Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
PALETTE is a perpetual adaptive platform to efficiently study sepsis interventions within 'treatable traits' in all-ages patients enabling prompt evaluation of pandemic treatments. Treatable traits, therapeutic targets identified by phenotypes or endotypes (defined by biological mechanism or by treatment response) through validated biomarkers (measurable characteristic reflecting normal or pathogenic processes, or treatment responses), may include multi-omics, cellular, immune, metabolic, endocrine features, or intelligent algorithms. PALETTE Bayesian adaptive design enables parallel investigations of multiple interventions for sepsis, and quick inclusion of pandemic pathogens. PALETTE's new conceptual model will respond to the challenges of standard approaches, i.e. series of sepsis trials, each investigating one or two interventions, expensive, time consuming, and inappropriate in pandemic context.
Not provided
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Hyperinflammation : Tocilizumab | Experimental |
| |
| Hyperinflammation: Baricitinib | Experimental |
| |
| Hyperinflammation: Anakinra | Experimental |
| |
| Hyperinflammation : blood purification with MTx.100 Plasma Adsorption Column | Experimental |
| |
| Hyperinflammation : usual care | Active Comparator |
| |
| Hypoinflammation : G CSF filgrastim | Experimental |
| |
| Hypoinflammation : Interferon gamma-1b | Experimental |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tocilizumab | Drug | 8 mg per kilogram of body weight enterally (oral or via a gastric tube) once daily for 14 days (or hospital discharge pending which will occur first) (same for adults and children) |
| Measure | Description | Time Frame |
|---|---|---|
| All-cause mortality | Dual primary endpoint | At day 28 |
| Number of days alive without persistent life-supportive therapies | Dual primary endpoint Respiratory support: high flow oxygen, non-invasive or invasive mechanical ventilation, extracorporeal membrane oxygenation or CO2 removal; cardiovascular support: continuous infusion of any dose of vasopressor or inotrope, or mechanical circulatory assistance; renal support: intermittent or continuous renal replacement therapy | At day 28 |
| Measure | Description | Time Frame |
|---|---|---|
| Net benefit probability of intervention vs. control, assessed with a Generalized Pairwise Comparison (mortality prioritized over life-support-free days) | The Generalized Pairwise Comparison (GPC) method will be used to derive a single composite outcome. Each patient in the intervention group will be compared to each patient in the control group. For each pair, a score of +1, -1, or 0 will be assigned according to prioritized outcomes: (1) all-cause mortality at day 28, and (2) number of days alive without life-supportive therapies at day 28 if both patients have the same mortality status. The net benefit will be calculated as the sum of all pairwise scores divided by the total number of pairs, corresponding to the probability that a randomly chosen patient has a better outcome in one group than in the other. |
| Measure | Description | Time Frame |
|---|---|---|
| Circulating levels of cytokines | At inclusion | |
| Circulating levels of chemokines | At inclusion | |
| Circulating levels of cytokines |
Platform inclusion criteria will be:
Briefly, all following criteria will be required:
Documented or suspected infection,
Sequential Organ Failure Assessment (SOFA) score ≥2 for adults, and PHOENIX sepsis score of ≥2 for children.
Platform exclusion criteria:
Any of the following:
Treatable trait inclusion criteria :
There are also inclusion and exclusion criteria related to treatable traits and interventions.
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Djillali Annane, Pr | Contact | +33147107787 | djillali.annane@aphp.fr | |
| Jérôme Lambert | Contact | +33142499742 | jerome.lambert@u-paris.fr |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Randomization will concern 6 specific treatable traits (hyperinflammation, hypoinflammation, Macrophage Activation Like Syndrome, Corticoid response, hypercoagulation, Hypofibrinolysis). In each treatable trait, patients will be randomly allocated between control (usual care) and 1 to 4 experimental treatments using parallell arms.
Not provided
Not provided
Not provided
Not provided
| Hypoinflammation : usual care | Active Comparator |
|
| MALS : Anakinra | Experimental |
|
| MALS : blood purification with MTx.100 Plasma Adsorption Column | Experimental |
|
| MALS : usual care | Active Comparator |
|
| Corticoids response : Hydrocortisone | Experimental |
|
| Corticoids response : Fludrocortisone | Experimental |
|
| Corticoids response : Hydrocortisone + Fludrocortisone | Experimental |
|
| Corticoids response : usual care | Active Comparator |
|
| Hypercoagulation : Prophylactic unfractionated heparin (UFH) | Experimental |
|
| Hypercoagulation : Therapeutic UFH | Experimental |
|
| Hypercoagulation : Therapeutic low molecular weight heparin (LMWH) | Experimental |
|
| Hypercoagulation : Thrombomodulin | Experimental |
|
| Hypercoagulation : usual care | Active Comparator |
|
| Hypofrinolysis : Sivelestat | Experimental |
|
| Hypofrinolysis : OctaplasLG | Experimental |
|
| Hypofrinolysis : Plasminogen | Experimental |
|
| Hypofrinolysis : Usual care | Active Comparator |
|
| Baricitinib | Drug | 4mg, enterally (oral or via a gastric tube) once daily for 14 days (or hospital discharge pending which will occur first) (same for adults and children) |
|
| Anakinra | Drug | 100 mg subcutaneously once daily for 10 days (or hospital discharge pending which will occur first) (same for adults and children) |
|
| Hydrocortisone | Drug | 50mg (in children: 1-2 mg/kg) IV Q6 for 7 days |
|
| Hydrocortisone and fludrocortisone | Drug | Hydrocortisone 50mg IV Q6 for 7 days + Fludrocortisone 50mg orally or via gastric tube once a day for 7 days. |
|
| Heparin | Drug | Therapeutic unfractionated heparin (UFH) starting at 400 (in children: 20 IU/kg/h) IU/kg/24h (target between 0.3 and 0.5 IU/ml), adapted to the therapeutic Partial Thromboplastin Time targeting values in the range of 60 to 100 seconds, with lower intensity dosing in the range of 60 to 80 seconds, for 7 days (or ICU discharge, pending which will occur first). |
|
| Low molecular weight heparin | Drug | Therapeutic low weight molecular heparin (LMWH) tinzaparin, considering its contraindications, recommended dose ranges and monitoring if applicable, as follows: 175 (in children 100 U/kg) IU/kg/24h, for 7 days (or hospital discharge pending which will occur first). |
|
| Recombinant humanThrombomodulin( rhTM) | Drug | Recombinant human thrombomodulin (rhTM) 0.06 mg/kg/j IV, for 7 days (or ICU discharge, pending which will occur first). |
|
| Sivelestat | Drug | 0.2 mg/kg/h for 7 days (or ICU discharge, pending which will occur first) |
|
| Usual care | Other | Usual care |
|
| blood purification with MTx.100 Plasma Adsorption Column | Other | up to 4 hours a day, up to four days in a row |
|
| G-CSF filgrastim | Drug | 0.5 MIU (5μg)/kg/day subcutaneously for 5 consecutive days (or up to ICU discharge pending which occurs first) - same for adults and children . |
|
| Interferon gamma-1b | Drug | rhIFNg subcutaneously at 50 µg/m2 if body surface >0,5 m2, or 1.5µg/kg if body surface of 0,5 m2or less, every other day for 15 days (or up to ICU discharge pending which occurs first) |
|
| Fludrocortisone | Drug | 50µg orally (or via the gastric tube) once a day for 7 days (or ICU discharge pending which will occur first) (same for adults and children) |
|
| Prophylactic unfractionated heparin (UFH) | Drug | 100 IU/kg/24h for 6 days |
|
| Octaplas LG | Drug | 12 mL/kg on day 1; repeated daily from day 2 to day 5, provided that PT/INR remains ≥ 1.40 (This intervention will be opened for randomisation once a supply circuit is in place) |
|
| Plasminogen | Drug | 2,2 mg/kg/day (intravenous infusion) during 3 days. |
|
| At day 28 |
| Overall Survival | At day 90 |
| Overall Survival | At 1 year |
| Overall Survival | At 3 years |
| Number of hospital free days | At 1 year |
| Number of hospital free days | At 3 years |
| Time to recover walking | At day 90 |
| Time to resume previous social and professional activities | At 1 year |
| Quality of life score for adults assessed by SF-36 | The Short Form (36) (SF-36) Health Survey is a 36-item measure if health status. The score obtained varies between 0 and 100. The higher the score the less disability. Ware JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36): I. Conceptual framework and item selection. Med Care 1992;30:473-83. | At day 90 |
| Quality of life score for adults assessed by EQ-5D-5L | EQ-5D-5L : It evaluates five dimensions : mobility, self-care, usual activities, pain/discomfort and anxiety/depression and each dimension has five levels : no problems, slight problems, moderate problems, severe problems and extreme problems. Answers are given on a 5-point scale by domain, the higher the score, the poorer the quality of life. | At day 90 |
| Pediatric Quality of Life Inventory (PedsQL) | Standardized tool used to measure health-related quality of life (HRQoL) in children and adolescents (ages 2-18) It is a 23-item score divided in four domains : Phtsical functioning, Emotional functioning, Social functioning, School functioning The total score vary from 0 to 100. The higher the score the hiher the quality of life. | At day 90 |
| Quality of life score for children assessed by FSS | Functional Status Scale (FFS) : It examines 6 domains of functioning, and each domain receives a score of 1 (normal), 2 (mild dysfunction), 3 (moderate dysfunction), 4 (severe dysfunction), or 5 (very severe dysfunction). Final scores range from 6 to 30. | At day 90 |
| Quality of life score for adults assessed by SF-36 | The Short Form (36) (SF-36) Health Survey is a 36-item measure if health status. The score obtained varies between 0 and 100. The higher the score the less disability. Ware JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36): I. Conceptual framework and item selection. Med Care 1992;30:473-83. | At 1 year |
| Quality of life score for adults assessed by EQ-5D-5L | EQ-5D-5L : It evaluates five dimensions : mobility, self-care, usual activities, pain/discomfort and anxiety/depression and each dimension has five levels : no problems, slight problems, moderate problems, severe problems and extreme problems. Answers are given on a 5-point scale by domain, the higher the score, the poorer the quality of life. | At 1 year |
| Quality of life score for children assessed by FSS | Functional Status Scale (FFS) : It examines 6 domains of functioning, and each domain receives a score of 1 (normal), 2 (mild dysfunction), 3 (moderate dysfunction), 4 (severe dysfunction), or 5 (very severe dysfunction). Final scores range from 6 to 30. | At 1 year |
| Pediatric Quality of Life Inventory (PedsQL) | Standardized tool used to measure health-related quality of life (HRQoL) in children and adolescents (ages 2-18) It is a 23-item score divided in four domains : Phtsical functioning, Emotional functioning, Social functioning, School functioning The total score vary from 0 to 100. The higher the score the hiher the quality of life. | At 1 year |
| Quality of life score for adults assessed by SF-36 | The Short Form (36) (SF-36) Health Survey is a 36-item measure if health status. The score obtained varies between 0 and 100. The higher the score the less disability. Ware JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36): I. Conceptual framework and item selection. Med Care 1992;30:473-83. | At 3 years |
| Quality of life score for adults assessed by EQ-5D-5L | EQ-5D-5L : It evaluates five dimensions : mobility, self-care, usual activities, pain/discomfort and anxiety/depression and each dimension has five levels : no problems, slight problems, moderate problems, severe problems and extreme problems. Answers are given on a 5-point scale by domain, the higher the score, the poorer the quality of life. | At 3 years |
| Quality of life score for children assessed by FSS | Functional Status Scale (FFS) : It examines 6 domains of functioning, and each domain receives a score of 1 (normal), 2 (mild dysfunction), 3 (moderate dysfunction), 4 (severe dysfunction), or 5 (very severe dysfunction). Final scores range from 6 to 30. | At 3 years |
| Pediatric Quality of Life Inventory (PedsQL) | Standardized tool used to measure health-related quality of life (HRQoL) in children and adolescents (ages 2-18) It is a 23-item score divided in four domains : Phtsical functioning, Emotional functioning, Social functioning, School functioning The total score vary from 0 to 100. The higher the score the hiher the quality of life. | At 3 years |
| Number of adverse events | Tolerance of interventions considering any grade of 3 serious adverse events. | Up to 3 years |
| Incidence of new sepsis episodes | At day 90 |
| Incidence of new sepsis episodes | At 1 year |
| Incidence of new sepsis episodes | At 3 years |
| Incidence of new unscheduled hospitalizations | At day 90 |
| Incidence of new unscheduled hospitalizations | At 1 year |
| Incidence of new unscheduled hospitalizations | At 3 years |
| Incidence of sequels in neurocognitive, neuromuscular; cardiovascular, respiratory, renal, metabolic, and immune systems | At 3 years |
| Number of grade 3 serious adverse events | At day 28 |
| At day 1 |
| Circulating levels of chemokines | At day 1 |
| Circulating levels of cytokines | At day 7 |
| Circulating levels of chemokines | At day 7 |
| Circulating levels of cytokines | At 1 year |
| Circulating levels of chemokines | At 1 year |
| Circulating levels of cytokines | At 3 years |
| Circulating levels of chemokines | At 3 years |
| ID | Term |
|---|---|
| D018805 | Sepsis |
| ID | Term |
|---|---|
| D007239 | Infections |
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
Not provided
Not provided
| ID | Term |
|---|---|
| C502936 | tocilizumab |
| C000596027 | baricitinib |
| D053590 | Interleukin 1 Receptor Antagonist Protein |
| D006854 | Hydrocortisone |
| D005438 | Fludrocortisone |
| D006493 | Heparin |
| D006495 | Heparin, Low-Molecular-Weight |
| C069195 | sivelestat |
| C554125 | interferon gamma-1b |
| D010958 | Plasminogen |
| ID | Term |
|---|---|
| D016207 | Cytokines |
| D036341 | Intercellular Signaling Peptides and Proteins |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D011506 | Proteins |
| D001685 | Biological Factors |
| D011282 | Pregnenediones |
| D011283 | Pregnenes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D015062 | 11-Hydroxycorticosteroids |
| D006889 | Hydroxycorticosteroids |
| D000305 | Adrenal Cortex Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D015065 | 17-Hydroxycorticosteroids |
| D006025 | Glycosaminoglycans |
| D011134 | Polysaccharides |
| D002241 | Carbohydrates |
| D004792 | Enzyme Precursors |
| D045762 | Enzymes and Coenzymes |
| D001609 | Beta-Globulins |
| D012712 | Serum Globulins |
| D001798 | Blood Proteins |
| D005916 | Globulins |
| D011498 | Protein Precursors |
Not provided
Not provided