Microsampling Assays for Immunosuppressive Drugs in Children

Study Overview
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Brief Summary
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Immunosuppressive therapy is used to treat and manage solid organ and bone marrow/stem cell transplants in children. However, it can be harmful if too little or too much is given. Monitoring immunosuppressive drug (cyclosporine A, tacrolimus, and sirolimus) concentrations in the blood is important to ensure that the drug is given safely and effectively, but current approaches for collecting blood from a vein are painful and often difficult in children. Investigators seek to compare a new approach for monitoring immunosuppressive drug concentrations using a novel small volume blood sampling device, called Tasso-M20, to the traditional way of collecting blood from a vein. Additionally Investigators are interested in assessing patient and family perceptions of the Tasso-M20 device being used for immunosuppressive therapy and their comfortability using the device outside of a clinical setting. The primary objective of this project is to identify the relationship between cyclosporine A (CYA), tacrolimus (TAC), and sirolimus (SIR) concentrations in the venous blood (gold-standard) and capillary whole blood obtained using the microsampling device Tasso-M20. The secondary objective of this study is to investigate the stability of CYA, TAC, and SIR in blood samples collected using the Tasso-M20 device under the conditions of shipping and storage. The sub-study objective is to thematically compare subjects' and families' perceptions of blood collection via the Tasso-M20 device and standard venous blood collection.

Detailed Description
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Immunosuppressive therapy is used to treat and manage solid organ and bone marrow/stem cell transplants; however, suboptimal dosing can lead to organ rejection and graft failure. Immunosuppressant drugs require therapeutic drug monitoring (TDM) to ensure dosing is adequate and therapeutic concentrations are achieved and maintained. The optimal blood concentrations of these drugs are critical to minimize toxicity and simultaneously prevent allograft rejection in an individual transplant patient. Often life-long TDM is required necessitating hospital or laboratory visits for routine venous blood sampling by phlebotomy. Immunosuppressive drugs, cyclosporine A (CYA), tacrolimus (TAC), and sirolimus (SIR) require routine TDM. This entails immunocompromised people leaving their homes for laboratory visits, potentially increasing their risk of acquiring infections. TDM for CYA, TAC, and SIR are required due to their narrow therapeutic targets: CYA 150-400 ng/mL, TAC 5-12 ng/mL, and SIR 4-12 ng/mL. CYA, TAC, and SIR are primarily distributed in erythrocytes and should be quantified in whole blood. Immunoassays and the liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays are the two commonly used methods of TDM for CYA, TAC, and SIR. While immunoassays provide an accurate measurement of concentrations, they often have some limitations on specificity. LC-MS/MS assays are very specific and efficient since they can quantify multiple analytes with a single method. At the Children's Hospital of Philadelphia (CHOP), the clinical TDM immunoassays for CYA, TAC, and SIR require 0.5-1.0 mL of blood. TDM immunoassays require blood collection by a trained practitioner. Volumetric absorptive microsampling (VAMS) with an FDA-approved Tasso-M20 device allows for the accurate and precise collection of a fixed volume of blood from a capillary needle without the need for phlebotomy. The Tasso-M20 (FDA Class 1 exempt device) consists of a sample head with a lancet that is activated with the push of a button to accurately and painlessly collect blood samples from the deltoid (or similar) muscle (capillary sampling) of the subjects on all four tips (17.5 µL each). An LC-MS/MS assay with 20 µL blood, as obtained by the Tasso device, was shown to provide the required test range for TDM of trough values. This microsampling technique could be utilized clinically to promote the provision of TDM in children but has not been studied for immunosuppressive drugs (CYA, TAC, and SIR) in children. Children and their parents/guardians who consent to the optional sub-study will be administered a brief survey after one study visit, to ask about their perceptions of the two methods of blood collection that they experienced at the visit.

Official Title
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Microsampling Assays for Immunosuppressive Drugs in Children

Conditions
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Immunosuppression

Intervention / Treatment
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* Other: Microsampling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females <18 years of age Weight greater than 5 kg Receiving CYA, TAC, and/or SIR as standard of care Has scheduled/anticipated blood draw to quantify the concentration of CYA, TAC, and SIR* for clinical indications Parental/guardian permission (informed consent), and subject's assent if applicable. Exclusion Criteria: 1) Unable to provide blood samples. * Potential subjects and their parents/guardians may be approached prior to having a blood draw scheduled if they meet all other eligibility criteria. Sub-Study Criteria: Sub-study criteria for child participants will not differ from the main study. Adult participants are required to be a parent/legal guardian of a study subject.

Ages Eligible for Study
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Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cyclosporine A<br>Males and females <18 years of age Weight greater than 5 kg Receiving cyclosporine A as the standard of care Has scheduled/anticipated blood draw to quantify the concentration of cyclosporine A for clinical indications Parental/guardian permission (informed consent), and subject's assent if applicable. | Other: Microsampling<br>* Volumetric absorptive microsampling (VAMS) with Tasso-M20 devices allows for the accurate and precise collection of a fixed small volume of blood from a capillary needle without the need for phlebotomy.<br>|
| Tacrolimus<br>Males and females <18 years of age Weight greater than 5 kg Receiving tacrolimus as the standard of care Has scheduled/anticipated blood draw to quantify the concentration of tacrolimus for clinical indications Parental/guardian permission (informed consent), and subject's assent if applicable. | Other: Microsampling<br>* Volumetric absorptive microsampling (VAMS) with Tasso-M20 devices allows for the accurate and precise collection of a fixed small volume of blood from a capillary needle without the need for phlebotomy.<br>|
| Sirolimus<br>Males and females <18 years of age Weight greater than 5 kg Receiving sirolimus as the standard of care Has scheduled/anticipated blood draw to quantify the concentration of sirolimus for clinical indications Parental/guardian permission (informed consent), and subject's assent if applicable. | Other: Microsampling<br>* Volumetric absorptive microsampling (VAMS) with Tasso-M20 devices allows for the accurate and precise collection of a fixed small volume of blood from a capillary needle without the need for phlebotomy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical validation of microsampling assay of Tacrolimus | Capillary whole blood specimens will be obtained via the Tasso M-20 sampling device to determine validity of the assay compared to venous blood samples (gold standard and used clinically) in measuring Tacrolimus concentration levels. | up to 20 months | 
| Clinical validation of microsampling assay of Sirolimus | Capillary whole blood specimens will be obtained via the Tasso M-20 sampling device to determine validity of the assay compared to venous blood samples (gold standard and used clinically) in measuring Sirolimus concentration levels. | up to 20 months | 
| Clinical validation of microsampling assay of Cyclosporine A | Capillary whole blood specimens will be obtained via the Tasso M-20 sampling device to determine validity of the assay compared to venous blood samples (gold standard and used clinically) in measuring Cyclosporin A concentration levels. | up to 20 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stability of blood samples which contains immunosuppressive drug Tacrolimus under conditions of shipping | Blood specimens obtained by the Tasso M20 device will be used to investigate the stability of blood samples obtained from the Tasso M-20 device containing immunosuppressive drugs Tacrolimus under the conditions of shipping | up to 20 months | 
| Stability of blood samples obtained which contains immunosuppressive drug Sirolimus under conditions of shipping | Blood specimens obtained by the Tasso M20 device will be used to investigate the stability of blood samples obtained from the Tasso M-20 device containing immunosuppressive drugs sirolimus under the conditions of shipping | up to 20 months | 
| Stability of blood samples containing immunosuppressive drug Cyclosporine A under conditions of shipping | Blood specimens obtained by the Tasso M20 device will be used to investigate the stability of blood samples obtained by the Tasso M-20 device which contains immunosuppressive drugs cyclosporine A under the conditions of shipping | up to 20 months | 
| Stability of blood samples which contains immunosuppressive drug Tacrolimus under conditions of storage | Blood specimens obtained by the Tasso M20 device will be used to investigate the stability of blood samples containing immunosuppressive drugs Tacrolimus under the conditions of storage | up to 20 months | 
| Stability of blood samples which contains immunosuppressive drug Sirolimus under conditions of storage | Blood specimens obtained from the Tasso device will be used to investigate the stability of blood samples containing immunosuppressive drugs Sirolimus under the conditions of storage | up to 20 months | 
| Stability of blood samples obtained which contains immunosuppressive drug Cyclosporine A under conditions of storage | Blood specimens obtained from the Tasso M20 device will be used to investigate the stability of blood samples containing immunosuppressive drugs Cyclosporin A under the conditions of storage | up to 20 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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microsampling, cyclosporine A, tacrolimus, sirolimus, Tasso-M20