There are 2 clinical trials
Heart transplantation (HT) is a lifesaving procedure for patients with end-stage heart failure and provides a better survival and quality of life if compared to medical treatment. HT is subject to alloimmune response, which, if left uncontrolled, is capable of jeopardizing long-term cardiac function. Advances in immunosuppression have enhanced the survival of HT patients. Nearly 2500 HT per year have been performed in the US during the last 10 years and despite significant improvements, long-term survival rates remain poor. More than 20% of patients do not survive more than 3 years, and those who survive are afflicted by long-term complications of alloimmunity and chronic immunosuppression. Life expectancy of patients who lose cardiac allografts is dramatically poor due to the absence of any therapeutic tool apart from re-transplantation, which is plagued by poor outcomes. The identification of novel therapeutic targets is thus mandatory. ATP/P2X7R signaling in T cells is highly relevant for cardiac allograft survival. ATP is a small molecule present at high concentrations inside cells; it is released as extracellular ATP (eATP) following cell damage or death where it acts as a danger signal. ATP is sensed by the P2X receptors (seven receptors named P2X1-7), mainly expressed by T lymphocytes. We have recently demonstrated that the ATP/P2X7R axis has a key role in cardiac allograft survival in humans and mice. Cardiac allograft vasculopathy (CAV) is a major limiting factor for HT survival; indeed CAV occurs in 50% of HT recipients by 5 years after transplantation and invariably results in allograft failure. CAV is clearly of immunological origin, as syngeneic murine grafts do not develop it. Once CAV occurs, the most definitive treatment is re-transplantation, but survival remains poor. We hypothesize that a single nucleotide polymorphysm (SNP) loss-of-function P2X7R mutation (p.Glu496Ala / c.1513A>C, rs3751143) generates a compensatory upregulation of the other purinergic receptors (P2XsR), thus creating a state of hypersensitivity to eATP. This eATP hypersensitivity results in an abnormal generation of Th1/Th17 cells, that leads to CAV and early cardiac allograft loss. Our study will answer a fundamental question: What is the effect of the P2X7R loss-of-function mutation on the immune system? Our goal is to generate the first targeted-therapy for a selected group of cardiac transplant recipients.
We hypothesize that a single nucleotide polymorphysm (SNP) loss-of-function P2X7R mutation (p.Glu496Ala / c.1513A>C, rs3751143) generates a compensatory upregulation of the other purinergic receptors (P2XsR), thus creating a state of hypersensitivity to eATP.
Loss-of-function single nucleotide mutations (SNPs) have been detected for P2X7R gene; particularly the Glu496 to Ala 1513A>C (rs3751143) P2X7R loss-of-function mutation is relatively common (1-3% of individuals are mutated omozygous and 25% are heterozygous).
To test this hypothesis, we will follow two main paths: i) we will evaluate in the CTOT-05 cohort of cardiac transplant recipients the effect of the Glu496 to Ala 1513A>C (rs3751143) P2X7R loss-of-function mutation on clinical end points (development of coronary artery vasculopathy, death, re-transplantation or re-listed for transplantation, any rejection) in the first year post transplant; ii) we will explore in vivo and ex vivo in the CTOT-05 cohort of cardiac transplant recipients the effects of P2X7R loss-of-function mutation on the immune system.
Description: nominal change from baseline to 1 year in percent atheroma volume measured by intravascular ultrasoundMeasure: Cardiac Allograft Vasculopathy Time: 1 year
Description: Death re-transplant biopsy proven acute rejection antibody mediated rejection cellular rejection; treated rejection hemodynamic compromise-associated rejection chronic allograft vasculaopathy at 12-months total atheroma volume; change in average maximal intimal thickness rapid progressive chronic allograft vasculaopathy (change in maximal intimal thickness) ≥0.5 mm in the first year (intravascular ultrasound) histological changes of antibody mediated rejection (Immunohistochemistry).Measure: Heart Rejection or Patient Death Time: 6 months; 12 months
Depression is one of the most important causes of disability in the world today, with major personal, social and economic costs. Although some moderately effective drug treatments are already available, about a third of patients with major depressive disorder (MDD) remain depressed despite current treatment. There is growing evidence that inflammation - the response of the body's immune system to physical and social stresses - can cause depressive symptoms in some patients. It is therefore predicted that anti-inflammatory drugs could have anti-depressant effects and the research team aims to test this using a new drug, JNJ-54175446, which blocks the activity of a receptor called P2X7. P2X7 is present on many immune cells and plays a key role in the release of inflammatory molecules during stress, which may be linked to stress-related depression. The research team will recruit approximately up to 142 participants with MDD to this clinical trial. Patients will have moderate-severe depressive symptoms despite ongoing treatment with a conventional anti-depressant drug, and they will have blood test results at screening that indicate they are likely to have active P2X7 signalling in the brain. Eligible participants will be randomly allocated to receive either 50mg/day JNJ-54175446 or placebo for 8 weeks. Participants will be assessed at weeks 2, 5 and 8 using a standard clinical depression scale and the scores compared between those treated with placebo and those treated with JNJ-54175446. To understand more about the effects of JNJ-54175446 on the immune system and the brain, patients will also complete additional blood tests, questionnaires and magnetic resonance imaging (MRI) brain scans at different visits throughout the trial. The trial will be carried out across 5 centres in the UK.
3. Presence of two copies of the loss-of-function C allele at rs3751143, and/or has one copy of the loss-of-function A allele at rs1653624 in the P2RX7 gene.
Description: The Montgomery Asberg Depression Rating Scale (MADRS), a researcher-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The test consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. (Visit 4)Measure: Change from baseline in total score on the MADRS scale at week 8 Time: At baseline and at 8 weeks of treatment
Description: The Montgomery Asberg Depression Rating Scale (MADRS), a researcher-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The test consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition.Measure: Change from baseline in total score on the MADRS scale Time: At baseline, 2 and 5 weeks of treatment
Description: Perceived Stress Scale is a questionnaire measure of recent or current social stress. This scale ranges from 0 to 40; scores ranging from 0-13 would be considered low stress; scores ranging from 14-26 would be considered moderate stress; scores ranging from 27-40 would be considered high perceived stress.Measure: Change in scores on Perceived Stress Scale Time: At baseline, 2, 5 and 8 weeks of treatment
Description: Snaith-Hamilton Pleasure Scale. SHAPS is an instrument developed for the assessment of hedonic capacity and consists of 14-items. Four major domains are covered in the scale, namely interest/pastimes, social interaction, sensory experience, and food/drink. The score range is 0-14. The higher the score the lower the ability to experience pleasure of the patient.Measure: Change in scores on SHAPS Time: At baseline, 2, 5 and 8 weeks of treatment
Description: Chalder Fatigue Questionnaire (CFQ). The Fatigue Scale, sometimes referred to as the Chalder Fatigue Questionnaire, is a self-administered questionnaire for measuring the extent and severity of fatigue within both clinical and non-clinical, epidemiological populations. The respondent's global score can range from 0 to 33. The global score also spans two dimensions—physical fatigue (measured by items 1-7) and psychological fatigue (measured by items 8-11).Measure: Change in scores on CFQ Time: At baseline, 2, 5 and 8 weeks of treatment
Description: Quick Inventory of Depressive Symptomatology (QIDS-SR16). The QIDS-SR16 is designed to assess the severity of depressive symptoms and is sensitive to change due to with medications, psychotherapy, or other treatments. Participants will provide responses to each item of this instrument with a 4-point Likert scale, with scores ranging from 0-3 for each item. The total score ranges from 0 to 27. Using a scale of severity of depression of none, mild, moderate, severe, and very severe, corresponding QIDS-SR16 total scores are none 1 to 5, mild 6 to 10, moderate 11 to 15, severe 16 to 20 and very severe 21 to 27.Measure: Change in scores on QIDS-SR16 Time: At baseline, 2, 5 and 8 weeks of treatment
Description: Generalized Anxiety Disorder 7 (GAD-7). GAD-7 is a self-reported questionnaire for screening and severity measuring of GAD. GAD-7 has seven items, which measure severity of various signs of GAD according to reported response categories with assigned points. Assessment is indicated by the total score, which made up by adding together the scores for all 7 items. The score ranges from 0 to 21. Using a scale of severity of anxiety of none, mild, moderate and severe, corresponding to GAD-7 total scores are none 0 to 4, mild 5 to 9, moderate 10 to 14 and severe 15 to 21.Measure: Change in scores on GAD-7 Time: At baseline, 2, 5 and 8 weeks of treatment
Description: Participants will be asked to self-assess their depression using the Beck Depression Inventory scale (BDI). BDI is a 21-question multiple-choice self-report inventory, widely used for assessment of depression, including in the NIMA BIODEP study, with a score range of 0-63. Each of the 21 items is rated by the participant on a 4 point scale.Measure: Change in score on participant self-reported depression scale Time: At baseline and at 8 weeks of treatment
Description: Revere-D is an application developed by Johnson and Johnson, and consists of a battery of eight validated cognitive tasks that assesses cognitive functions, such as memory and learning, that do not involve cognitive processing of emotionally salient stimuli.Measure: Change in scores in the cognitive function test ReVeRe-D Time: At baseline, 2, 5 and 8 weeks of treatment
Description: The continuous performance test is a computerised test of sustained attention which provides a measure of cognitive fatigue.Measure: Change in scores in Continuous performance test Time: At baseline, 2, 5 and 8 weeks of treatment
Description: The emotional test battery will consist of 3 validated computerised tasks which are used to assess cognitive functions that involve processing emotionally salient stimuli, such as human faces expressing emotional states.Measure: Change in scores in Emotional Test battery Time: At baseline and 2 weeks of treatment
Description: Participants will be asked to provide saliva samples before treatment commencement and during the last week of treatment in order for the cortisol levels to be analysed.Measure: Change in Salivary cortisol levels as a measure of biological stress Time: Samples collected within 7 days prior to Baseline visit and within 7 days prior to visit 4
Description: Brain structure and function will be assessed using fMRI/MRIMeasure: Change in Brain structure and function Time: Baseline and at 8 weeks fo treatment
Description: Heart rate variability will be measured for 15 minutes during rest and whilst completing one of the cognitive tasks.Measure: Change in heart rate variability Time: Baseline and at 8 weeks fo treatment
Description: Blood samples will be collected for the analysis of cytokine and chemokine levels with a multiplex immunoassay using the MSD Multi-spot assay system with the Cytokine Panel 1, Proinflammatory panel 1 and Chemokine panel 1 kits providing concentration of all analytes of the panel in pg/ml.Measure: Measurement of peripheral blood peripheral cytokine and chemokine levels Time: Baseline and at 8 weeks fo treatment
Description: The immune cellular content of the blood samples will be analysed with mass cytometry using the commercial kit Maxpar® Direct™ Immune Profiling Assay.Measure: Measurement of peripheral blood immunophenotypes Time: Baseline and at 8 weeks fo treatment