P-hacking in clinical trials and how incentives shape the distribution of results across phases

Clinical research should conform to high standards of ethical and scientific integrity, given that human lives are at stake. However, economic incentives can generate conflicts of interest for investigators, who may be inclined to withhold unfavorable results or even tamper with data in order to achieve desired outcomes. To shed light on the integrity of clinical trial results, this paper systematically analyzes the distribution ofPvalues of primary outcomes for phase II and phase III drug trials reported to the ClinicalTrials.gov registry. First, we detect no bunching of results just above the classical 5% threshold for statistical significance. Second, a density-discontinuity test reveals an upward jump at the 5% threshold for phase III results by small industry sponsors. Third, we document a larger fraction of significant results in phase III compared to phase II. Linking trials across phases, we find that early favorable results increase the likelihood of continuing into the next phase. Once we take into account this selective continuation, we can explain almost completely the excess of significant results in phase III for trials conducted by large industry sponsors. For small industry sponsors, instead, part of the excess remains unexplained.

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P-hacking in clinical trials and how incentives shape the distribution of results across phases*

10.1101/19001495 ◽

2019 ◽

Author(s):

Jérôme Adda ◽

Christian Decker ◽

Marco Ottaviani

Keyword(s):

Phase Ii ◽

Conflicts Of Interest ◽

Statistical Significance ◽

Economic Incentives ◽

Phase Iii ◽

Scientific Integrity ◽

Small Industry ◽

Upward Jump ◽

High Standards ◽

Clinical Trial Results

AbstractClinical research should conform to high standards of ethical and scientific integrity, given that human lives are at stake. However, economic incentives can generate conflicts of interest for investigators, who may be inclined to withhold unfavorable results or even tamper with data in order to achieve desired outcomes. To shed light on the integrity of clinical trial results, this paper systematically analyzes the distribution of p-values of primary outcomes for phase II and phase III drug trials reported to the ClinicalTrials.gov registry. First, we detect no bunching of results just above the classical 5% threshold for statistical significance. Second, a density discontinuity test reveals an upward jump at the 5% threshold for phase III results by small industry sponsors. Third, we document a larger fraction of significant results in phase III compared to phase II. Linking trials across phases, we find that early favorable results increase the likelihood of continuing into the next phase. Once we take into account this selective continuation, we can explain almost completely the excess of significant results in phase III for trials conducted by large industry sponsors. For small industry sponsors, instead, part of the excess remains unexplained.

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Analysis of Outcomes of Patients with Relapsed/Refractory Acute Myeloid Leukemia Treated in Randomized Clinical Trials

Blood ◽

10.1182/blood.v128.22.4000.4000 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4000-4000 ◽

Cited By ~ 1

Author(s):

Raffi Tchekmedyian ◽

Paul Elson ◽

Aaron T. Gerds ◽

Navneet Majhail ◽

Hetty E. Carraway ◽

...

Keyword(s):

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Randomized Clinical Trials ◽

Statistical Significance ◽

Phase Iii ◽

Advisory Committees ◽

The Past ◽

American Society ◽

Over Time

Abstract Introduction The major reasons for failure to achieve cure in the majority of AML patients (pts) are primary refractoriness of disease to initial chemotherapy or failure to maintain complete remission (CR) that has been achieved (relapse). There is no uniformly accepted standard treatment for relapsed or refractory (RR) AML, with most available therapies regarded as palliative or as a bridge to allogeneic transplantation. While the past two decades have witnessed trials of several investigational therapies in RR AML, data regarding the effectiveness of these interventions remains unclear. We studied the impact of experimental drugs in RR AML pts by undertaking a comprehensive analysis of all phase 2 and 3 randomized clinical trials (RCTs) reported in the past 3 decades. Methods We searched PubMed, Embase, Cochrane Controlled Trials Register electronic databases, ClinicalTrials.gov and conference abstracts from the American Society of Hematology (ASH), American Society of Clinical Oncology (ASCO) and European Hematology Association (EHA) websites covering a period from 1988 to 2015. Key words used during this search included "refractory" or "relapsed" or "AML" or "phase II" or "phase III" or "randomized". Only double-arm, phase II with a sample size of at least 50 pts and phase III RCTs conducted in RR AML pts were included. Two reviewers independently extracted data on study methods, participants, therapies, and outcomes from all eligible trials: differences in how to classify agents in RCTs were resolved by discussion. The primary outcomes examined in the experimental arms (EAs) and standard arms (SAs) included CR rates, disease-free survival (DFS), refractory disease rates, treatment-related mortality (TRM) rates and overall survival (OS). Odds ratios (OR) were used to summarize differences between EAs and SAs. The DerSimonian and Laird random-effects model was used to compare them and to assess the overall impact of time. Results Of 5500 included pts, 40.5% were treated on 21 double-arm, phase II trials, 51% on 10 phase III trials and 6.6% analyzed through 4 retrospective studies. There was no change in CR rates in either EAs (p=.21) or SAs (p=.15) over time (Figure 1). The CR rates in EAs tended to be higher than in SAs [OR=1.24; 95% CI, 1.02-1.50, p=.03). Rates of disease refractoriness to salvage regimens in both EAs (p=.70) and CAs (p=.31) did not change over time and these rates were not significantly different between treatment arms [OR=0.82; 95% CI, 0.62-1.08, p=.16]. TRM rates tended to decrease over time but the change was not significant in either group [p=.24 for SAs and p=.33 for EAs]. TRM rates were higher in SAs compared to CAs but did not reach statistical significance [OR=1.21; 95% CI, 0.97-1.50, p=.09]. Over time, there was no significant change inDFS in either group (p=.32 for CAs and p=.58 for EAs). DFS rates did not differ between EAs and SAs [OR=1.01; 95% CI, 0.86-1.19, p=.89] (Figure 2). OS tended to remain stable over time in both groups [p=.85 for SAs and p=.66 for EAs]. While OS tended to be higher in SAs, it did not reach statistical significance [OR=0.93; 95% CI, 0.83-1.05, p=.27]. Conclusions: These findings indicate a lack of significant or clinically meaningful improvement in disease outcomes, including OS, in RR AML pts treated within RCTs over the past 3 decades. Greater efforts need to be directed towards designing RCTs using novel statistical approaches and directed agents based on recent discoveries of targetable mutations. Disclosures Carraway: Amgen: Membership on an entity's Board of Directors or advisory committees; Baxalta: Speakers Bureau; Celgene Corporation: Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Advani:Pfizer Inc.: Consultancy, Research Funding; Blinatumomab: Research Funding. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

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Concordance between abstracts, virtual meeting (VM) presentations, and final publication of phase III clinical trials presented at the Annual Meeting of the American Society of Clinical Oncology.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.6622 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 6622-6622 ◽

Cited By ~ 1

Author(s):

Suneil Kumar Khanna ◽

Matthew John Boyko ◽

Daniel Yick Chin Heng ◽

Michael M. Vickers ◽

Vincent Channing Tam

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Annual Meeting ◽

Primary Endpoint ◽

Statistical Significance ◽

Phase Iii ◽

Key Comparisons ◽

Inclusion Criteria ◽

Phase Iii Clinical Trials ◽

Clinical Trial Results

6622 Background: Phase III clinical trial results described in abstracts in the ASCO Annual Meeting Proceedings often differ from final results seen in publication. We hypothesize that the abstracts may act only as place holders, while the results presented at the ASCO Annual Meeting are more highly concordant with the final publication. Methods: A retrospective review of all abstracts submitted to the ASCO Annual Meeting in 2005 to 2007 was conducted. Inclusion Criteria: randomized, prospective phase III clinical trials of greater than 200 patients with at least one quantitative primary endpoint such as OS or PFS. For each abstract, we viewed the VM presentation and searched Pubmed and Medline for the corresponding publications. Data regarding the clinical trials was extracted from all three sources and statistical comparisons were made. Results: A total of 7,900 abstracts were screened from the ASCO 2005 and 2007 Annual Meetings, of which 124 met the inclusion criteria. An additional 43 studies were excluded due to absence of either a VM presentation or publication. The majority (96%) of these trials were presented as either an oral presentation or poster discussion. Key comparisons of the concordance between the abstract or VM presentation and the final publication are shown in the Table below. Conclusions: While the statistical significance of the primary endpoint and conclusions from all three sources are very similar, the results reported in VM presentations at ASCO Annual Meetings are a better representation of the final publication compared to the abstract. When relying on clinical trial results from these meetings to change clinical practice, physicians should refer to the VM presentation rather than the abstract. [Table: see text]

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Myelofibrosis Drug Development through the Decade: Novel JAK Inhibitors

Blood ◽

10.1182/blood-2018-99-115408 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5477-5477

Author(s):

Ali Younas Khan ◽

Muhammad Junaid Tariq ◽

Muhammad Usman ◽

Awais Ijaz ◽

Abdul Rafae ◽

...

Keyword(s):

Phase I ◽

Phase Ii ◽

Phase I Trial ◽

Conflicts Of Interest ◽

Myeloproliferative Neoplasm ◽

Phase Iii ◽

Jak Inhibitor ◽

Jak Inhibitors ◽

Phase Iii Trial ◽

Grade 3

Abstract Introduction Myelofibrosis (MF), a BCR-ABL negative myeloproliferative neoplasm (MPN), has an annual incidence of 1 in 100000 for the primary MF and 0.3-0.7 in 100000 for secondary MF in the USA. MF patients have a median survival of 6.5 years. The primary mutation, JAK2V617F, occurs in 40-60% of MF cases. Ruxolotinib, a JAK inhibitor, has been the mainstay in treating high risk, debilitating MF but largely clinical needs are unmet. Methods A comprehensive literature research was performed using PubMed, Cochrane, EMBASE, Web of Science and Clinicaltrials.gov. We included all trials that were under development in phase I/II/III trials. Our search identified 1642 full-length manuscripts or abstracts with published results in the last decade ( Jan 2007 till Dec 2017) were screened for relevant studies. After screening by 2 independent reviewers, 212 articles were finalized for our final analyses. We have reviewed the mechanism of action, safety and efficacy of 2nd generation JAK inhibitors in this review. Results JAK1 inhibitor: Itacitinib reduced total symptom score (TSS) ≥ 50% in 15/42 (36%) patients. Mild gastrointestinal (GI) disturbances and some grade 3-4 myelosuppression (anemia: 33%, thrombocytopenia: 29%) were reported. JAK2 inhibitors: In PERSIST-1, pacritinib when compared to best available therapy (BAT) showed SVR ≥ 35% in 19.1% vs. 4.7% patients, with lower rates of myelosuppression (thrombocytopenia: 17%, anemia: 11%). In PERSIST-2, a phase III trial of pacritinb vs. BAT in patients with baseline cytopenias, similar efficacy was demonstrated (SVR ≥ 35%: 18% vs. 3%). Increasing rates of heart failure and intracranial hemorrhages led to a temporary hold which was lifted in August 2017. Lestaurtinib showed CI in 7 (44%) patients in a phase I trial (n=16) and 6 (27%) patients in a phase II trial (n=22). Most notable toxicities were G 1/2 GI disturbances, anemia occurred in 14% and thrombocytopenia in 23% of patients. In a phase III trial (n=193), fedratinib showed a SVR ≥ 35% and a TSS ≥ 50% in 40% and 36% patients, respectively. However, incidence of significant neurotoxicity and Wernicke's encephalopathy led to its suspension. Similarly, a trial of XL019 was terminated due to emergence of central and peripheral neurotoxicity. In a phase I trial (n=48), NS-018 exhibited a spleen length reduction (SLR) ≥ 50% in 20 (56%) patients along with prompt improvement in bone marrow fibrosis (37%). Anemia and thrombocytopenia were reported in 15% and 27% of patients, respectively. Dizziness (23%) and nausea (19%) were also reported. Gandotinib demonstrated SLR ≥50% in 62% patients, in a phase I trial (n=38). G1 diarrhea (55.3%) and nausea (42.1%) were the most common toxicities. JAK 1/2 inhibitors: SIMPLIFY-1 (S1), a phase III clinical trial (n=432) of momelotinib vs. ruxolotinib in JAK inhibitor-naïve patients, demonstrated non-inferiority for momelotinib, in spleen volume reduction (SVR) ≥ 35% (26.5% vs. 29%; p=0.01). However, SIMPLIFY-2 trial (S2), that compared these two drugs in JAK inhibitor exposed patients did not achieve similar responses with momelotinib (6.7% vs. 5.8%; p=0.90). Interestingly, momelotinib excelled at achieving transfusion independency in both trials (S1: 66.5% vs. 49.3%; p=0.001, S2: 43.3% vs 21.2%; p=0.001). Grade ≥ 3 infections and peripheral neuropathy were the major toxicities noted. These trials were suspended after 89% of patients failed to achieve the primary endpoint of SVR. AZD1480 demonstrated clinical improvement (CI) in four (11%) patients in a phase I trial (n=35). Most common adverse events included grade (G) 1-2 dizziness and anemia. Conclusion Novel JAK pathway inhibitors have shown promising efficacy in MF but safety concerns regarding the hematological (cytopenias) and non-hematological adverse effects needs to be addressed until their use in clinical practice is established. Momelotinib success in achieving anemia related endpoints is note-worthy and should be further explored in this regard. A phase II study [NCT03165734] evaluating pacritinib monotherapy as a second line treatment in patients with baseline thrombocytopenia is ongoing. Disclosures No relevant conflicts of interest to declare.

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A randomized clinical trial of a new anti–cervical stenosis device after conization by loop electrosurgical excision

PLoS ONE ◽

10.1371/journal.pone.0242067 ◽

2021 ◽

Vol 16 (1) ◽

pp. e0242067

Author(s):

Marcelo de Andrade Vieira ◽

Raphael Leonardo Cunha de Araújo ◽

Carlos Eduardo Mattos da Cunha Andrade ◽

Ronaldo Luis Schmidt ◽

Agnaldo Lopes Filho ◽

...

Keyword(s):

Clinical Trial ◽

Randomized Clinical Trial ◽

Phase Ii ◽

Statistical Significance ◽

Phase Iii ◽

Cervical Stenosis ◽

New Device ◽

Significant Difference ◽

Complications Rate ◽

Loop Electrosurgical Excision

Background The complications inherent to conization include vaginal bleeding, cervical stenosis, amenorrhea, dysmenorrhea, and deep dyspareunia. Cervical stenosis is the most important complication due to the clinical repercussions. Studies show rates of cervical stenosis ranging from 1.3 to 19% after the Loop Electrosurgical Excision Procedure (LEEP). Objective Our primary outcome was to compare the role of a new endocervical device to prevent cervical stenosis after LEEP in patients with high-grade squamous intraepithelial lesions (HSILs). Methods A randomized clinical trial was performed including phases II and III for evaluation of a new device for cervical stenosis prevention. In Phase II, we included 25 patients who underwent LEEP and placement of the device to assess its toxicity and efficacy. In phase III, we compared two groups (with and without the use of an anti-stenosis device) to evaluate its efficacy and safety. Results From August 2015 to June 2018, 265 participants were randomized (Phase II: 25, Phase III: 120 with DUDA and 120 without DUDA). The toxicity during phase II was observed in only one patient (4%) with pain grade > 7. There were 7 cases of toxicity during Phase III, 2 in the DUDA group (1.8%), and 5 in the No DUDA group (4.5%). The complications rate was numerically higher in the No DUDA group (2.5x higher) than the DUDA group, but this difference did not reach statistical significance (p = 0.52). The rate of cervical stenosis in DUDA group was (4–7,3%), and in No DUDA group was (4.3–5.8%) (p = 0.5). We did not find a significant difference when comparing the evolution at 3, 6, and 12 months in terms of cervical patency and visualization of the squamocolumnar junction (SCJ) during colposcopy. The DUDA group exhibited 15% to 19% nonvisualization of the SCJ, whereas that rate ranged from 10 to 12% in the No DUDA group. Conclusions The rate of cervical stenosis was not different comparing the use of a new device, specifically produced to prevent cervical stenosis, compared to no use after LEEP procedure. This clinical trial opens up space for a discussion of the utility of using cervical stenosis devices after LEEP. Perhaps in another type of conization it can be evaluated to avoid cervical stenosis.

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Sequencing Therapy for Elderly Chronic Lymphocytic Leukemia Patients in the Era of Novel Therapies: An Overview of Randomized Clinical Trials

Blood ◽

10.1182/blood-2018-99-117084 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5559-5559

Author(s):

Malik Qistas Ahmad ◽

Chaudhry Saad Sohail ◽

Muhammad Yasir ◽

Muhammad Junaid Tariq ◽

Arshia Akbar ◽

...

Keyword(s):

Clinical Trials ◽

High Risk ◽

Elderly Patients ◽

Phase Ii ◽

Randomized Clinical Trials ◽

Conflicts Of Interest ◽

The Elderly ◽

Phase Iii ◽

Female Ratio ◽

Tp53 Mutations

Abstract Background: For most of the elderly or unfit CLL patients, treatment algorithms focus on achievement of clinical response, relief of symptoms and prolongation of life expectancy. Comorbidities, frailty and reduced functional status in elderly patients make some of the standard treatments intolerable and less efficacious. However, recent advancements in understanding of CLL biology, approval of target agents including novel monoclonal antibodies and kinase inhibitors have expanded the horizons for treatment of CLL in elderly. Methods: We conducted a literature search on PubMed, Embase, Web of Science and ClinicalTrials.gov which was completed on July 1, 2018. To assess the CLL treatment protocols in the elderly population, we included data from phase II and phase III clinical trials from the last decade (Jan 2008 to Jan 2018). Results: From a total of 1259 studies, we selected 34 studies (n=3122) after inclusion criteria were met. The patients included are from the age group of ≥65 years with the mean age of 68.8 years. Male to female ratio was 3:2. On comparison of different parameters to look for the drug or regimen efficacy, we found that ibrutinib is very effective and tolerable in older (aged ≥65 years) treatment-naïve (TN) as well as relapsed refractory patients (RR), with overall response rate (ORR) of 91% for combined group in one study when compared to ofatumumab. When used in combination with ublituximab, the ORR peaked to 80% as compared to ibrutinib alone in patients with high risk cytogenetics (ORR=47%, p<0.001). Phase III RESONATE trial showed a comparison between ibrutinib and chlorambucil treated del 17p negative elderly patients; ibrutinib was superior in terms of ORR (86% vs. 35%) and overall survival (OS) (2-year OS, 98% vs. 85%, p=0.001). The OS with ibrutinib turned out to be 89% showing better disease control as compared to idelalisib (OS= 61%) when used in combination with rituximab, with a 33% reduction in mortality with ibrutinib as compared with idelalisib in RR patients. The combination of rituximab with idelalisib has shown promising results in patients with specific mutations (i.e. 100% ORR in those with del (17)/ Tp53 mutations, 97% ORR in those with unmutated IGHV). Similarly, when compared with placebo and rituximab combination progression free survival (PFS) was 13%, idelalisib is found to have PFS of 66% at 12 months in patients with del 17p/ Tp53 mutations and unmutated IGHV status. Moreover, in a phase II study, ofatumumab monotherapy showed ORR of 72%. In newly diagnosed (ND) CLL, an ORR of 98% is found with the pentostatin, cyclophosphamide, rituximab, and lenalidomide regimen. Other worth sharing results include; complete remission (CR) in 71% (24 out of 34 included) patients who were given lenalidomide as an initial therapy, with OS of 88% and ORR of 65%. The OS is surprisingly as high as 97.9% in those who were given pentostatin and cyclophosphamide in combination with ofatumumab. Traditional chemotherapy with fludarabine and rituximab (FR) showed OS of 67% in one study with rates of grades II and III-IV acute GVHD as 60% and 15% respectively. The most common hematological side effects seen with ibrutinib in one of the studies are neutropenia (12%), thrombocytopenia (4%) and anemia (7%). The non-hematological complications may be secondary due to cytopenias (infections, pneumonia, bleeding, and neutropenic fever) or due to constitutional symptoms like myalgia, fatigue, vomiting, or nausea. Conclusion: The rapid clinical development of novel therapy agents has changed the prognosis for CLL patients. Ibrutinib is considered as a standard option and an up front therapy for high risk CLL patients especially who are elderly and have del 17p, despite its significant toxicity profile in very elderly patients (80 years and above) where multiple deaths were reported. Future prospects include ibrutinib combinations with frontline chemo-immunotherapy (CIT) and other novel agents for TN and RR del 17p negative patients. Disclosures No relevant conflicts of interest to declare.

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Bewegungstherapie und körperliche Aktivität bei Patienten mit Herzinsuffizienz

Praxis ◽

10.1024/1661-8157/a003050 ◽

2018 ◽

Vol 107 (17-18) ◽

pp. 951-958 ◽

Cited By ~ 1

Author(s):

Matthias Wilhelm

Keyword(s):

Phase I ◽

Phase Ii ◽

Körperliche Aktivität ◽

Phase Iii

Zusammenfassung. Herzinsuffizienz ist ein klinisches Syndrom mit unterschiedlichen Ätiologien und Phänotypen. Die überwachte Bewegungstherapie und individuelle körperliche Aktivität ist bei allen Formen eine Klasse-IA-Empfehlung in aktuellen Leitlinien. Eine Bewegungstherapie kann unmittelbar nach Stabilisierung einer akuten Herzinsuffizienz im Spital begonnen werden (Phase I). Sie kann nach Entlassung in einem stationären oder ambulanten Präventions- und Rehabilitationsprogramm fortgesetzt werden (Phase II). Typische Elemente sind Ausdauer-, Kraft- und Atemtraining. Die Kosten werden von der Krankenversicherung für drei bis sechs Monate übernommen. In erfahrenen Zentren können auch Patienten mit implantierten Defibrillatoren oder linksventrikulären Unterstützungssystemen trainieren. Wichtiges Ziel der Phase II ist neben muskulärer Rekonditionierung auch die Steigerung der Gesundheitskompetenz, um die Langzeit-Adhärenz bezüglich körperlicher Aktivität zu verbessern. In Phase III bieten Herzgruppen Unterstützung.

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Exploring new uses for existing drugs: innovative mechanisms to fund independent clinical research

Trials ◽

10.1186/s13063-021-05273-x ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Ciska Verbaanderd ◽

Ilse Rooman ◽

Isabelle Huys

Keyword(s):

Clinical Trials ◽

Clinical Research ◽

Financial Support ◽

Social Impact ◽

Grey Literature ◽

Economic Incentives ◽

Phase Iii ◽

Medical Needs ◽

The Future ◽

Funding Mechanisms

Abstract Background Finding new therapeutic uses for existing medicines could lead to safe, affordable and timely new treatment options for patients with high medical needs. However, due to a lack of economic incentives, pharmaceutical developers are rarely interested to invest in research with approved medicines, especially when they are out of basic patent or regulatory protection. Consequently, potential new uses for these medicines are mainly studied in independent clinical trials initiated and led by researchers from academia, research institutes, or collaborative groups. Yet, additional financial support is needed to conduct expensive phase III clinical trials to confirm the results from exploratory research. Methods In this study, scientific and grey literature was searched to identify and evaluate new mechanisms for funding clinical trials with repurposed medicines. Semi-structured interviews were conducted with 16 European stakeholders with expertise in clinical research, funding mechanisms and/or drug repurposing between November 2018 and February 2019 to consider the future perspectives of applying new funding mechanisms. Results Traditional grant funding awarded by government and philanthropic organisations or companies is well known and widely implemented in all research fields. In contrast, only little research has focused on the application potential of newer mechanisms to fund independent clinical research, such as social impact bonds, crowdfunding or public-private partnerships. Interviewees stated that there is a substantial need for additional financial support in health research, especially in areas where there is limited commercial interest. However, the implementation of new funding mechanisms is facing several practical and financial challenges, such as a lack of expertise and guidelines, high transaction costs and difficulties to measure health outcomes. Furthermore, interviewees highlighted the need for increased collaboration and centralisation at a European and international level to make clinical research more efficient and reduce the need for additional funding. Conclusions New funding mechanisms to support clinical research may become more important in the future but the unresolved issues identified in the current study warrant further exploration.

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AB0332 IMMUNOSUPPRESSIVE AND IMMONOMODULATING AGENTS IN RHEUMATOID ARTHRITIS: A SYSTEMATIC REVIEW OF CLINICAL TRIALS AND THEIR CURRENT DEVELOPMENT STAGE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.1124 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1464.1-1465

Author(s):

J. Blaess ◽

J. Walther ◽

J. E. Gottenberg ◽

J. Sibilia ◽

L. Arnaud ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Systematic Review ◽

B Cells ◽

Phase I ◽

Phase Ii ◽

Clinical Development ◽

Phase Iii ◽

Jak Inhibitors ◽

Exclusion Criteria ◽

Immunomodulating Drugs

Background:Rheumatoid arthritis (RA) is the most frequent chronic inflammatory diseases with an incidence of 0.5% to 1%. Therapeutic arsenal of RA has continuously expanded in recent years with the recent therapeutic progress with the arrival of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), biological (bDMARDs) and targeted synthetic (tsDMARDs), JAK inhibitors. However, there are still some unmet needs for patients who do not achieve remission and who continue to worsen despite treatments. Of note, only approximately 40% of patients are ACR70 responders, in most randomized controlled trials. For these patients, finding new therapeutic avenues is challenging.Objectives:The objective of our study was to analyze the whole pipeline of immunosuppressive and immunomodulating drugs evaluated in RA and describe their mechanisms of action and stage of clinical development.Methods:We conducted a systematic review of all drug therapies in clinical development in RA in 17 databases of international clinical trials. Inclusion criterion: study from one of the databases using the keywords “Rheumatoid arthritis” (search date: June 1, 2019). Exclusion criteria: non-drug trials, trials not related to RA or duplicates. We also excluded dietary regimen or supplementations, cellular therapies, NSAIDs, glucorticoids or their derivatives and non-immunosuppressive or non-immunomodulating drugs. For each csDMARD, bDMARD and tsDMARD, we considered the study at the most advanced stage. For bDMARDs, we did not take into account biosimilars.Results:The research identified 4652 trials, of which 242 for 243 molecules met the inclusion and exclusion criteria. The developed molecules belong to csDMARDs (n=21), bDMARDs (n=117), tsDMARDs (n=105).Among the 21 csDMARDs molecules: 8 (38%) has been withdrawn, 4 (19%) are already labelled in RA (hydroxychloroquine, leflunomide, methotrexate and sulfasalazine) and 9 (43%) are in development: 1 (11%) is in phase I/II, 5 (56%) in phase II, 3 (33%) in phase IV.Among the 117 bDMARDs molecules: 69 (59%) has been withdrawn, 9 (8%) are labeled in RA (abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, sarilumab, tocilizumab) and 39 (33%) are in development: 9 (23%) in phase I, 3 (8%) in phase I/II, 21 (54%) in phase II, 5 (12%) are in phase III, 1 (3%) in phase IV. bDMARDs currently under development target B cells (n=4), T cells (n=2), T/B cells costimulation (n=2),TNF alpha (n=2), Interleukine 1 or his receptor (n=3), Interleukine 6 or his receptor (n=7), Interleukine 17 (n=4), Interleukine 23 (n=1), GM-CSF (n=1), other cytokines or chemokines (n=5), integrins or adhesion proteins (n=3), interferon receptor (n=1) and various other targets (n=4).Among the 105 tsDMARDs molecules: 64 (61%) has been withdrawn, 6 (6%) JAK inhibitors, have just been or will probably soon be labelled (baricitinib, filgotinib, peficitinib, tofacitinib and upadacitinib), 35 (33%) are in development: 8 (24%) in phase I, 26 (74%) in phase II, 1 (3%) in phase III and. tsDMARDs currently under development target tyrosine kinase (n=12), janus kinase (JAK) (n=3), sphingosine phostate (n=3), PI3K pathway (n=1), phosphodiesterase-4 (n=3) B cells signaling pathways (n=3) and various other targets (n=10).Conclusion:A total of 242 therapeutic trials involving 243 molecules have been or are being evaluated in RA. This development does not always lead to new treatments since 141 (58%) have already been withdrawn. Hopefully, some of the currently evaluated drugs will contribute to improve the therapeutic management of RA patients, requiring a greater personalization of therapeutic strategies, both in the choice of molecules and their place in therapeutic sequences.Disclosure of Interests:Julien Blaess: None declared, Julia Walther: None declared, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, Jean Sibilia: None declared, Laurent Arnaud: None declared, Renaud FELTEN: None declared

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Determination of Efficacy of Single and Double 4.7 mg Deslorelin Acetate Implant on the Reproductive Activity of Female Pond Sliders (Trachemys scripta)

Animals ◽

10.3390/ani11030660 ◽

2021 ◽

Vol 11 (3) ◽

pp. 660

Author(s):

Edoardo Bardi ◽

Martina Manfredi ◽

Raffaella Capitelli ◽

Emanuele Lubian ◽

Alessandro Vetere ◽

...

Keyword(s):

Phase Ii ◽

Egg Production ◽

Reproductive Activity ◽

Trachemys Scripta ◽

Phase Iii ◽

Control Group ◽

Sexual Hormones ◽

Significant Difference ◽

Group 6 ◽

Plasmatic Concentration

The use of long-acting gonadotropin-releasing hormone (GnRH) agonists to suppress fertility has been poorly investigated in reptiles, and the few available studies show inconsistent results. The efficacy of single and double intramuscular 4.7 mg deslorelin acetate implants in captive pond sliders (Trachemys scripta) was investigated, with 20 animals divided into three groups: a single-implant group (6 animals), a double-implant group (6 animals), and a control group (no implant). During one reproductive season (March to October), plasmatic concentration of sexual hormones (estradiol, progesterone, and testosterone) and ovarian morphometric activity via computed tomography were monitored about every 30 days. A significative decrease in the number of phase II ovarian follicles was detected in the double-implant group compared with the control group, but no significant difference was noted in the number of phase III and phase IV follicles, egg production, and plasmatic concentration of sexual hormones. Results show that neither a single nor a double deslorelin acetate implant can successfully inhibit reproduction in female pond sliders during the ongoing season, but the lower number of phase II follicles in the double-implant group can possibly be associated with reduced fertility in the following seasons.

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