Retrospective Study of COVID-19 Vaccines in Patients Undergoing Immunotherapy for Cancer.
The recent outbreak of Coronavirus 2019 (COVID-19) caused by a new zoonotic coronavirus SARS-Cov-2 poses a major public health threat, with at least 100,000,000 people infected worldwide by the end of January 2021 and over 2 million deaths. Given the scale of the pandemic, it has become imperative to quickly develop a vaccine and over 30 vaccine candidates have entered clinical evaluation. The first vaccine to receive marketing authorization in Europe and France was an mRNA vaccine, Comirnaty® (Bnt162b2; Pfizer/BioNtech). In a Phase III study of 43,448 participants, after a median follow-up of 2 months, the number of cases of COVID-19 was 8 in the vaccine arm vs. versus 162 in the placebo arm, respectively, with 1 versus 9 serious cases (Polack et al. 2020). Adverse events occurred in more than 50% of vaccinated participants and included local reactions as well as frequent systemic reactogenicity such as fatigue and headache. Fever occurred in about 15% of the participants who received the vaccine. The second vaccine to be licensed was also an mRNA vaccine: the Moderna COVID-19 mRNA (nucleoside modified) vaccine (mRNA-1273, Moderna). A Phase III trial involving 30,420 volunteers reported efficacy and safety comparable to the Pfizer/BioNtech vaccine. A severe form of COVID-19 occurred in 30 subjects, with one death; all 30 cases were in the placebo group. Moderate and transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare and the incidence was similar in both groups. Within the vaccination strategy implemented on a national level, the Comirnaty® vaccine (Pfizer/BioNtech) and the Moderna COVID-19 mRNA vaccine (nucleoside modified) may be used interchangeably, depending on logistical constraints. For several weeks now, the Oxford-AstraZeneca chimpanzee adenovirus vector vaccine ChAdOx1 nCoV-19 (AZD1222) has been available in France and its efficacy and safety of use have been evaluated. Also the non-replicating viral vector (adenovirus) vaccine for CVD 19 from Janssen Laboratories (a subsidiary of Johnson & Johnson; other names: Ad26COV2.S; JMJ Vaccine or J & J COVID-19 Vaccine) was launched in France a few weeks ago. Its efficacy and safety have been validated in a phase III trial. A number of other candidate vaccines using various techniques such as mRNA, protein subunit, viral vector or inactivated vaccines are currently under investigation and will be available soon. Cancer patients are particularly at risk of developing a severe form of COVID-19. Patients with solid tumors appear to be at a greater risk, particularly in the first year after diagnosis. Severity and mortality rates in the COVID-19 and Cancer Consortium (CCC19) registry and other cohorts range from 5% to 61% (a meta-analysis showed 26%), which is well above the general population. Although data on vaccination in cancer patients are limited, there is sufficient evidence to support anti-infective vaccination in general, even in cancer patients on immunosuppressive therapy. In its notice dated January 25th, 2021, the National Cancer Institute defined its recommendations for prioritizing cancer patients for vaccination against SARS-CoV-2. This report stresses that the data acquired from science is limited in quantity and quality concerning the emerging field of vaccination against SARS-CoV-2 and even more so in sub-populations including cancer patients. It reminds us that the challenge remains to vaccinate the entire population of patients who have or have had cancer, i.e. approximately 3.8 million people. The level of efficacy can be expected to be generally reduced in certain cancer patient populations with intense immunosuppression, such as haematopoietic stem cell transplant recipients. However, based on extrapolation of data from other vaccines and the mechanism of action of COVID-19 (non-live) vaccines, it is conceivable that the efficacy and safety of COVID-19 vaccination could be estimated to be similar to that of non-cancer patients, although data from clinical trials are lacking. The efficacy and duration of immunity in cancer patients is still unknown and unexplored. It is therefore legitimate to propose surveillance through dedicated registries and clinical trials. Furthermore, close monitoring and follow-up of cancer patients is required after COVID-19 vaccination to assess potential adverse events and measure clinical outcomes, e.g. infection, severity and mortality from COVID-19, cancer complications etc… The investigators wish to set up a pharmaco-epidemiological cohort within the Hospital Territorial Groups of the Cévennes-Gard Camargue, East-Hérault and Haute-Garonne and West Tarn on a specific population, patients undergoing immunotherapy for cancer, as currently there is no data available under "real life" conditions following anti-COVID vaccination19. Our hypothesis is that patients undergoing immunotherapy will not develop more vaccine-related adverse events than those observed in the efficacy and safety validation studies of the BNT162b2 mRNA Covid-19, mRNA-1273 SARS CoV-2, Oxford/AstraZeneca and Ad26COV2.S, JMJ Vaccine or J & J COVID-19 Vaccine.
Phase
N/ASpan
137 weeksSponsor
Centre Hospitalier Universitaire de NīmesCahors
Recruiting
Personalized Management of Psycho-behavioral Symptoms in Alzheimer's Disease: Impact on Health Resources Use
PERSON-AL is a multicentric, interventional, open-label, randomized, parallel-group, stratified by centre, study comparing two arms: usual care versus intervention (personalized care preceded by a standardized assessment) Principal Objective : To evaluate the impact of a personalized intervention for the management of agitation due to psycho-behavioral symptoms on the use of scheduled and unscheduled hospitalizations at 18 months in patients with AD and related disorders. Secondary Objectives: A- To evaluate the impact of a personalized intervention at 18 months on: For the patient: 1. Unscheduled hospitalizations, 2. Severity of agitation symptoms, 3. The frequency and severity of emerging psycho-behavioral symptoms, other than agitation, 4. Prescription of psychotropic drugs, 5. Quality of life. For the caregiver: 6. Distress related to psycho-behavioral symptoms, 7. All causes hospitalizations, 8. Quality of life. B- Evaluate the medico-economic impact of this personalized intervention, and in particular: 1. Its efficiency compared to usual management by means of cost-effectiveness and cost-utility analyses, from the community perspective and over a time horizon of 18 months, 2. The actual cost of patient's standardized assessment and personalized management 3. The use of care and associated costs for the caregiver and the efficiency of caregiver targeted intervention.
Phase
N/ASpan
157 weeksSponsor
University Hospital, ToulouseCahors
Recruiting
Tolerability and Efficacy of INSTYLAN in Subjects With Moderate to Severe Hemorrhagic Cystitis
This is a multicenter single-arm clinical study including male and female subjects with moderate to severe hemorrhagic cystitis caused by pelvic radiation therapy and/or chemotherapy as determined by the physician. A total of 30 subjects are anticipated and will be enrolled in 10 study sites in France. The patients will receive intravesical instillations with INSTYLAN weekly for 6 weeks. The objectives of the study are to assess the efficacy of intravesical instillations of INSTYLAN on the basis of hemorrhagic cystitis symptoms disappearance. The primary endpoint is the evaluation of pain using a verbal rating scale one week and four weeks after treatment versus Baseline.
Phase
N/ASpan
63 weeksSponsor
LIDDE TherapeuticsCahors
Recruiting
A Clinical-biological Prospective Cohort of Patients With BRAFV600E-mutated Metastatic Colorectal Cancer
Despite substantial progress made in the first- and second line mCRC settings, there are still unmet clinical needs for patients harboring BRAFV600E mutations, especially those with microsatellite stability (MSS) / proficient mismatch repair (pMMR) tumor. The overall survival and access to different treatment in the real-life setting are unknown. Moreover, patient prognosis remains poor and therapeutic resistance to combinations with BRAF inhibitors, is at present, nearly universal. Therefore, it seems essential to prospectively collect clinical and biological data about this rare mCRC subtype. These data will allow us to improve knowledge and to identify clinical and biological factors that could drive therapeutic decisions, predict resistance to treatments, and that are prognostic for survival. In this context, we designed this large, prospective, cohort study to collect clinical data and biological samples to be used for research but also to gather real-world clinical data concerning the treatments and the survival outcomes in patients with BRAFV600E mCRC. This collection of clinical and biological data (tumor tissue and blood samples) will allow us to identify predictive and prognostic biomarkers with several research work packages planned: i. To evaluate the circulating tumor DNA (ctDNA) during the metastatic first-, second-, and third-line treatment to: - Evaluate its positive and negative predictive value. - Identify molecular alterations preceding and explaining clinical resistance during BRAF/EGFR inhibition therapy and immunotherapy. ii. To evaluate BRAFV600E mCRC immune environment both at the tumor and blood level (immunomonitoring). iii. To study specific the dMMR/MSI BRAFV600E subgroup. Furthermore, the data collected will describe the therapeutic management of BRAFV600E mCRC patients in the routine-practice setting which will bring very useful data. The results of the COBRAF study could lay the groundwork to better understand BRAFV600E mCRC and to identify prognostic and predictive biomarkers helping the development of new therapeutic approaches in this population.
Phase
N/ASpan
262 weeksSponsor
UNICANCERCahors
Recruiting
SAPHIR : Assessment of Predictive Factors for Persistence of Treatment After Initiation of Adalimumab With a Biosimilar (Adalimumab Fresenius KaBI or Substitution of Reference Adalimumab With the Fresenius Kabi Adalimumab Biosimilar in Patients With Chronic Inflammatory Diseases
In a population of adult patients who are targeted to initiate adalimumab or previously treated with Humira® to get switched to a biosimilar (FK adalimumab) and followed up for a period of 12 months under routine medical practice conditions. - Primary objective: to define predictive factors for the persistence of treatment - Secondary objectives: - To assess the therapeutic benefit and the tolerability of the treatment - To describe the reasons for treatment discontinuations occurring during follow-up
Phase
N/ASpan
162 weeksSponsor
Fresenius Kabi, FranceCahors
Recruiting
Efficacy of a Sequential Treatment Strategy in Rheumatoid Arthritis
In rheumatoid arthritis (RA), the consensual 1st line conventional synthetic disease modifying antirheumatic drugs (csDMARD) of RA is methotrexate (MTX) (1). In case of contra-indication or intolerance to MTX, leflunomide is an alternative. If the treatment target is not achieved with csDMARD strategy, addition of a biological (b) DMARD (TNF inhibitors, anti-IL6, abatacept, or rituximab) or a targeted synthetic (ts) DMARD (JAK inhibitors) is considered. Current practice is to start a bDMARD and especially TNF inhibitors (etanercept or monoclonal anti-TNF antibodies) with the benefit of hindsight. However, abatacept and TNF inhibitors have demonstrated similar efficacy in patients with insufficient response to csDMARD (AMPLE trial). Although abatacept has shown a very good tolerance profile that might be superior to other bDMARDs rheumatologists might be reluctant to use it as a first line bDMARD as there is a belief of a slower efficacy compared to other bDMARDs or JAK inhibitors. Indeed, in real world study, compared to TNF inhibitors it seems that discontinuation of abatacept is more related to lack of effectiveness than safety issues. This is the first study to propose a therapeutic sequential strategy with an induction therapy using a TNF inhibitor for 12 weeks to control inflammation followed by a cell-targeted biological DMARD targeting T cells (abatacept) in order to decrease auto-antibodies (rheumatoid factor and/or ACPA). Presence of auto-antibodies (ACPA/RF) are predictive of better response to cell- targeted DMARDs. In early AMPLE trial, RA patients ACPA+ with insufficient response to MTX were treated with abatacept or adalimumab. DAS28-CRP remission rates were 55% in abatacept group and 30% in adalimumab group. Patients carrying the shared epitope (HLA-DR (Human Leucocyte Antigen-DR) alleles associated with RA), were also more likely to reach remission (DAS28-CRP<2.6) with abatacept (50%) than adalimumab (23%) at 24 weeks. The clinical trial offered by investigateors here could change the paradigm in the strategy used in RA supporting the importance to first control inflammation environment in order to allow the cell-targeted bDMARDs to control immunological process which has been recently associated with a higher percentage of clinical remission. To compare the percentage of remission (DAS28-CRP<2.6) obtained during the 36 weeks following randomization, with a sequential therapeutic strategy using abatacept versus a routine strategy continuing TNF inhibitors (TNFi), in ACPA positive RA patients responding to a first TNFi, initiated 12 weeks before randomization. The primary endpoint will be analyzed with a generalized estimating equations (GEE) model for repeated data. It is a multicentric, open label, randomized controlled trial comparing two different strategies of treatment with an independent efficacy assessor. For this clinical trial, to limit response bias, bDMARDs with a similar mode of administration (subcutaneous) are proposed. In the experimental arm, a therapeutic sequential strategy will be proposed and in the control arm TNF inhibitors will be proposed for 48 weeks. All included patients will receive TNF inhibitors subcutaneous for 12 weeks. At 12 weeks (W12), patients who have at least a moderate EULAR response (delta DAS28-CRP between W0 and W12>0.6 and DAS28-CRP≤5.1 at W12) will be randomized with a 1:1 ratio in the sequential strategy arm or the control arm. In the sequential strategy arm, the 88 randomized RA patients will be switched to abatacept subcutaneous for 36 weeks. Patients who will withdraw abatacept during the follow-up will be considered as a failure. In the control group, the 88 randomized RA patients will be treated with TNF inhibitor subcutaneous for another 36 weeks. In case of insufficient response to a first TNF inhibitor at 24 or 36 weeks, a second TNF inhibitor will be proposed. Anti-TNF drugs withdrawal will be considered as a failure. Steroids 0.1mg/kg/ day will be allowed but at stable dose 2 weeks before and with guided step-down strategy targeting withdrawal before 24 weeks following randomization. Clinical evaluation of disease activity using different scores (DAS28-ESR, CDAI, SDAI, Boolean criteria) and tolerance will be performed at all visits.
Phase
3Span
262 weeksSponsor
University Hospital, MontpellierCahors
Recruiting
Tofacitinib in Adult Patients With Moderate to Severe Ulcerative Colitis
TO FAst is a non-interventional study in France with primary objective to describe the clinical benefit of tofacitinib 1 year after its initiation for the treatment of moderate to severe UC in routine clinical practice. The study will also make it possible to report the clinical benefit 2 years after its initiation, to search for predictors of clinical benefit, improve our understanding of the efficacy of treatment in a real-life setting (in terms of response and speed of response), describe the characteristics of patients starting a treatment by tofacitinib, its real-life patterns of use as well as patient adherence to treatment.
Phase
N/ASpan
291 weeksSponsor
PfizerCahors
Recruiting
Abatacept vs Tocilizumab for the Treatment of RA in TNF Alpha Inhibitor Inadequate Responders
Rheumatoid arthritis (RA) is the most common inflammatory rheumatoid disease in France, affecting 0.3% of the general population. Without effective treatment, the persistent inflammation causes invalidating pain and joint destruction, leading to major functional disability as well as progressive structural damage resulting in major joint deformity. Biologic agents are taking on an increasingly important role in the management of patients with an inadequate response to conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs). Biological DMARD (bDMARD) therapy consists in the use of monoclonal antibodies or fusion proteins, administered intravenously or subcutaneously. The earliest developed biologic agents have been available for more than 15 years. Tumor necrosis factor alpha (TNFα), a pro-inflammatory cytokine, was the first cytokine successfully targeted by a biologic agent for RA treatment. TNF inhibitors (TNFi) are historically proposed as the first bDAMRD for inadequate responder patients to csDMARDs. More recently non-anti-TNFα drugs have emerged, with other biological targets such as interleukin-6 receptor (tocilizumab) or B- (rituximab) and T-lymphocytes (abatacept) that are implicated in the inflammatory response. Initially administered strictly intravenously, these drugs are now available in formulations adapted to subcutaneous administration, which allows ambulatory care for patients who otherwise would require repeated in-hospital care. National and international guidelines, especially those issued in 2013 by the European League Against Rheumatism (EULAR) and also in 2013 by the French Society of Rheumatology now recommend first-line treatment not only with TNFi but also with non-anti-TNFα biologic agents. However, in routine practice, most clinicians preferably prescribe TNFi for the first-line regimen, reserving non-anti-TNFα drugs to TNFi inadequate responder patients. There is a growing body of research focusing on first-line biologic agents but there is very little solid data on the direct randomized comparison between them. Actually, all three of the published studies have systematically compared a non-anti-TNFα biomedication versus TNFi (one study with a blinded design and two open studies). The therapeutic strategy that should be adapted after failure of a TNFi regimen has also been investigated. Those studies favor non-anti-TNF drugs over an alternate TNFi. There is adequate evidence of the efficacy of the different non-anti-TNFα biologic agents versus placebo after TNFi failure. In other hands, industrial trials have not provided any comparative data between drugs. An academic trial from The Netherlands using medico-economic performance as the primary outcome found no difference in efficacy between abatacept and rituximab (a non-anti-TNFα drug administered exclusively intravenously) after failure of a TNFi. Meta-analyses using data from care networks have not reported any difference between different non-anti-TNFα drugs after failure of a TNFi. Data from national registries have provided interesting complementary information since in everyday practice these agents are generally used after failure of at least one TNFi. The Danish registry thus suggests that the therapeutic response would be better with tocilizumab than with abatacept. This observation was confirmed by an analysis of French registries data presented at the American College of Rheumatology (ACR) congress in November 2016 showing that tocilizumab exhibits superiority for treatment persistence over 2 years. These results were fully in agreement with the findings of the French ROC trial comparing intravenous administration of a second anti-TNFα drug versus a non-anti-TNFα agent after failure of an anti-TNFα drug that suggested a superiority of tocilizumab over abatacept in the subgroup of patients given a non-anti-TNFα agent. A recent Bayesian network meta-analysis showed better efficacy in the non-anti-TNFα groups for ACR20 in patients who responded insufficiently to an anti-TNFα. Subcutaneous formulations have been recently developed for both tocilizumab and abatacept. Subcutaneous administration is important because it enables ambulatory care for a substantial number of patients who to date are recurrently hospitalized in day-care units for their intravenous infusions. Excepting specific situations, the subcutaneous formulation will be favored for a large majority of patients because of economic as well as practical considerations. Phase III trials have demonstrated the equivalence of the intravenous versus subcutaneous routes of administration focusing on efficacy and tolerance. The subcutaneous formulation is now also available for routine administration of both tocilizumab and abatacept. Nevertheless, despite large-scale industrial trials on drug equivalence, data issuing from clinical practice suggest a potential difference in the behavior of these two formulations which needs to be explored. Rituximab is apart in the treatment strategy because of its exclusive intravenous administration at spaced intervals and because it is used for specific patient profiles (extra-articular involvement, history of neoplasia, rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) positivity). There is no perspective for the development of a subcutaneous formulation of rituximab for RA patients. Furthermore, the routine treatment schedule for rituximab (one-time injections at a mean interval of 9 months) would compromise comparison, especially short-term comparison, with other subcutaneous treatments. These findings illustrate the need for a new multicentric, prospective, randomized trial designed to demonstrate the superiority of tocilizumab over abatacept in patients exhibiting inadequate response to a first anti-TNFα. A direct comparison of subcutaneous formulation is the need for the promising route of administration for future ambulatory care.
Phase
4Span
358 weeksSponsor
Lille Catholic UniversityCahors
Recruiting
Intra-nodal Injection of Gentamicin for the Treatment of Suppurated Cat Scratch Disease's Lymphadenitis
Double blind controlled study versus placebo. Patients with suppurated CSD's lymphadenitis will receive immediately after the pus aspiration (performed for a diagnostic purpose) an intra-nodal injection of gentamicin or of placebo (NaCl 0,9%) and be treated with oral azithromycin for 5 days.
Phase
3Span
448 weeksSponsor
University Hospital, ToulouseCahors
Recruiting
Can Nephrocheck™ Predict the Reversibility of Early, Acute Kidney Injury During Septic Shock?
Patients with septic shock in the intensive care unit have an elevated risk of developing acute kidney injury (AKI). AKI is an independent factor for mortality. Interventions that limit the worsening of renal function might have an impact on the mortality rate in these patients. Given the absence of validated pharmacological treatments for limiting the progression of AKI or for accelerating recovery from AKI, early intervention and the restoration of the glomerular filtration rate (GFR) in this context of hemodynamic change during the initial phase of septic shock might improve the patients' prognosis. One major challenge is therefore how to determine whether or not the AKI is reversible. The best-studied biomarkers (NGAL and KIM 1) have little discriminant power in septic patients because of their poor specificity or unsuitable kinetics for very early diagnosis. The combination of urine assays for tissue inhibitor of metalloproteinase 2 (TIMP2) and insulin-like growth factor binding protein 7 (IGFBP7) has shown good diagnostic performance for the very early detection of the risk of developing AKI in the following 12 hrs. Urine levels of these two markers specifically reflect damage to kidney tubules. Moreover, the levels appear to be strongly correlated with the severity of tubule damage. Thus, one can reasonably hypothesize that measurement of these markers in the very early stages of septic shock might determine the presence and severity of kidney tubule damage. A threshold (yet to be defined) would help to differentiate between (i) transient, non-severe injury and (ii) injury that is already too severe to be reversible.
Phase
N/ASpan
155 weeksSponsor
Centre Hospitalier Universitaire, AmiensCahors
Recruiting