, Cyprus, Greece, Italy, United Kingdom, Egypt, Tunisia) was carried out in the context of a FP7 project (HEALTH-F4-2010-G.A. n. 261483) and included in an agreed Paediatric Investigation Plan. Aims: The aims of this paper are to describe in a complex multi-national/multi-ethnic framework the different provisions and procedures to authorise a paediatric trial in EU/non-EU countries and to evaluate the possible impact of the following key indicators on the timing of ECs approval and CAs authorisation: complexity of the national/local provisions and procedures to authorise a paediatric trial, including the number of ECs and CAs to be addressed; number and type of additional local/national documentation; number of queries from CAs and ECs; geographic setting (EU and non-EU). Methods: The following information was collected from official websites and through a survey addressed to Principal Investigators: The regulatory and legal frameworks in force at the time of the submission of DEEP-2 in each involved country;The procedures required at local/national level (i.e. number of ECs and CAs to be addressed, parallel or subsequent submission to the CA and the EC, preparation of the CTA form and documents required from CAs and ECs);The timing of ECs approval and CAs authorisation, including number and types of queries, were collected from DEEP-2 Trial Master File. Descriptive analysis, Wilcoxon Rank-Sum test and General Linear Model (GLM) analysis were used to describe results and to analyse significance of the considered indicators. Results: In the EU countries, relevant legislative acts apply and include GCP and specific procedures for paediatric trials, in non-EU countries GCP guidelines apply but have not been implemented in the national laws regulating clinical trials. Moreover, within the 4 EU Member States a different approach was in place, even if under the same rules (i.e. Directive 2001/20/EC as implemented in the national law) with distinctive documents required for the CTA in almost all the EU countries compared with the EC provisions. The CTAs were performed in the period June 2012 - September 2015 in 23 trial sites. The EC approvals and CA authorisations were issued between January 2013 - September 2015. In the EU countries, the authorisation process was completed within 7,3 to 33,8 months (median = 15 months), while in non-EU countries, the authorisation process was completed by 7 months (median = 4 months) (figure 1). In particular, the comparison of the CA time authorisation shows a significant difference between EU and non-EU clusters (p = 0.001); however, if the statistical model is adjusted for the number of EC requests as covariate, the difference is not significant. Thus, it seems that the main factor influencing the time for EC approval is the number of requests for changes/clarifications (mainly on informed consent/assent, study protocol, insurance) (figure 2). Conclusion: Delays in completion of the authorisation phase in many countries seems to be a relevant issue and the timeframes for the authorisation in EU countries are not compliant with the European requirements (60 days for single opinion release and 30 days for its acceptance, as stated in Directive 2001/20/EC). The main reasons for delay is the complexity of the procedures and the requests from the ECs/CAs. In non-EU countries, procedures are different and faster with less requests from ECs and CAs. The upcoming application of a stronger set of rules, CT-Regulation (EU) 536/2014, is expected to harmonise practices in Europe and possibly outside Europe. The final aim of this change should be to assure a good balance between a timely approval and a high-level of children protection. Disclosures Reggiardo: CVBF: Consultancy. Tricta:ApoPharma: Employment.

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SAFETY AND EFFICACY OF CONCOMITANTLY USED DIRECT ORAL ANTICOAGULANT AND AMIODARONE IN PATIENTS WITH NON-VALVULAR ATRIAL FIBRILLATION: A META-ANALYSIS OF PROSPECTIVE RANDOMIZED CLINICAL TRIALS

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(18)30837-4 ◽

2018 ◽

Vol 71 (11) ◽

pp. A296

Author(s):

Bradley Peltzer ◽

Florentino Lupercio ◽

Jorge Romero ◽

Carola Maraboto Gonzalez ◽

David Briceno ◽

...

Keyword(s):

Atrial Fibrillation ◽

Clinical Trials ◽

Oral Anticoagulant ◽

Randomized Clinical Trials ◽

Meta Analysis ◽

Direct Oral Anticoagulant ◽

Safety And Efficacy

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Safety and efficacy outcomes with nivolumab plus ipilimumab in patients with advanced renal cell carcinoma and low Karnofsky performance status: Results from the CheckMate 920 trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.315 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 315-315

Author(s):

Thomas E. Hutson ◽

Bradley Curtis Carthon ◽

Jeffrey Yorio ◽

Sunil Babu ◽

Heidi Ann McKean ◽

...

Keyword(s):

Clinical Trial ◽

Renal Cell Carcinoma ◽

Clinical Trials ◽

Adverse Events ◽

Clear Cell ◽

Karnofsky Performance Status ◽

Performance Status ◽

Objective Response ◽

Safety And Efficacy ◽

Grade 3

315 Background: Combination therapy with nivolumab + ipilimumab (NIVO+IPI) has demonstrated long-term efficacy and tolerability for patients (pts) with previously untreated advanced renal cell carcinoma (aRCC). Most pivotal clinical trials in pts with aRCC have excluded pts with low Karnofsky performance status (KPS; < 70%). CheckMate 920 is a multi-arm, phase IIIb/IV, open-label clinical trial of NIVO+IPI treatment in pts enrolled in a community practice setting with aRCC and a high unmet medical need. We present safety and efficacy results for the cohort of pts with aRCC of any histology and KPS 50%–60% from CheckMate 920 (NCT02982954). Methods: Pts with previously untreated advanced/metastatic RCC and KPS 50%–60% received NIVO 3 mg/kg + IPI 1 mg/kg Q3W × 4 doses followed by 480 mg NIVO Q4W for ≤ 2 years or until disease progression/unacceptable toxicity. The primary endpoint was incidence of grade ≥ 3 immune-mediated adverse events (imAEs) within 100 days of last dose of study drug. Key secondary endpoints included progression-free survival (PFS) and objective response rate (ORR) by RECIST v1.1 (both per investigator). Exploratory endpoints included overall survival (OS). Results: Of 25 treated pts with KPS 50%–60%, 76% were men; median age was 67 years (range, 34–81). IMDC risk was favorable in 0%, intermediate in 32%, and poor in 68% of pts; 84% had clear cell and 16% had non-clear cell RCC histology. With a minimum follow-up of 25 months, median duration of therapy (95% CI) was 2.3 months (2.1–7.7) for NIVO and 2.1 months (2.1–2.1) for IPI. The median number of doses (range) received was 4 (1–27) for NIVO and 4 (1–4) for IPI; 76% of pts received ≥ 4 NIVO doses and 68% received all 4 IPI doses. The only grade 3–4 imAEs by category were hepatitis (4.0%) and adrenal insufficiency (4.0%). No grade 5 imAEs occurred. Overall, 4 (16%) pts discontinued due to any-grade adverse events (n = 1 each for elevated AST, malignant neoplasm progression, back pain, and acetabulum fracture). Of 18 evaluable pts, ORR was 33.3% (95% CI, 13.3–59.0); no pts had a complete response and 6 had partial response. Median time to objective response was 4.5 months (range, 2.5–24.7). Median duration of objective response was 20.6 months (range, 0.03+–24.2+). Median PFS was 4.6 months (95% CI, 2.5–14.8). Median OS was 15.6 months (95% CI, 5.3–25.1). Conclusions: NIVO+IPI demonstrated an acceptable safety profile and promising antitumor activity in pts with previously untreated aRCC and KPS 50%–60%. The combination was tolerated at a dose intensity similar to that observed in clinical trials conducted in pts with higher KPS (≥ 70%). These data support the value of NIVO+IPI in pts who may not be considered ideal candidates for this therapy and consequently may have limited treatment options. Clinical trial information: NCT02982954 .

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A Model of a Zebrafish Avatar for Co-Clinical Trials

Cancers ◽

10.3390/cancers12030677 ◽

2020 ◽

Vol 12 (3) ◽

pp. 677 ◽

Cited By ~ 8

Author(s):

Alice Usai ◽

Gregorio Di Franco ◽

Patrizia Colucci ◽

Luca Emanuele Pollina ◽

Enrico Vasile ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Drug Efficacy ◽

Cost Effective ◽

Zebrafish Embryos ◽

General Criterion ◽

Safety And Efficacy ◽

Animal Trial ◽

Chemotherapy Dose ◽

Efficacy Studies

Animal “avatars” and co-clinical trials are being developed for possible use in personalized medicine in oncology. In a co-clinical trial, the cancer cells of the patient’s tumor are xenotransplanted into the animal avatar for drug efficacy studies, and the data collected in the animal trial are used to plan the best drug treatment in the patient trial. Zebrafish have recently been proposed for implementing avatar models, however the lack of a general criterion for the chemotherapy dose conversion from humans to fish is a limitation in terms of conducting co-clinical trials. Here, we validate a simple, reliant and cost-effective avatar model based on the use of zebrafish embryos. By crossing data from safety and efficacy studies, we found a basic formula for estimating the equivalent dose for use in co-clinical trials which we validated in a clinical study enrolling 24 adult patients with solid cancers (XenoZ, NCT03668418).

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