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Fabry Disease Registry & Pregnancy Sub-registry
Laurie Bailey - laurie.bailey@cchmc.org
ALL
NCT00196742
Inclusion Criteria
* Fabry Registry: All patients with a confirmed diagnosis of Fabry disease who have signed the informed consent and patient authorization form(s) are eligible for inclusion. Confirmed diagnosis is defined as a documented deficiency in plasma or leukocyte αGAL (alpha-galactosidase) enzyme activity and/or mutation(s) in the gene coding for αGAL.
* Fabry Pregnancy Sub-registry:
* Eligible women must:
* be enrolled in the Fabry Registry.
* be pregnant, or have been pregnant with appropriate medical documentation available.
* provide a signed informed consent and authorization form(s) to participate in the Sub-Registry prior to any Sub-Registry-related data collection being performed.
Exclusion Criteria Fabry Registry: There are no exclusion criteria. Fabry Pregnancy Sub-registry: There are no exclusion criteria.
Fabry Disease
alpha Galactosidase A, aGAL (alpha-galactosidase), Fabry, GL3 (globotriaosylceramide), Anderson-Fabry Disease, angiokeratomas, GLA deficiency (gene deficiency), errors in metabolism
ATHN Transcends: A Natural History Study of Non-Neoplastic Hematologic Disorders
Kenzie Nolte - mackenzie.nolte@cchmc.org
ALL
NCT04398628
Participants who meet the following inclusion criteria and none of the exclusion criteria are eligible for enrollment in one of the open disease-specific arms.
• Any age
• Having a congenital or acquired blood disorder; or
• Having a bleeding phenotype as indicated by an age adjusted abnormal ISTH Bleeding Assessment Tool score with an unknown diagnosis; or
• Connective tissue disorder with bleeding tendency as indicated by an age adjusted abnormal ISTH Bleeding Assessment Tool score.
• Eligible for a currently active disease-specific arm.
• Concurrent enrollment in the ATHNdataset or current ATHNdataset participant.
• Factor VIII or factor IX activity \<50%, without another explanation for low clotting factor other than congenital hemophilia or being a known carrier for congenital hemophilia; OR
• Carrier for congenital hemophilia with a factor VIII \>=50% or factor IX activity \>=50% with or without a bleeding phenotype as indicated by an ISTH Bleeding Assessment Tool score of ≥4 for adult males, ≥6 for adult females, or ≥3 for children younger than 18 years OR
• Known congenital hemophilia that have a factor level \>50% after receiving vector, OR 4. Acquired hemophilia.
• Abnormalities of platelet function a. Glanzmann thrombasthenia (GPIIb or GPIIIa) b. Bernard-Soulier syndrome (GPIbalpha, GPIbbeta, or GPIX)
• Abnormalities of platelet granules
• Abnormalities of platelet signal transduction
• Abnormalities of platelet secretion
• Collagen Receptor Defect
• ADP Receptor Defect
• Thromboxane Receptor Defect
• Giant Platelet Disorder
• Abnormalities in platelet aggregation testing due to another or unknown cause (not drug related)
• PAI-1 deficiency
• Factor I, II, V, VII, X, XI, XIII deficiencies
• Combined FV and FVIII deficiency
• Plasminogen deficiency
• Decreased tissue plasminogen activator
• Afibrinogenemia/hypofibrinogenemia/dysfibrinogenemia
• Thrombotic Thrombocytopenia Purpura or Congenital Hemolytic Uremic Syndrome
• Wiskott-Aldrich
• Methylenetetrahydrofolate Reductase Deficiency
• Have a bleeding phenotype as indicated by an ISTH Bleeding Assessment Tool score of ≥4 for adult males, ≥6 for adult females, or ≥3 for children younger than 18 years with an unknown diagnosis, OR
• Connective tissue disorder with bleeding tendency as indicated by an ISTH Bleeding Assessment Tool score of ≥4 for adult males, ≥6 for adult females, or ≥3 for children younger than 18 years.
• Diagnosis of congenital hemophilia A (FVIII \<40%) or hemophilia B (FIX \<40% or below lower limit for age)
• Age \<18 years at time of enrollment
• Parent or authorized guardian or legally authorized representative (LAR) can provide informed consent
• Care established at one of the ATHN Transcends participating HTCs
• Clotting Factor Concentrate (CFC) exposure, fresh frozen plasma (FFP), cryoprecipitate, and single donor platelets \<3 exposure days (ED) Exclusion Criteria
• Concomitant diagnosis with another bleeding disorder
• History of a confirmed, positive inhibitor INHIBIT Module
• Concomitant diagnosis with bleeding disorder other than hemophilia A
• Immune disorder
• Previous history or presence of factor VIII inhibitor. A confirmed, positive inhibitor is defined as two consecutive positive inhibitor titers (≥ 0.6 BU) that result in changes in treatment recommendations. Efanesoctocog alfa (ALTUVIIIO®) Module Inclusion criteria:
• Ability of the potential participant's legally authorized representative (e.g., their parent or legal guardian) to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use confidential health information in accordance with national and local participant privacy regulation.
• People with severe HA with a baseline FVIII activity of less than 1%. (While inclusion for participation in ATHN Transcends lists \<5% FVIII activity, this proposed module will limit enrollment to people with FVIII activity levels of \<1%.) Other severities may be included per ATHN Transcends PI approval.
• \<18 years of age.
• No history of a confirmed, positive FVIII inhibitor.
• Sex assigned at birth of male, female, or intersex.
• Participants should have no more than three (3) exposure days of blood products (fresh frozen plasma, cryoprecipitate, or platelets), no more than three (3) doses of any FVIII concentrate other than efanesoctocog alfa, and up to three (3) doses of efanesoctocog alfa prior to enrollment.
• Site PI confirmed all inclusion criteria has been met. Exclusion criteria:
• Not meeting all the inclusion criteria; confirmed by site PI.
• Any exposure to blood products or FVIII replacement products except as described in the inclusion criteria.
• History of positive inhibitor testing.
• History of hypersensitivity reactions associated with efanesoctocog alfa administration.
• Other coagulation disorder(s) in addition to Hemophilia A.
• Any concurrent clinically significant major disease such as cancer that, in the opinion of the investigator, would make the participant unsuitable for enrollment.
• Concurrent systemic treatment with chemotherapy and/or other immunosuppressant medications. Use of corticosteroids for the treatment of asthma or management of acute allergic or otherwise life-threatening episodes is allowed except for systemic corticosteroid treatment given to children daily or on an alternate day schedule at \> 2 mg/kg/day of prednisone or its equivalent or \> 20 mg/day if the duration is longer than 14 days.
• Enrollment in a concurrent clinical interventional drug study.
• Intake of an Investigational Medicinal Product within three (3) months prior to inclusion in this study.
• Inability to comply with study requirements.
• Other, unspecified reasons that, in the investigator's opinion, make the participant unsuitable for enrollment. Hemophilia Natural History Arm Inclusion Criteria
• Congenital or acquired hemophilia A or B of any severity with or without inhibitors receiving a current therapy, a non-factor product, or for whom use of a non-factor product is a possibility, OR
• Females of any age, with confirmed congenital hemophilia A or B carrier status with genetic mutational analysis and any factor level. Exclusion Criteria
• Presence of any known bleeding disorder other than congenital hemophilia A or B
• Presence of concurrent hemophilia and a second hemostatic defect (low von Willebrand Factor (vWF) without vWD diagnosis is not excluded)
• Unable or unwilling to comply with the study arm protocol. Nonacog beta pegol (Rebinyn®) Module
• Has provided signed written consent for the nonacog beta pegol (Rebinyn®)Module before any study-related activities.
• Male participants, at any age with hemophilia B, naïve or minimally exposed (up to 3 EDs) to nonacog beta pegol treatment at time of study enrollment. Additional doses may be allowable per ATHN Transcends PI approval.
• Decision to initiate continuous prophylaxis treatment with commercially available nonacog beta pegol has been made by the participant(s)/Legally Authorized Representative(s) (LAR(s)) and the treating physician before and independently from the decision to include the participant in this study.
• Previous participation in this study. Participation is defined as having given informed consent in this study.
• Mental incapacity, unwillingness or language barriers precluding adequate understanding or cooperation, including a diagnosis or suspicion of attention deficit hyperactivity disorder (ADHD) or autism spectrum disorder (ASD) per the discretion of the Principal Investigator.
• Known or suspected hypersensitivity to nonacog beta pegol or related products.
• Clinical suspicion or presence of FIX inhibitor at time of inclusion.
• Inability or unwillingness to undergo neurological assessment/structured developmental history. Emicizumab (Hemlibra®) Module
• Participant currently treated with emicizumab (Hemlibra®)
• Currently enrolled in the Hemophilia Natural History Arm of ATHN Transcends
• Congenital hemophilia A or B of any severity with or without inhibitors receiving a current therapy, a non-factor product, or for whom use of a non-factor product is a possibility
• Age 18 years of age or older
• English speaking
• Presence of any known bleeding disorder other than congenital hemophilia A or B;
• Presence of concurrent hemophilia and a second hemostatic defect (low von Willebrand Factor (vWF) without vWD diagnosis is not excluded); and
• Unable or unwilling to comply with the study arm protocol Hemophilia Gene Therapy Outcomes Arm Inclusion Criteria
• Hemophilia A or B of any severity with or without inhibitors having received or will receive a hemophilia gene transfer product in the next 6 months.
• Age 18 years and older.
• Able to give informed consent. Exclusion Criteria None Etranacogene dezaparvovec (HEMGENIX®) Module
• Age 18 years of age or older
• Treatment with commercial etranacogene dezaparvovec (HEMGENIX®)
• Have provided signed written informed consent within 3 months before or within 6 months after etranacogene dezaparvovec (HEMGENIX®) treatment, or within 6 months of when the study is initiated at the treating site. FIX Prophylaxis Cohort
• Age 18 years of age or older
• Treatment with FIX prophylaxis therapy
• Has provided signed written consent at any time for ATHN Transcends Study Exclusion Criteria, both cohorts: 1\. Have been treated with etranacogene dezaparvovec in a clinical trial prior to commercial availability. These patients are still eligible for enrollment in the Gene Therapy Outcomes Arm, and their data may be collected for separate analysis. Congenital Platelet Disorders Arm Inclusion Criteria
• Platelet adhesion defect
• Bernard Soulier syndrome (Defective GPIb-IX-V receptor, impaired adhesion to vWF)
• Velocardio-facial syndrome/DiGeorge syndrome (Defective GPIb-IX-V receptor)
• Platelet type vWD (Defective GPIb-IX-V, gain of function interaction between vWF-GP1bα)
• Platelet aggregation defect
• Glanzmann thrombasthenia (Defective integrin αIIbβ3 (GPIIb/IIIa)
• Platelet aggregation defect, NOS
• Agonist receptor defects
• Epinephrine
• ADP
• Collagen
• Thromboxane A2
• Platelet signaling defects
• Cyclooxygenase deficiency (PTGS1 mutation)
• Phospholipase A2 deficiency
• Thromboxane synthase deficiency (TBXAS1 mutation)
• G protein activation defect (GNAS mutation)
• Scott syndrome (defect in phosphatidyl serine translocation)
• Platelet Granule disorders
• Dense granule storage pool disorder * Hermansky Pudlak syndrome * Chediak Higashi syndrome * Griscelli syndrome
• Alpha granule storage pool disorder * Grey platelet syndrome * Arthrogryposis-Renal Dysfunction-Cholestasis (ARC) syndrome * Quebec platelet disorder * Paris-Trousseau syndrome
• Combined alpha delta granule deficiency
• Platelet cytoskeletal structure defects
• Wiskott Aldrich syndrome
• MYH9 associated disorders (myosin heavy chain) * May Hegglin syndrome * Fechtner syndrome * Sebastian syndrome * Epstein syndrome
• Other mutations * FLNA mutations (Filamin) * DIAPH1 (Actin and microtubules) * ACTN1 (alpha actinin) * TPM4 (tropomyosin) * TUBB1 (beta tubulin)
• Other Congenital thrombocytopenias
• Familial platelet disorders and predisposition to AML (RUNX1)
• X linked thrombocytopenia with dyserythropoiesis (GATA1)
• Congenital amegakaryocytic thrombocytopenia (MPL) Exclusion Criteria
• Diagnosis of von Willebrand Disease (Meeting the definition of vWD or low vWF per most recent international guidelines)
• Diagnosis of Hemophilia A or Hemophilia B (Factor VIII or IX ≤ 40%) Glanzmann Thrombasthenia (GT) Module Inclusion Criteria
• Participant has signed the informed consent/assent form
• Participant has flow cytometry or aggregometry or genetics confirmed GT
• Participant is willing to perform study procedures, including daily bleed tracking for 3 months and further if requested
• Participants are 2 years or older at time of consent Exclusion Criteria None
Inclusion Criteria:
• Any age
• Having a congenital or acquired blood disorder; or
• Having a bleeding phenotype as indicated by an age adjusted abnormal ISTH Bleeding Assessment Tool score with an unknown diagnosis; or
• Connective tissue disorder with bleeding tendency as indicated by an age adjusted abnormal ISTH Bleeding Assessment Tool score.
• Eligible for a currently active disease-specific arm.
• Concurrent enrollment in the ATHNdataset or current ATHNdataset participant.
Exclusion Criteria:
1\. Does not qualify for inclusion in a currently activedisease-specific arm; participants may be eligible to enroll as future cohorts and arms are activated; 2. Unable to give informed consent or assent 3. Unwilling to perform study procedures
Cohort Participant Selection
Each participant is to be enrolled in the cohort for which they qualify as defined below.
Hemophilia Cohort
Inclusion Criteria:
Participants who meet any of the following inclusion criteria are eligible for enrollment into this cohort:
• Factor VIII or factor IX activity \<50%, without another explanation for low clotting factor other than congenital hemophilia or being a known carrier for congenital hemophilia; OR
• Carrier for congenital hemophilia with a factor VIII \>=50% or factor IX activity \>=50% with or without a bleeding phenotype as indicated by an ISTH Bleeding Assessment Tool score of ≥4 for adult males, ≥6 for adult females, or ≥3 for children younger than 18 years OR
• Known congenital hemophilia that have a factor level \>50% after receiving vector, OR 4. Acquired hemophilia.
Exclusion Criteria:
None
Von Willebrand Disease Cohort
Inclusion Criteria:
Participants who meet the following inclusion criteria are eligible for enrollment into this cohort:
1\. Meeting the definition of VWD or low VWF per most recent international guidelines
Exclusion Criteria:
None
Congenital Platelet Disorders Cohort
Inclusion Criteria:
Participants who meet the following inclusion criteria are eligible for enrollment into this cohort:
• Abnormalities of platelet function a. Glanzmann thrombasthenia (GPIIb or GPIIIa) b. Bernard-Soulier syndrome (GPIbalpha, GPIbbeta, or GPIX)
• Abnormalities of platelet granules
• Abnormalities of platelet signal transduction
• Abnormalities of platelet secretion
• Collagen Receptor Defect
• ADP Receptor Defect
• Thromboxane Receptor Defect
• Giant Platelet Disorder
• Abnormalities in platelet aggregation testing due to another or unknown cause (not drug related)
Exclusion Criteria:
1\. Platelet disorders secondary to medications or other substances
Rare Disorders Cohort
Inclusion Criteria:
Participants who meet the following inclusion criteria are eligible for enrollment into this cohort:
1\. Have an established Rare Coagulation Disorder (RCD) diagnosis of one of the following:
• PAI-1 deficiency
• Factor I, II, V, VII, X, XI, XIII deficiencies
• Combined FV and FVIII deficiency
• Plasminogen deficiency
• Decreased tissue plasminogen activator
• Afibrinogenemia/hypofibrinogenemia/dysfibrinogenemia
• Thrombotic Thrombocytopenia Purpura or Congenital Hemolytic Uremic Syndrome
• Wiskott-Aldrich
• Methylenetetrahydrofolate Reductase Deficiency
Exclusion Criteria:
None
Bleeding NOS Cohort
Inclusion Criteria:
Participants who meet the following inclusion criteria are eligible for enrollment into this cohort:
• Have a bleeding phenotype as indicated by an ISTH Bleeding Assessment Tool score of ≥4 for adult males, ≥6 for adult females, or ≥3 for children younger than 18 years with an unknown diagnosis, OR
• Connective tissue disorder with bleeding tendency as indicated by an ISTH Bleeding Assessment Tool score of ≥4 for adult males, ≥6 for adult females, or ≥3 for children younger than 18 years.
Exclusion Criteria:
None
Thrombosis/Thrombophilia Cohort
Inclusion Criteria
Participants who meet the following inclusion criteria are eligible for enrollment into this cohort:
1\. Have a prior history of arterial or venous thrombosis. 2. Participants with a known congenital or acquired thrombophilia with or without thrombosis.
a. Common congenital thrombophilias: i. Protein C deficiency ii. Protein S deficiency iii. Antithrombin deficiency iv. Factor V Leiden v. Prothrombin gene mutation b. Rare genetic factors i. Hyperhomocysteinemia c. Indeterminate genetic factors i. Elevated factor VIII ii. Elevated factor IX iii. Elevated factor XI iv. Elevated lipoprotein (a) d. Acquired thrombophilias i. Lupus anticoagulant ii. Anti-cardiolipin antibodies/Beta2 glycoprotein antibodies iii. Antiphospholipid syndrome
Exclusion Criteria Acquired thrombophilia secondary to medications (birth control pills or hormone replacement therapy), overweight or obesity, smoking, cancer, pregnancy, surgery, injury, prolonged inactivity/bedrest, heart failure, inflammatory bowel disease, or kidney disease
Non-Neoplastic Hematologic Conditions Cohort
Inclusion Criteria
Participants who meet the following inclusion criteria are eligible for enrollment into this cohort:
1\. Having any congenital or acquired non-neoplastic hematologic disorder not included in any other cohort
Exclusion Criteria None
Arm/Module Participant Selection
Previously Untreated Patients Arm
Inclusion Criteria:
• Diagnosis of congenital hemophilia A (FVIII \<40%) or hemophilia B (FIX \<40% or below lower limit for age)
• Age \<18 years at time of enrollment
• Parent or authorized guardian or legally authorized representative (LAR) can provide informed consent
• Care established at one of the ATHN Transcends participating HTCs
• Clotting Factor Concentrate (CFC) exposure, fresh frozen plasma (FFP), cryoprecipitate, and single donor platelets \<3 exposure days (ED) Exclusion Criteria
• Concomitant diagnosis with another bleeding disorder
• History of a confirmed, positive inhibitor INHIBIT Module
Inclusion Criteria:
1\. Diagnosis of severe factor VIII deficiency with baseline factor VIII level \<1% 2. Initiating or plan to initiate prophylaxis with emicizumab or factor replacement 3. Factor concentrate exposure, Fresh Frozen Plasma (FFP), cryoprecipitate, and single donor platelets ≤3 EDs 4. ≤5 years of age
Exclusion Criteria
• Concomitant diagnosis with bleeding disorder other than hemophilia A
• Immune disorder
• Previous history or presence of factor VIII inhibitor. A confirmed, positive inhibitor is defined as two consecutive positive inhibitor titers (≥ 0.6 BU) that result in changes in treatment recommendations. Efanesoctocog alfa (ALTUVIIIO®) Module Inclusion criteria:
• Ability of the potential participant's legally authorized representative (e.g., their parent or legal guardian) to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use confidential health information in accordance with national and local participant privacy regulation.
• People with severe HA with a baseline FVIII activity of less than 1%. (While inclusion for participation in ATHN Transcends lists \<5% FVIII activity, this proposed module will limit enrollment to people with FVIII activity levels of \<1%.) Other severities may be included per ATHN Transcends PI approval.
• \<18 years of age.
• No history of a confirmed, positive FVIII inhibitor.
• Sex assigned at birth of male, female, or intersex.
• Participants should have no more than three (3) exposure days of blood products (fresh frozen plasma, cryoprecipitate, or platelets), no more than three (3) doses of any FVIII concentrate other than efanesoctocog alfa, and up to three (3) doses of efanesoctocog alfa prior to enrollment.
• Site PI confirmed all inclusion criteria has been met. Exclusion criteria:
• Not meeting all the inclusion criteria; confirmed by site PI.
• Any exposure to blood products or FVIII replacement products except as described in the inclusion criteria.
• History of positive inhibitor testing.
• History of hypersensitivity reactions associated with efanesoctocog alfa administration.
• Other coagulation disorder(s) in addition to Hemophilia A.
• Any concurrent clinically significant major disease such as cancer that, in the opinion of the investigator, would make the participant unsuitable for enrollment.
• Concurrent systemic treatment with chemotherapy and/or other immunosuppressant medications. Use of corticosteroids for the treatment of asthma or management of acute allergic or otherwise life-threatening episodes is allowed except for systemic corticosteroid treatment given to children daily or on an alternate day schedule at \> 2 mg/kg/day of prednisone or its equivalent or \> 20 mg/day if the duration is longer than 14 days.
• Enrollment in a concurrent clinical interventional drug study.
• Intake of an Investigational Medicinal Product within three (3) months prior to inclusion in this study.
• Inability to comply with study requirements.
• Other, unspecified reasons that, in the investigator's opinion, make the participant unsuitable for enrollment. Hemophilia Natural History Arm Inclusion Criteria
• Congenital or acquired hemophilia A or B of any severity with or without inhibitors receiving a current therapy, a non-factor product, or for whom use of a non-factor product is a possibility, OR
• Females of any age, with confirmed congenital hemophilia A or B carrier status with genetic mutational analysis and any factor level. Exclusion Criteria
• Presence of any known bleeding disorder other than congenital hemophilia A or B
• Presence of concurrent hemophilia and a second hemostatic defect (low von Willebrand Factor (vWF) without vWD diagnosis is not excluded)
• Unable or unwilling to comply with the study arm protocol. Nonacog beta pegol (Rebinyn®) Module
Inclusion Criteria:
• Has provided signed written consent for the nonacog beta pegol (Rebinyn®)Module before any study-related activities.
• Male participants, at any age with hemophilia B, naïve or minimally exposed (up to 3 EDs) to nonacog beta pegol treatment at time of study enrollment. Additional doses may be allowable per ATHN Transcends PI approval.
• Decision to initiate continuous prophylaxis treatment with commercially available nonacog beta pegol has been made by the participant(s)/Legally Authorized Representative(s) (LAR(s)) and the treating physician before and independently from the decision to include the participant in this study.
Exclusion Criteria:
• Previous participation in this study. Participation is defined as having given informed consent in this study.
• Mental incapacity, unwillingness or language barriers precluding adequate understanding or cooperation, including a diagnosis or suspicion of attention deficit hyperactivity disorder (ADHD) or autism spectrum disorder (ASD) per the discretion of the Principal Investigator.
• Known or suspected hypersensitivity to nonacog beta pegol or related products.
• Clinical suspicion or presence of FIX inhibitor at time of inclusion.
• Inability or unwillingness to undergo neurological assessment/structured developmental history. Emicizumab (Hemlibra®) Module
Inclusion Criteria:
• Participant currently treated with emicizumab (Hemlibra®)
• Currently enrolled in the Hemophilia Natural History Arm of ATHN Transcends
Exclusion Criteria:
1\. Unable or unwilling to comply with the protocol
Distress Module
Inclusion Criteria:
• Congenital hemophilia A or B of any severity with or without inhibitors receiving a current therapy, a non-factor product, or for whom use of a non-factor product is a possibility
• Age 18 years of age or older
• English speaking
Exclusion Criteria:
• Presence of any known bleeding disorder other than congenital hemophilia A or B;
• Presence of concurrent hemophilia and a second hemostatic defect (low von Willebrand Factor (vWF) without vWD diagnosis is not excluded); and
• Unable or unwilling to comply with the study arm protocol Hemophilia Gene Therapy Outcomes Arm Inclusion Criteria
• Hemophilia A or B of any severity with or without inhibitors having received or will receive a hemophilia gene transfer product in the next 6 months.
• Age 18 years and older.
• Able to give informed consent. Exclusion Criteria None Etranacogene dezaparvovec (HEMGENIX®) Module
Inclusion Criteria:
Etranacogene dezaparvovec (HEMGENIX®) Cohort
• Age 18 years of age or older
• Treatment with commercial etranacogene dezaparvovec (HEMGENIX®)
• Have provided signed written informed consent within 3 months before or within 6 months after etranacogene dezaparvovec (HEMGENIX®) treatment, or within 6 months of when the study is initiated at the treating site. FIX Prophylaxis Cohort
• Age 18 years of age or older
• Treatment with FIX prophylaxis therapy
• Has provided signed written consent at any time for ATHN Transcends Study Exclusion Criteria, both cohorts: 1\. Have been treated with etranacogene dezaparvovec in a clinical trial prior to commercial availability. These patients are still eligible for enrollment in the Gene Therapy Outcomes Arm, and their data may be collected for separate analysis. Congenital Platelet Disorders Arm Inclusion Criteria
• Platelet adhesion defect
• Bernard Soulier syndrome (Defective GPIb-IX-V receptor, impaired adhesion to vWF)
• Velocardio-facial syndrome/DiGeorge syndrome (Defective GPIb-IX-V receptor)
• Platelet type vWD (Defective GPIb-IX-V, gain of function interaction between vWF-GP1bα)
• Platelet aggregation defect
• Glanzmann thrombasthenia (Defective integrin αIIbβ3 (GPIIb/IIIa)
• Platelet aggregation defect, NOS
• Agonist receptor defects
• Epinephrine
• ADP
• Collagen
• Thromboxane A2
• Platelet signaling defects
• Cyclooxygenase deficiency (PTGS1 mutation)
• Phospholipase A2 deficiency
• Thromboxane synthase deficiency (TBXAS1 mutation)
• G protein activation defect (GNAS mutation)
• Scott syndrome (defect in phosphatidyl serine translocation)
• Platelet Granule disorders
• Dense granule storage pool disorder * Hermansky Pudlak syndrome * Chediak Higashi syndrome * Griscelli syndrome
• Alpha granule storage pool disorder * Grey platelet syndrome * Arthrogryposis-Renal Dysfunction-Cholestasis (ARC) syndrome * Quebec platelet disorder * Paris-Trousseau syndrome
• Combined alpha delta granule deficiency
• Platelet cytoskeletal structure defects
• Wiskott Aldrich syndrome
• MYH9 associated disorders (myosin heavy chain) * May Hegglin syndrome * Fechtner syndrome * Sebastian syndrome * Epstein syndrome
• Other mutations * FLNA mutations (Filamin) * DIAPH1 (Actin and microtubules) * ACTN1 (alpha actinin) * TPM4 (tropomyosin) * TUBB1 (beta tubulin)
• Other Congenital thrombocytopenias
• Familial platelet disorders and predisposition to AML (RUNX1)
• X linked thrombocytopenia with dyserythropoiesis (GATA1)
• Congenital amegakaryocytic thrombocytopenia (MPL) Exclusion Criteria
• Diagnosis of von Willebrand Disease (Meeting the definition of vWD or low vWF per most recent international guidelines)
• Diagnosis of Hemophilia A or Hemophilia B (Factor VIII or IX ≤ 40%) Glanzmann Thrombasthenia (GT) Module Inclusion Criteria
• Participant has signed the informed consent/assent form
• Participant has flow cytometry or aggregometry or genetics confirmed GT
• Participant is willing to perform study procedures, including daily bleed tracking for 3 months and further if requested
• Participants are 2 years or older at time of consent Exclusion Criteria None
Hematologic Disorder, Bleeding Disorder, Connective Tissue Disorder, Hemophilia, Thrombosis, Von Willebrand Diseases, Thrombophilia, Rare Bleeding Disorder, Platelet Disorder, Factor IX Deficiency, Factor VIII Deficiency, Thalassemia, Sickle Cell Disease
Study of Lurbinectedin Monotherapy in Pediatric and Young Adult Participants With Relapsed/Refractory Ewing Sarcoma
cancer@cchmc.org
ALL
2 years to 30 years old
PHASE1
NCT05734066
Key
Inclusion Criteria:
Age
* Participant must meet the following age requirements at the time the informed consent form (ICF) (and assent form, if applicable) is signed:
* Phase 1 Part 1: participants must be ≥ 2 to \< 18 years of age.
* Phase 1 Part 2: participants must be ≥ 2 to ≤ 30 years of age.
* Phase 2: participants must be ≥ 2 to ≤ 30 years of age.
Type of Participant and Disease Characteristics
* Participant has a confirmed solid tumor
* The participant has a Lansky/Karnofsky performance status score of ≥ 50%.
* The participant has adequate liver function, evidenced by the following laboratory values:
* Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN).
* Total bilirubin ≤ 1.5 × institutional ULN (with the exception of participants with Gilbert's syndrome who must have bilirubin \< 3 × institutional ULN).
* The participant has adequate bone marrow function, evidenced by the following:
* Absolute neutrophil count (ANC) ≥ 1.0 × 10\^9/L (independent of growth factor support within 1 week of screening laboratories).
* Platelets ≥ 100 × 10\^9/L (without platelet transfusion within previous 7 days of screening laboratories).
* Hemoglobin ≥ 8 g/dL (note: may have been transfused).
* The participant has an adequate renal function:
* Calculated creatinine clearance (use Cockcroft-Gault formula for participants ≥ 18 years; Schwartz equation for participants \< 18 years) ≥ 60 mL/min.
* The participant has an adequate cardiac function:
* Left ventricular ejection fraction or shortening fraction per institutional norm ≥ institutional lower level of normal.
* The participant has creatine phosphokinase ≤ 2.5 × institutional ULN.
Weight
* The participant has body weight ≥ 15 kg.
Sex and Contraceptive/Barrier Requirements
Male participants:
Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 4 months after the last dose of study intervention:
* Refrain from donating sperm.
PLUS, either:
* Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent.
OR
* Must agree to use contraception/barrier as detailed below:
* Agree to use a male condom with female partner and use of an additional highly effective contraceptive method with a failure rate of \< 1% per year when having sexual intercourse with a Woman of childbearing potential (WOCBP) who is not currently pregnant.
* Note: male participants who are azoospermic (vasectomized or due to a medical cause) are still required to follow the protocol-specified contraception/barrier criteria.
Female participants:
A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:
* Is a Woman of nonchildbearing potential (WONCBP). OR
* Is a WOCBP and using an acceptable contraceptive method during the study intervention period (at least 7 months after the last dose of study intervention). The investigator should evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of study intervention.
* A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 7 days before the first dose of study intervention.
* If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
* Additional requirements for pregnancy testing during and after study intervention.
* The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
Informed Consent
* Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Key Exclusion Criteria:
Medical Conditions
* corrected QT interval (QTc) prolongation defined as a QTc ≥ 460 ms using the Bazett formula in age \< 18 years and QTc ≥ 470 ms using the Bazett formula in age ≥ 18 years.
* Known symptomatic Central nervous system (CNS) metastases requiring steroids. Participants with previously diagnosed CNS metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to enrollment, have discontinued high dose steroid treatment for these metastases for at least 2 weeks, and are neurologically stable (physiologic doses of steroids and short courses of steroids for other indications are acceptable).
* Persisting toxicity related to prior therapy; however, alopecia, sensory neuropathy, hypothyroidism, and rash Grade ≤ 2 are acceptable, and other Grade ≤ 2 adverse events (AEs) not constituting a safety risk based on the investigator's judgement are acceptable.
* An uncontrolled intercurrent illness including but not limited to ongoing or active infection requiring antibiotic, antifungal, or antiviral therapy, symptomatic heart failure, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Any other major illness that, in the investigator's judgment, could substantially increase the risk associated with participation in this study.
* Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the participant at high-risk for treatment complications.
Prior/Concomitant Therapy
* Received prior treatment with lurbinectedin or trabectedin.
* Received prior treatment with any investigational product within 4 weeks of first infusion of study intervention. Observational studies are permitted.
* Received live or live attenuated vaccines within 4 weeks of the first dose of study treatment or plans to receive live vaccines during study participation. Administration of inactive vaccines or messenger ribonucleic acid (mRNA) vaccines (for example, inactivated influenza vaccines or COVID-19 vaccines) are allowed.
* Had major surgery ≤ 4 weeks or radiation therapy ≤ 2 weeks prior to enrollment unless fully recovered. Prior palliative radiotherapy is permitted, provided it was completed at least 2 weeks prior to participant enrollment.
* Received prior allogeneic bone marrow transplantation or solid organ transplant.
* Received chemotherapy ≤ 3 weeks prior to start of study intervention.
Diagnostic Assessments
* Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or Polymerase chain reaction (PCR) test for HCV RNA if HCV antibody test is positive).
* Human immunodeficiency infection at screening (positive anti-HIV antibody).
Other Exclusions
* Has a known or suspected hypersensitivity to any of the components of the study intervention.
* The participant or parent(s)/guardian(s) is/are unable to comply with the study visit schedule and other protocol requirements, in the opinion of the investigator DRUG: Lurbinectedin
Refractory Ewing Sarcoma, Relapsed Ewing Sarcoma, Ewing Sarcoma
Solid Tumors, lurbinectedin, ewing's sarcoma, soft tissue sarcoma, sarcomas
Collection of Research Data and Samples From Patients Treated With Immunotherapy to Study Its Side Effects
- cancer@cchmc.org
ALL
NCT04242095
* PRE-REGISTRATION ELIGIBILITY CRITERIA: Planning to receive a regimen containing one or more IO therapeutics
* PRE-REGISTRATION ELIGIBILITY CRITERIA: Has not previously been treated with CTLA-4, PD-1 or PD-L1 inhibitors
* PRE-REGISTRATION ELIGIBILITY CRITERIA: Willing and able to provide baseline blood and stool samples
* REGISTRATION ELIGIBILITY CRITERIA: Received a regimen containing one or more immuno-oncology therapeutics
* Must have received one or more IO therapeutics
* In addition to one or more IO therapeutics, patients may also have received other therapeutics such as chemotherapy, hormonal or targeted therapy, as long as these are reported
* REGISTRATION ELIGIBILITY CRITERIA: Must have experienced one or more of the following:
* One or more serious (grade 3-54) AEs that are likely immune-related. AEs included in Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 5.0 that may be immune-related
\*\* Patients who experience only hematologic cytopenia(s) who have received cytotoxic therapies, e.g., chemotherapy, within 60 days prior to registration should be excluded
* One or more grade 2 dermatologic, endocrine (except diabetes/hyperglycemia) or rheumatologic AEs that are likely immune-related. AEs included in CTCAE v. 5.0 that may be immune-related
* Diagnosis of a rare infection, e.g., fungal or mycobacterial, after starting IO treatment
\*\* Note: Diagnosis of SARS-CoV-2 (COVID-19) is excluded
* Hyperprogression. Image submission for patients experiencing hyperprogression is required. For assistance in determining hyperprogression for purposes of eligibility, institutions may contact the study chair and submit images for central review
* REGISTRATION ELIGIBILITY CRITERIA: Has not previously been registered to this study \* The same patient cannot be enrolled more than once to this study due to development of subsequent irAEs
PROCEDURE: Biospecimen Collection, OTHER: Medical Chart Review
Hematopoietic and Lymphoid Cell Neoplasm, Immune System Disorder, Malignant Solid Neoplasm
Cytokine-Induced Memory-Like Natural Killer Cells (CIML-NK) for Relapsed & Refractory Acute Myeloid Leukemia (AML)
Caitlin Cottrell - caitlin.cottrell@cchmc.org
ALL
2 years and over
PHASE1
NCT05580601
Inclusion Criteria:
* Of age ≥ 2 years of age at the time of study enrollment
* With AML diagnosed per 2016 WHO criteria (11)
* With relapsed or refractory AML in their bone marrow
* Refractory disease: Patients must have ≥ 5% blasts in the bone marrow after 2 courses of intensive induction treatment
* Relapsed disease: Patients must have ≥ 5% blasts in the bone marrow, or reappearance of blasts in the blood, within 6 months of initial CR
* With available haploidentical related donors. Donor specific antibody (DSA) testing will be done on the recipient prior to or upon enrollment.
* With performance level of ≥ 50% on Karnofsky scale for patients \> 16 years of age and ≥ 50% on Lansky scale for patients ≤ 16 years of age
Exclusion Criteria:
* Disease: isolated central nervous system (CNS) disease, or isolated extramedullary disease, or diagnosis of acute promyelocytic leukemia (APML). Patients with extramedullary disease in combination with bone marrow disease are eligible for enrollment.
* Infectious Disease: Active uncontrolled infection
* Cardiac function: Systolic ejection fraction \<45% by echocardiogram
* Pulmonary Function: Oxygen saturation \<92% on room air
* Hepatic function: Total bilirubin \> 2mg/dL, AST and ALT more than three times the upper limit of normal
* Concomitant medications: receiving either \>10mg prednisone equivalent daily, or \>0.5mg/kg prednisone equivalent daily, whichever is less
* Concomitant investigational treatments: receiving other investigational therapies
* Known allergy or hypersensitivity reaction to IL-2 injections
* Pregnant or breastfeeding women will not be entered on this study due to risks of fetal and teratogenic adverse events with lymphodepleting chemotherapy. Pregnancy tests must be obtained for female patients. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method while on study treatment and for six months following completion. Effective contraceptive methods include oral contraceptive pills, patches, or injections, intrauterine devices, having a tubal ligation, having a partner who has had a vasectomy, or not having sex. DRUG: CIML-NK Cells
Acute Myeloid Leukemia
Autism Doula Program Evaluation
Teresa Smith, PhD - teresa.smith@cchmc.org
ALL
18 months to 71 months old
NA
NCT06896942
Inclusion Criteria:
caregivers of children who are 18 months to five years and recently diagnosed with autism. Caregivers must identify as Black and be over the age of 18 and identify their children as Black. OTHER: Autism Doula, OTHER: DDBP Family Navigation
Health Equity, Autism Spectrum Disorder
health equity, autism spectrum disorder, family navigation
Ziftomenib in Combination With Chemotherapy for Children With Relapsed/Refractory Acute Leukemia
- cancer@cchmc.org
ALL
0 years to 21 years old
PHASE1
NCT06376162
Inclusion Criteria:
* Age: 0-21 years (and at least 5 kg body weight), with a minimum of 80% of participants under 18 years of age.
* Diagnosis: KMT2A-r, NPM1-m, or NUP98-r acute leukemia in first or greater relapse or refractory to standard (re-) induction treatment (including HSCT). Please note that genetic alteration must be confirmed by the central laboratory, or the participant will discontinue protocol therapy.
* Eligible participants also must fulfill one of the following conditions:
• First or subsequent relapse:
• Bone marrow relapse is defined as: a single bone marrow sample or bone biopsy showing ≥ 5% leukemic blasts by local morphology.
• Participants with combined extramedullary and bone marrow relapse (defined as above), including central nervous system (CNS) disease, are eligible.
• Participants with asymptomatic CNS3 disease are eligible if they do not have isolated CNS3 extramedullary relapse.
• Refractory disease/induction failure:
• Acute myeloid leukemia (AML): The bone marrow contains ≥ 5% leukemic blasts by local morphology at the end of 2 cycles of induction therapy.
• Acute lymphoblastic leukemia (ALL)/mixed-phenotype acute leukemia (MPAL)/acute undifferentiated leukemia (AUL): The bone marrow contains ≥ 5% leukemic blasts by local morphology multiparameter flow cytometry at the end of induction and consolidation. * Performance status: Participants must have a performance status corresponding to Lansky or Karnofsky scores of ≥60. Use Karnofsky score for patients ≥16 years of age and Lansky score for patients \<16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. * Adequate organ function:
• Renal function defined as: Creatinine clearance (CrCl) ≥60 mL/min (as measured by a nuclear glomerular filtration rate \[GFR\] scan or calculated by the Schwartz formula and normalized to a body surface area of 1.73 m\^2).
• Liver function defined as:
• Direct bilirubin \< 1.5x ULN unless increase is due to Gilbert's disease or leukemic involvement and ASAT or ALAT ≤ 3 x ULN unless considered due to leukemic involvement, in which case direct bilirubin \< 3x ULN or ASAT and/or ALAT \< 5x ULN will be considered eligible.
• If liver abnormality is due to radiographically identifiable leukemia infiltrate, the participant will remain eligible.
• Cardiac function defined as: Pre-treatment left ventricular function on echocardiography: Fractional shortening (FS) ≥ 25% or ejection fraction (EF) ≥ 40%, and no signs of congestive heart failure within 4 weeks before start of screening. * Prior therapy: Participants must have recovered from the acute toxic effects of all prior anti-cancer therapy (excluding Grade 2 toxicities that are not considered a safety risk or medically significant toxicity deemed irreversible by the Investigator and confirmed by Sponsor's medical monitor) and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment.
• Cytotoxic chemotherapy: Must not have received within 14 days or within 5 drug half-lives (whichever is longer), of entry onto this trial, except for hydroxyurea or corticosteroids. Use of steroids and hydroxyurea for other purposes such as differentiation syndrome, or to premedication to prevent allergic reaction or during anesthesia is allowed.
• Intrathecal cytotoxic therapy: No washout or waiting period is required for participants having received any combination of intrathecal cytarabine, methotrexate, and/or hydrocortisone.
• Antibodies: ≥ 21 days must have elapsed from infusion of last dose of an antibody-drug conjugate. For unmodified antibodies or T cell engaging antibodies, 2 half-lives must have elapsed before enrollment. Any toxicity related to prior antibody therapy must be recovered back to baseline.
• Interleukins, interferons and cytokines (other than hematopoietic growth factors): ≥ 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors).
• Hematopoietic growth factors: ≥ 14 days after the last dose of a long-acting growth factor (e.g., peg-filgrastim) or 7 days for short-acting growth factor.
• Radiation therapy (RT): 14 days have elapsed for local palliative RT (small port); ≥ 84 days must have elapsed if prior craniospinal RT or if ≥ 50% radiation of pelvis; ≥ 42 days must have elapsed if other substantial bone marrow (BM) radiation.
• Stem cell infusions:
• Participants who have relapsed after allogeneic (non-autologous) BM or stem cell transplant (with or without total body irradiation \[TBI\]) or boost infusion (any stem cell product; not including donor lymphocyte infusion \[DLI\]) must be at least 84 days post HSCT and without evidence of graft versus host disease (GVHD) of any severity except: the use of topical steroids for cutaneous GVHD is allowed and stable steroid doses less than or equal to 10 mg of prednisone daily is permitted. Prednisone dose must be adjusted for body surface area (BSA) in young children. Physiologic doses of hydrocortisone for participants with adrenal insufficiency is allowed.
• Participants who after relapse and continue to receive cyclosporine, tacrolimus or other agents to treat or prevent either GVHD post BM transplant or organ rejection post-transplant are not eligible for this trial. In the relapse setting, participants must be off medications to treat or prevent either GVHD post BM transplant or organ rejection post-transplant for at least 14 days prior to enrollment. A stable steroid dose as mentioned above is allowed.
• Cellular therapy: ≥ 30 days after the completion of DLI or any type of cellular Therapy (e.g., modified T cells, NK cells, dendritic cells, etc.).
• Prior exposure to a different menin inhibitor: Participants who received previous treatment with a different menin inhibitor are allowed to enrol in the trial with the exception of those who experienced a severe adverse event attributable to the strong anti-proliferative/pro-differentiation effects of other menin inhibitors (such as severe differentiation syndrome). Participants who experienced a severe adverse event, which can directly be attributed to specific effects (e.g., long QT syndrome) observed with other menin inhibitors can participate in the trial if they fulfill the inclusion criteria. A washout period of 5x the drug half-life is required for prior menin inhibitors before enrollment. * Informed consent: Written, signed and dated informed consent and pediatric assent (if applicable) according to local law and legislation should be collected before start of any trial procedures. * Female participants of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment. * Female participants with infants must agree not to breastfeed their infants while on this trial. * Contraception:
• Participants of reproductive potential, starting from menarche and onwards, may not participate unless they have agreed to use a highly effective contraceptive method per Clinical Trial Facilitation Group (CTFG) guidelines for the duration of trial therapy and for 6 months after the completion of all trial therapy. For further guidance please review the CTFG website.
• Male participants must use a condom during intercourse and agree not to father a child or donate sperm during therapy and for the duration of trial therapy and for 4 months after the completion of all trial therapy. * Enrollment APAL2020SC trial (US and Canada only): Participants in the US and Canada must have enrolled in the APAL2020SC trial prior to enrollment in the APAL2020K trial.
Exclusion Criteria:
* Participants who in the opinion of the investigator may not be able to comply with the trial requirements of the trial.
* Participants with Down syndrome.
* Participants with EMD are not eligible. EMD relapse is defined as biopsy proven extramedullary disease without bone marrow disease after documented CR following initial therapy.
* Participants with isolated CNS relapse are not eligible, as well as symptomatic CNS3 disease.
* Participants with acute promyelocytic leukemia (APL) or juvenile myelomonocytic leukemia (JMML).
* Participants with malabsorption syndrome or any other condition that precludes enteral administration of a menin inhibitor.
* Concomitant therapy: Gastric pH has great influence on absorption of ziftomenib; therefore, the use of proton pump inhibitors is prohibited, if necessary H2 Blockers may provide an alternative treatment option.
* Participants who are currently receiving another investigational drug.
* Participants with any known congenital bone marrow failure syndrome.
* Participants with known prior allergy to any of the medications used in protocol therapy.
* Participants with documented active, uncontrolled infection at the time of trial entry.
* Active/uncontrolled known human immunodeficiency virus (HIV) infection, hepatitis B virus (HBV) and hepatitis C virus (HCV). Note: HIV testing does not need to be conducted at screening unless it is required per local guidelines or institutional standard.
* Post menarche female participants with positive pregnancy test, and a lactating female participant.
* Participant has a pre-existing disorder predisposing the participant to a serious or life-threatening infection (e.g., cystic fibrosis, congenital or acquired immunodeficiency, bleeding disorder, or cytopenia not related to the leukemia or its treatment).
* Participants must not be receiving other investigational medications (defined as medicinal products not yet approved for any indications, including alternative/herbal therapies) within 30 days of first dose of trial drug or while on trial.
* Significant congenital cardiovascular disease including, but not limited to conditions such as long QT syndrome, fundamental uncorrected cardiac defect (e.g., coarctation of the aorta) that poses a significant risk to the participant (ventricular septal defect or atrial septal defect are considered non-significant).
* Underlying medical condition that, in the Principal Investigator's opinion, will make the administration of trial treatment hazardous or obscure the interpretation of toxicity determination or AEs.
* For fludarabine and cytarabine: Hypersensitivity to the active substance or to any of the excipients.
* Recent live vaccinations for at least 6 months. DRUG: Ziftomenib, DRUG: Cytarabine, DRUG: Fludarabine
Relapsed/Refractory KMT2A-r Acute Leukemia, Relapsed/Refractory NUP98-r Acute Leukemia, Relapsed/Refractory NPM1-m Acute Leukemia
Ziftomenib, Acute leukemia, KMT2A-r, NUP98-r, NPM1-m
Advancing Transplantation Outcomes in Children (ADVANTage)
Nina Kanis - Nina.Kanis@cchmc.org
ALL
13 years to 20 years old
PHASE2
NCT06055608
Inclusion Criteria:
• Participant and/or parent/guardian must be able to understand and provide informed consent
• Male or female, 13-20 years of age at time of enrollment
• Candidate for primary renal allograft from a living or deceased donor
• EBV IgG seropositive, defined as evidence of acquired immunity shown by the presence of IgG antibodies to viral capsid antigen (VCA) and EBV nuclear antigen (EBNA)
• EBV VCA IgM seronegative OR EBV VCA IgM seropositive on two occasions at least 3 months apart and an undetectable EBV PCR result within 1 month prior to enrollment
• If a female participant of childbearing potential, a negative pregnancy test prior to conducting any study procedures
• If participant has reproductive potential, agrees to use Food and Drug Administration (FDA) approved methods of birth control for the duration of the study
• Negative test result for latent tuberculosis infection by tuberculosis skin test (purified protein derivative \[PPD\]) or Tuberculosis (TB) blood test (interferon gamma release assay \[IGRA\] i.e., QuantiFERON, T- SPOT.TB) within 12 months
• In the absence of contraindication, vaccinations must be up to date per the Centers for Disease Control and Prevention (CDC) Guidelines and Division of Allergy, Immunology, and Transplantation (DAIT) Guidance for Patients in Transplant Trials Enrollment criteria for donor source and age will be expanded using a stepwise approach determined by safety monitoring. Expansion criteria will include recipients down to age 6 and living donors. Safety data from each step will be reviewed by the study team, DSMB and FDA. If no safety concerns are identified, inclusion criteria will be expanded.
Exclusion Criteria:
• Inability or unwillingness to comply with study protocol
• Active infection requiring treatment, or viremia
• History of malignancy
• Receipt of any licensed or investigational live attenuated vaccine(s) within 4 weeks of enrollment
• Prior history of organ transplantation
• Listed for multi-organ transplant (e.g. heart- kidney, liver-kidney, multivisceral- kidney, lung- kidney)
• Active systemic autoimmune disease at time of enrollment
• Idiopathic Focal Segmental Glomerulosclerosis (FSGS), Membranoproliferative Glomerulonephritis (MPGN), C3 glomerulopathy, or atypical Hemolytic Uremic Syndrome (HUS) suspected at risk for recurrence
• Use of immunosuppressants, biologics (including IVIG), chronic corticosteroids or investigational drug(s) within 8 weeks of enrollment
• Known bleeding disorder
• Sustained platelet count \< 75,000 cells/microliters within 3 months of enrollment
• History of inherited hypercoagulability requiring therapy more than aspirin
• Panel Reactive Antibody (cPRA) greater than 80 percent
• Clinically significant unrepaired congenital heart disease causing hemodynamic compromise
• Uncontrolled diagnosed psychiatric disorder or self-reported drug or alcohol abuse that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements
• Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study Randomization
Inclusion Criteria:
Individuals who meet all of the following criteria are eligible for randomization.
1\. If EBV serology to meet enrollment criteria was performed within 8 weeks of receiving IVIG, EBV VCA IgG and EBV EBNA IgG seropositivity, confirmed between enrollment and time of transplant
Randomization Exclusion Criteria:
Individuals who meet any of these criteria are not eligible for randomization.
• Sustained WBC \<1500 or \>20,000 per microliter within 3 months of randomization
• Sustained liver function tests (AST and/or ALT) \> 2x normal within 3 months of randomization
• Active systemic autoimmune disease at time of transplant
• Known bleeding disorder
• Sustained platelet count \< 75,000 cells/microliters within 3 months of enrollment
• Current (within 45 days) or historical anti-HLA antibody to the donor prior to randomization
• Recent recipient of any licensed or investigational live attenuated vaccine(s) within 4 weeks of randomization
• Panel Reactive Antibody (cPRA) greater than 80 percent at any point in time
• If a female participant of childbearing potential, a positive pregnancy test within 48 hours of randomization (all female participants of childbearing potential must complete a pregnancy test within 48 hours of randomization)
• Treatment with immunosuppressants within 8 weeks of randomization, except in the case of planned transplant standard of care
• Treatment with biologics (including IVIG) within 8 weeks of randomization
DRUG: Sirolimus, BIOLOGICAL: Belatacept, DRUG: Mycophenolate Mofetil, DRUG: Tacrolimus (Group1), DRUG: Anti-Thymocyte Globulin (ATG), DRUG: Tacrolimus (Group 2)
Kidney Transplant
kidney transplant, belatacept, sirolimus
Quality of Life in Pediatric Participants With HHT
Katie Wusik, Master of Genetic Counseling - katie.wusik@cchmc.org
ALL
2 years to 25 years old
NCT07474428
Inclusion Criteria:
* • Patient aged 2-25 years with a confirmed (either genetic or clinical) diagnosis of definite HHT
* Parent or legal guardian willing and able to complete the caregiver survey for patients aged 2-17.
* For patients \>18, willing and able to complete the patient survey.
* Receipt of care through CCHMC (at least one visit with genetic counselor or director of HHT Center)
* Ability to complete survey in English
* For self-report: patient age greater than or equal to 8 years old that assent to survey.
Exclusion Criteria:
* Patients that are older than 25 years old.
* Patients that are younger than 2 years old.
* Individuals without definite HHT diagnosis. Hereditary Haemorrhagic Telangiectasia (HHT)
HHT, QOL, Pedatric
Observational Study of Pediatric Rheumatic Diseases: The CARRA Registry
Megan Quinlan-Waters - megan.quinlan-waters@cchmc.org
ALL
Up to 21 years old
NCT02418442
Inclusion Criteria:
• Onset of rheumatic disease prior to age 16 years for JIA and onset prior to age 19 years for all other rheumatic diseases (see appendix A).
• Subject (and/or parent/legal guardian when required) is able to provide written informed consent and willing to comply with study procedures.
• Subject and/or parent/legal guardian is willing to be contacted in the future by study staff.
Exclusion Criteria:
1\. Greater than 21 years of age at the time of enrollment. Rheumatic Joint Disease
Systemic Arthritis, Oligoarthritis, Polyarthritis (Rheumatoid Factor Negative), Polyarthritis (Rheumatoid Factor Positive), Psoriatic Arthritis, Enthesitis Related Arthritis (ERA), Undifferianted Arthritis, CARRA Consensus Treatment Plans
A Study to Learn More About How Safe the Study Treatment Finerenone is in Long-term Use When Taken With an ACE Inhibitor or Angiotensin Receptor Blocker Over 18 Months of Use in Children and Young Adults From 1 to 18 Years of Age With Chronic Kidney Disease and Proteinuria (FIONA OLE)
Kelli Krallman - Kelli.Krallman@cchmc.org
ALL
1 year to 18 years old
PHASE3
NCT05457283
Inclusion Criteria:
* Participants must be ≥1 year to 18 years of age, at the time of signing the informed consent/assent.
* Prior participation in the finerenone Phase 3 study FIONA (19920) and not permanently discontinued from treatment by the end of treatment (EoT) visit in FIONA.
* Participants must have a clinical diagnosis of chronic kidney disease (CKD) at Visit 1 which is defined as
* CKD stages 1-3 (estimated glomerular filtration rate \[eGFR\] ≥30 mL/min/1.73m\^2) for children ≥1 year to \<19 years of age at FIONA EoT and at Visit 1
* Treated with an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) at optimized doses defined as maximally tolerable doses within the recommended dose range according to guidelines on blood pressure (BP) management, unchanged for at least 30 days prior to Visit 1.
* K+ ≤5.0 mmol/L for children ≥2 years of age at both FIONA EoT and Visit 1, and ≤5.3 mmol/L for children \<2 years of age at both FIONA EoT and Visit 1
* Participants who have reached legal age of consent: Capable of giving signed informed consent.
* Participant is able to receive enteral feeding (solid food, bottle or cup fed, feeding through nasogastric or gastric feeding tubes) with or without breastfeeding.
Exclusion Criteria:
* Planned urological surgery expected to influence renal function
* Patients who are candidates for renal transplantation, i.e., a kidney transplantation scheduled within the study time frame
* Systemic hypertension Stage 2 defined according to institutional guidelines on BP management at Visit 1.
* Systemic hypotension defined as symptomatic hypotension or a mean systolic BP below the 5th percentile for age, sex and height but no lower than 80 mmHg for participants \<18 years and symptomatic hypotension or a mean systolic blood pressure (SBP) \<90 mmHg in participants ≥18 years at Visit 1.
* Known hypersensitivity to the study treatment (active substance or excipients)
* Severe hepatic insufficiency defined by e.g. Child-Pugh C or analogous scores.
* Participants using rituximab, cyclophosphamide, abatacept, or intravenous glucocorticoids
* Concomitant therapy with a mineralocorticoid receptor antagonist (MRA)(eplerenone, spironolactone, esaxerenone, canrenone), any renin inhibitor (aliskiren, enalkiren, remikiren), any sodium-glucose co-transporter-2 (SGLT2) inhibitor (SGLT2i), sacubitril/valsartan combination (ARNI), or potassium-sparing diuretic (amiloride, triamterene)
* Concomitant therapy with both ACEI and ARBs together
* Concomitant therapy with strong cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitors, moderate or strong CYP3A4 inducers
* Previous assignment to treatment during this study
* Simultaneous participation in another interventional clinical study (e.g., Phase 1 to 4 clinical studies).
* Any suspected (serious) adverse event related to study intervention which led to permanent discontinuation during the FIONA study.
* Pregnant or breastfeeding or intention to become pregnant during the study DRUG: Finerenone (Kerendia, BAY94-8862)
Chronic Kidney Disease, Proteinuria, Children
Multisite Inventory of Neonatal-Perinatal Interventions (MINI) Minimum Dataset
Faris Algharaibeh - faris.algharaibeh@cchmc.org
ALL
0 years to 1 year old
NCT05685745
Inclusion Criteria:
* All local births with gestational ages of 22 weeks 0 days - 23 weeks 6 days, regardless of pregnancy outcome or neonatal intensive care (NICU) admission; AND
* All outborn NICU admissions with gestational age at birth of 22 weeks 0 days - 23 weeks 6 days
* Optional: Centers who desire to include data for NICU admissions of infants born \<22 weeks' gestation may also submit these data. Infant, Extremely Premature, Obstetric Labor, Premature, Premature Birth, Intensive Care, Neonatal, Intensive Care Units, Neonatal
FST Analysis Supporting Timely Therapy and Risk Assessment Via Clinical Decision Support for Kids (FAST TRACK)
Natalja L Stanski, MD, MS - natalja.stanski@cchmc.org
ALL
NCT07718464
Inclusion Criteria:
* Admitted to the pediatric intensive care unit (PICU)
* Renal Angina Index (RAI) greater than or equal to 8 (RAI+)
* Urine NGAL greater than or equal to 150 ng/mL (NGAL+)
Exclusion Criteria:
* Receipt of renal replacement therapy prior to PICU admission OTHER: Furosemide Stress Test Clinical Decision Support Tool
Acute Kidney Injury, Renal Replacement Therapy, Pediatric Intensive Care Unit
NGAL, Renal Angina Index, Furosemide Stress Test
Treatment of Obstructive Sleep Apnea With Personalized Surgery in Children With Down Syndrome (TOPS-DS) (TOPS-DS)
Angie Duggins - angie.duggins@cchmc.org
ALL
2 years to 17 years old
NA
NCT05508971
Requirements to participate in study:
Child has a diagnosis of Down syndrome (Trisomy 21). Child has a diagnosis of moderate to severe OSA diagnosed by PSG (oAHI ≥ 5). Child age is 2.00 to 17.99 years of age. Caregiver can provide signed and dated consent and is 18 years of age or older at the time of consent.
Caregiver can speak, read, and write in English or Spanish. Caregiver is primary caretaker of the child. Child is not expecting their own child. Child is eligible for surgical treatment
Cannot participate in study if:
Child has history of previous tonsillectomy, tonsillotomy, or partial tonsillectomy.
Child has any contraindication to surgery (e.g. bleeding disorders). Child has significant cardiopulmonary comorbidity besides OSA requiring supplemental oxygen, subglottic or tracheal stenosis, tracheostomy dependence.
Caregiver is unwilling or unable to comply with study procedures. Child is or plans to have their own child.
PROCEDURE: DISE-Directed Surgery, PROCEDURE: Adenotonsillectomy
Obstructive Sleep Apnea, Down Syndrome
RChildUV:Study on Non-infectious Chronic Uveitis in Pediatric Age
Megan Megan Quinlan-Waters - Megan.Quinlan-Waters@cchmc.org
ALL
1 year to 16 years old
NCT06273748
Inclusion Criteria:
* diagnosis of non-infectious chronic uveitis before the age of 16;
* signed informed consent form.
Exclusion Criteria:
* Patients with a diagnosis of infectious uveitis
* history of malignant pathology,
* history of demyelinating pathology,
* history of cerebral vasculitis Uveitis
A Study of Enlicitide Decanoate (MK-0616, an Oral PCSK9 Inhibitor) in Children and Adolescents With Heterozygous Familial Hypercholesterolemia (MK-0616-029)
Cierra Farrell - cierra.farrell@cchmc.org
ALL
6 years to 17 years old
PHASE2
NCT07058077
Inclusion Criteria:
Inclusion criteria include, but are not limited to:
* Has possible or definite diagnosis of HeFH based on a locally accepted diagnostic algorithm or diagnosis by genetic testing results
* Has a fasted LDL-C value (evaluated by the central laboratory) that is ≥130 mg/dL
* Is receiving either:
* An optimized daily dose of statin (± nonstatin LLT)
* A nonstatin LLT with documented intolerance to at least 2 different statins, or documented intolerance to 1 statin plus refusal of statin therapy by the participant or legally acceptable representative
* Is on a stable dose of all background LLTs for at least 30 days prior to screening, with no medication or dose changes planned during participation in Part A or Part B
Exclusion Criteria:
Exclusion criteria include, but are not limited to:
* Has a history of homozygous FH based on genetic or clinical criteria, or history of known compound heterozygous FH, or double heterozygous FH
* Has a history of nephrotic syndrome
* Has any clinically significant malabsorption condition based on investigator assessment
* Was previously treated/is being treated with certain other cholesterol lowering medications, including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors without adequate washout DRUG: Enlicitide Decanoate, DRUG: Placebo
Heterozygous Familial Hypercholesterolemia (HeFH)
A Study With Eptinezumab in Adolescents (12-17 Years) With Chronic Migraine (PROSPECT-2)
Michelle Michelle Shin - Michelle.Shin@cchmc.org
ALL
12 years to 17 years old
PHASE3
NCT04965675
Inclusion Criteria:
* The participant has a diagnosis of migraine (with or without aura) as defined by International Classification of Headache Disorders 3 (ICHD-3) guidelines with history of chronic migraine, of at least 6 months prior to the screening visit.
* During the 28-day screening period, the participant must adequately complete the headache eDiary on at least 23 of the 28 days following the screening visit.
* During the 28-day screening period, the participant must have ≥15 to ≤26 headache days, of which at least 8 are migraine days as documented in the eDiary.
Exclusion Criteria:
* The participant has previously been randomised in this study and exposed to eptinezumab.
* The participant has been exposed to any monoclonal antibody treatment (including exposure in a study) \<6 months prior to the screening visit.
* The participant has been exposed to another calcitonin gene-related peptide (CGRP) antibody (including exposure in a study investigating a CGRP antibody) \<6 months prior to the screening visit.
* The participant has a history or diagnosis of complicated migraine (ICHD-3 version, 2018), chronic tension-type headache, hypnic headache, cluster headache, hemicrania continua, new daily persistent headache, or unusual migraine subtypes such as hemiplegic migraine (sporadic and familial), migraine with brainstem aura, ophthalmoplegic migraine, or migraine with neurological accompaniments that are not typical of migraine aura (diplopia, altered consciousness, or long duration; for example \>60 minutes). DRUG: Eptinezumab, DRUG: Placebo
Chronic Migraine in Children
Alpha Auditory Entrainment for Cognitive Enhancement and Sensory Hypersensitivity in Youth With Developmental Disorders (ENTRAIN)
Jae Citarella - Jae.Citarella@cchmc.org
ALL
5 years to 10 years old
NA
NCT06227780
Inclusion Criteria:
* FXS Cohort: 1) Aged 5-10 years, inclusive; 2) Patient has full FMR1 mutation confirmed by genetic testing.
* ASD Cohort: 1) Aged 5-10 years, inclusive; 2) Have no known genetic mutation; 3) Have documentation of ASD diagnosis; 4) Score ≤ 15 on SCQ screen; 5) Be in good health per investigator.
* TDC Cohort: 1) Aged 5-10 years, inclusive; 2) Have no known genetic mutation; 3) Have documentation of ASD diagnosis; 4) Score ≤ 15 on SCQ screen; 5) Be in good health per investigator; 6) Patient has met normal developmental milestones; Patient has no family history of heritable neuropsychiatric disorders; 7) Patient has an IQ greater than 85 on the Stanford-Binet; 8) Score ≤8 on an SCQ screen.
Exclusion Criteria:
* All subjects: 1) Patient has auditory or visual impairments that cannot be corrected; 2) History of substance abuse or dependence within the past 6 months OTHER: Alpha Auditory Entrainment, OTHER: Sham
Fragile X Syndrome, Autism Spectrum Disorder, Autistic Disorder, Asperger Syndrome
Neurodevelopmental Disorders, Autistic Disorder, Autism Spectrum Disorder, Fragile X Syndrome, Fragile X, FXS, ASD, Asperger, Autism
JUPITER 4.0 - Risk Factors for Failure of Isolated Medial Patellofemoral Ligament Reconstruction
Matthew Veerkamp - Matthew.Veerkamp@cchmc.org
ALL
10 years to 35 years old
NCT06883396
Inclusion Criteria:
* 10-35 years old
* Recurrent patellar instability with at least one episode defined as either (1) a dislocated patella requiring reduction in the emergency department or (2) a convincing history for dislocation, associated with full giving way, and the following physical findings: (a) hemarthrosis or effusion, (b) tenderness along the medial retinaculum, and (c) apprehension when laterally directed force was applied to the patella or (3) MRI-documented dislocation with associated bone bruises
Exclusion Criteria:
* Previous ipsilateral knee surgery
* Obligatory/fixed/habitual patella dislocation or subluxation
* Unloadable inferior or lateral chondral damage on the patella that would require a tibial tubercle transfer for unloading purposes
* Pathologic tibiofemoral instability PROCEDURE: Medial Patellofemoral Ligament (MPFL) Reconstruction
Patellar Dislocation, Recurrent, Patellar Dislocation, Patellar Instability, Patellofemoral Dislocation, Patellofemoral Joint Dislocation, Patellofemoral Disorder
Patella, Patella Dislocation, Patellar Instability, Recurrent Patellar Instability, MPFL, Medial Patellofemoral Ligament, Medial Patellofemoral Ligament Reconstruction, Patellofemoral Instability
NO During CPB in Neonates to Reduce Risk of AKI
Jaynee Bartsch - jaynee.bartsch@cchmc.org
ALL
1 day to 31 days old
PHASE3
NCT04216927
Inclusion Criteria:
* All neonates (≤31 days) undergoing cardiac surgery with CPB for CHD will be deemed eligible for enrollment.
Exclusion Criteria:
• Failure to obtain informed consent from parent/guardian
• Clinical signs of preoperative persistent elevated pulmonary vascular resistance,
• Emergency surgery,
• Episode of cardiac arrest within 1 week before surgery,
• Recent treatment with steroids and/or a condition that may require treatment with steroids (excluding steroid administration specifically for CPB),
• Use of inhaled NO (iNO) immediately prior to surgery,
• Structural renal abnormalities by ultrasound,
• Preoperative AKI,
• Use of other investigational drugs,
• Weight less than \<2 kg,
• Gestational age \<36 weeks,
• Major extracardiac congenital anomalies,
• Non-English speakers.
DRUG: Nitric Oxide, DRUG: Oxygen
AKI, CHD - Congenital Heart Disease, Surgery
Comparison of a Demand Oxygen Delivery (DOSA)
Suzie Hicks - suzie.hicks@cchmc.org
ALL
5 years to 17 years old
NA
NCT06609694
Inclusion Criteria:
• Age 5-17 years with or without Down Syndrome (DS).
• Children with obstructive sleep apnea (OSA) and obstructive apnea hypopnea index (OAHI) 5-40 / hour: The rationale for selecting this range of OAHI is that a large number of children with DS with this range of OSA severity are untreated for months to years. It is important to understand the response to oxygen across the spectrum of disease severity. Notably, children with severe disease are left with few options (e.g., tracheostomy).
• Absence of clinically significant hypoxia defined as oxygen saturation \< 88% for 5 minutes or episodic desaturation to 60% as these levels would otherwise identify children eligible to routinely receive oxygen.
Exclusion Criteria:
• Current CPAP use with documented compliance (\> 4 hrs/ night; \> 70% of nights).
• Oxygen saturation \< 90% at rest during wakefulness
• Chronic daytime or nighttime use of supplemental oxygen.
• Unable to participate in a Polysomnogram (PSG).
• Enrolled or planning to enroll in another study that may conflict with protocol requirements or confound results in this trial.
DEVICE: Portable oxygen concentrator Inogen G5 model
Obstructive Apnea
Sleep Apnea, Down Syndrome, Continuous Positive Airway Pressure (CPAP)
A Study Using Risk Factors to Determine Treatment for Children With Favorable Histology Wilms Tumors (FHWT)
- cancer@cchmc.org
ALL
Up to 30 years old
PHASE3
NCT06401330
Inclusion Criteria:
* Patients must be enrolled on APEC14B1 and consent to Part A - Eligibility Screening prior to enrollment on AREN2231.
* Patients must be \< 30 years old at enrollment.
* Patients with newly diagnosed Stage I-IV Favorable Histology Wilms Tumor confirmed by central review and with a qualifying Initial Stratum Assignment on APEC14B1-REN.
* Patients must receive a qualifying Initial Stratum Assignment on APEC14B1-REN by Day 14 post-diagnostic procedure (nephrectomy or biopsy), where that procedure is Day 0.
* Patients must enroll on AREN2231 by Day 14.
* Exceptions: If patient reaches Day 14 (post initial diagnostic nephrectomy or biopsy) without receiving an Initial Stratum Assignment on APEC14B1-REN, patient will not be eligible for enrollment on AREN2231 unless all required materials (reports and Case Report Forms and specimens) for an Initial Stratum Assignment arrived by Day 7, but an Initial Stratum Assignment was not completed by Day 14. In these circumstances, after obtaining appropriate protocol consent, the patient may proceed with treatment according to local institutional staging and enroll within 5 calendar days of notification of the central Initial Stratum Assignment being issued, only if the AREN2231 Initial Stratum Assignment is in agreement with any treatment already initiated. If the Initial Stratum Assignment is not in agreement with the local institution's assessment then the patient will be ineligible for AREN2231.
* All sites must have sent or plan to send diagnostic tumor sample for molecular testing through a Clinical Laboratory Improvement Act (CLIA)-certified (or equivalent if outside of the United States \[US\]) laboratory that can detect Loss of Heterozygosity (LOH) of chromosome 1p AND 16q, and gain of chromosome 1q. Patients potentially eligible for mVLR must also have LOH of chromosome 11p15 included.
* Note: Patients are eligible for enrollment prior to obtaining these molecular testing results, and it is strongly recommended that patients are enrolled before these results are available. However, molecular results must be returned and uploaded to APEC14B1-REN for integration into risk stratification by the required timepoints (specific timelines vary by treatment arm). Patients who do not have molecular results available by the arm-specific timepoints may be taken off protocol therapy.
* Patients who have an upfront nephrectomy must have at least one lymph node sampled and confirmed as a lymph node by central pathology review to be eligible.
* Note: Lymph node sampling will also be required at delayed nephrectomy. Patients who do not have a lymph node sampled and confirmed as a lymph node by central pathology review at delayed nephrectomy will be taken off protocol therapy.
* Karnofsky performance status must be ≥ 50 for patients \> 16 years of age and the Lansky performance status must be ≥ 50 for patients ≤ 16 years of age.
* ONLY TO PATIENTS WHO WILL RECEIVE CHEMOTHERAPY: Serum total bilirubin ≤ 1.5 X upper limit of normal (ULN) OR direct bilirubin ≤ 3X ULN for subjects with total bilirubin levels \> 1.5 ULN (within 7 days prior to enrollment).
* ONLY TO PATIENTS WHO WILL RECEIVE CHEMOTHERAPY: Aspartate aminotransferase (AST/serum glutamate oxaloacetic transaminase \[SGOT\]) OR alanine transaminase (ALT/serum glutamic pyruvate transaminase \[SGPT\]) ≤ 3X ULN OR ≤ 5 X ULN for patients with liver metastases (within 7 days prior to enrollment).
* ONLY TO PATIENTS WHO WILL RECEIVE CHEMOTHERAPY: Shortening fraction of ≥ 27% by echocardiogram, or ejection fraction of ≥ 50% (within 7 days prior to enrollment)
* Note: This criteria only applies to patients centrally classified as Stage IV. Stage II and III patients subsequently assigned to a doxorubicin arm will be off protocol therapy if they do not meet this criteria at time of cardiac function assessment.
* Known HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
* All patients and/or their parents or legal guardians must sign a written informed consent.
* All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.
Exclusion Criteria:
* Patient with a diagnosis of Stage V Bilateral Wilms Tumor.
* Patients who in the opinion of the investigator are not able to comply with the study procedures are not eligible.
* Patients with any uncontrolled, intercurrent illness including but not limited to symptomatic congestive heart failure.
* Patients with Stage I FHWT with a known or suspected Wilms Tumor predisposition syndrome or condition (contralateral nephrogenic rests and/or unilateral multicentric tumors) are excluded from treatment on the mVLR (Nephrectomy Only) arm.
* Notes:
* In the context of the renal tumor protocols, multicentric tumors and multifocal tumors are equivalent terms, and refer to the occurrence of two or more tumors arising within one kidney.
* Exclusion from the Nephrectomy Only arm applies to two groups of patients:
* Patients \< 4 years with Stage I FHWT other than epithelial subtype AND
* Stage I patients of any age with Epithelial WT
* For the purpose of exclusion from the Nephrectomy Only Arm, known or suspected WT predisposition syndromes or conditions are defined as follows:
* WT Predisposition Syndromes: Beckwith Wiedemann Spectrum, Denys Drash, Trisomy 18, Idiopathic Hemihypertrophy/Isolated Lateralized Overgrowth, WAGR, Simpson-Golabi-Behmel, Bohring-Opitz, or other conditions considered by treating physician to predispose to WT.
* WT Predisposing Conditions:
* A unilateral WT and (radiologic or pathologic) determination of contralateral nephrogenic rest(s) AND/OR
* Unilateral multicentric WT
* Patients treated with partial nephrectomy at initial diagnosis are excluded from mVLR (Nephrectomy Only) arm.
* Patients with lung metastases as the only metastatic site who already had complete resection of all radiologically evident lung nodules, and have at least one nodule confirmed pathologically as tumor.
* Please note: Those with lung metastases as the only metastatic site who have complete resection of all radiologically evident lung nodules after enrollment but prior to the lung imaging following Cycle 2 of DD-4A will be inevaluable for lung assessment and subsequent stratum assignment and will, therefore, come off protocol therapy.
* Patients with known Charcot-Marie-Tooth syndrome.
* Patients who have had prior tumor-directed chemotherapy or radiotherapy for the current diagnosis except for therapy delivered for an emergent issue, as medically indicated.
* Patients who will potentially require doxorubicin on this study and have previously received doxorubicin for another diagnosis.
* Patients receiving concurrent chemotherapy for a different diagnosis.
* Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.
* Lactating females who plan to breastfeed their infants.
* Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation. PROCEDURE: Bone Scan, DRUG: Carboplatin, PROCEDURE: Computed Tomography, DRUG: Cyclophosphamide, BIOLOGICAL: Dactinomycin, DRUG: Doxorubicin, DRUG: Etoposide, DRUG: Irinotecan, PROCEDURE: Magnetic Resonance Imaging, PROCEDURE: Nephrectomy, OTHER: Patient Observation, PROCEDURE: Positron Emission Tomography, PROCEDURE: Ultrasound Imaging, DRUG: Vincristine, PROCEDURE: X-Ray Imaging
Stage I Mixed Cell Type Kidney Wilms Tumor, Stage II Mixed Cell Type Kidney Wilms Tumor, Stage III Mixed Cell Type Kidney Wilms Tumor, Stage IV Mixed Cell Type Kidney Wilms Tumor
Comparative Effectiveness of Available Treatments for Sinus and Ear Infections in Children (Acute Sinusitis) (MEASURE)
Jane Luce, MPH - lucej2@upmc.edu
ALL
2 years to 12 years old
PHASE4
NCT07732699
Inclusion Criteria:
* Age 2 years to \<12 years.
* Clinical diagnosis of AS.
Exclusion Criteria:
* Known allergy or other contraindication to oral amoxicillin or clavulanate
* Prior use of systemic antibiotics in the last 7 days
* History of renal impairment
* History of hepatic impairment
* Phenylketonuria or allergy to aspartame
* History of craniofacial abnormalities
* Concurrent bacterial infection requiring systemic antibiotic therapy (e.g., pneumonia, streptococcal pharyngitis)
* Ill appearance, systemic toxicity, or immunodeficiency
* Incomplete pneumococcal vaccination, defined as receipt of fewer than three doses of a pneumococcal conjugate vaccine
* Parent or caregiver unable to complete study surveys in English or Spanish
* Previous randomization into either MEASURE trial within the last 6 months
* Periorbital redness and/or swelling, proptosis, or swelling of the forehead
* Individuals who qualify for both the AS and AOM trials (to avoid dual enrollment) will be excluded from the AS trial. DRUG: Amoxicillin, DRUG: Amoxi Clavulanate, DRUG: Amoxicillin Placebo, DRUG: Amoxicillin-Clavulanate Placebo
ACUTE SINUSITIS, Sinusitis
Pediatric Sinusitis, Sinusitis
DISCOVERY of Risk Factors for Type 2 Diabetes in Youth (DISCOVERY)
Hailey Eisenmann - discoveryinteens@cchmc.org
ALL
8 years to 15 years old
NCT06525259
Inclusion Criteria:
Screening will occur to enrich the yield of individuals who are highly predisposed to develop youth-onset T2D and include those with all of the following criteria:
* Overweight or obesity with BMI ≥85th percentile
* Age 8-13 year for girls, 9-15 year for boys (inclusion younger for girls as puberty tends to start a year earlier in girls)
* Tanner Stage 2, 3, or 4
* Elevated HbA1c 5.5-6.4%
Exclusion Criteria:
An individual who meets any of the following criteria will be excluded from participation:
* Diabetes based on history, or HbA1c ≥6.5% in the medical record or at screening
* Unable/unwilling to provide consent/participate fully
* Conditions predisposing to diabetes or altering the trajectory of puberty
* Medications affecting glucose dynamics during the screening and enrollment period
* Prior treatment with insulin
* Use of glucagon-like peptide-1 (GLP-1) receptor agonist or any weight loss medications in the 6 weeks prior to enrollment
* Planning treatment with glucagon-like peptide-1 (GLP-1) receptor agonist or any weight loss medications
* Use of metformin or any glucose lowering medication for a reason other than treatment of diabetes (e.g., for PCOS) in the 6 weeks prior to enrollment
* Planning treatment with metformin or any glucose lowering medication or planning to use such medications for a reason other than treatment of diabetes (e.g., for PCOS)
* Known syndromic/monogenic obesity
* Blood disorders impacting HbA1c (e.g., anemia, hemoglobin variants)
* Major systemic organ disease
* History of bariatric surgery or currently planning bariatric surgery
* Current pregnancy or currently planning pregnancy
* Use of GnRH agonist, estrogen, or testosterone
* Individuals who do not speak English or Spanish, given validation of the questionnaires to be utilized Diabetes Mellitus Type 2, Childhood-Onset
High vs.Standard Dose Influenza Vaccine in Pediatric Solid Organ Transplant (SOT) Recipients (PSOT)
Kerrigan Perkins - kerrigan.perkins@cchmc.org
ALL
3 years to 17 years old
PHASE2
NCT05947071
Inclusion Criteria:
• Male or female, 3-17 years of age at time of enrollment
• Pediatric kidney, heart, and/or liver transplant recipient ≥1 month and \<24 months post-transplant at the time of study immunization * Note: Inclusion of recipients of multiple organs is permitted but is limited to recipients of any combination of organs including kidney, heart and/or liver * Note: Participants undergoing re-transplantation are permitted
• Anticipated to be available for duration of the study
• Available by telephone, email, or text message
Exclusion Criteria:
• Inability (i.e. not able to understand and provide consent) or unwillingness of a participant/parent/legal guardian to give written informed consent or comply with study protocol
• History of severe hypersensitivity to influenza vaccination or anaphylaxis to eggs/egg protein
• History of severe latex hypersensitivity
• History of Guillain-Barre syndrome
• History of lung or intestine transplant
• HIV positive patients (testing within 24 months of enrollment)
• Receipt of current season's influenza vaccine post-transplant prior to enrollment in the study
• Currently pregnant or lactating (females of childbearing age may be enrolled based on self-report, urine pregnancy test must be performed prior to each influenza vaccine)
• Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.
BIOLOGICAL: Standard Dose Quadrivalent Inactivated Influenza Vaccine, BIOLOGICAL: High Dose Quadrivalent Inactivated Influenza Vaccine
Immunization, Infection, Transplantation Infection, Influenza
Influenza, Vaccination, Immunization, High Dose, Fluzone, Standard Dose, Influenza, Human, Communicable Diseases, Pediatric transplantation
AERA Pediatrics Registry
Katie Sawvell - Katie.Sawvell@cchmc.org
ALL
Up to 18 years old
NCT07071298
Inclusion Criteria:
• Age \<18
• Specific indications for ETBD are documented
• ETBD with AERA device attempted-
Exclusion Criteria:
• ETBD with device other than AERA®
• Previous ETBD procedure-
Dysfunction of Eustachian Tube
ETBD
Follow-up Visit of High Risk Infants (FU)
Traci Beiersdorfer - traci.beiersdorfer@cchmc.org
ALL
18 months to 26 months old
NCT00009633
* Infants inborn at NRN centers
* \<27 weeks gestational age
* Infants enrolled in one or more additional NICHD NRN Follow-up studies. For infants that do not meet the inclusion criteria above, inclusion and exclusion criteria are determined by the criteria for the additional trial(s). In these cases, infants that are larger than 1,000 grams and/or older than 27 weeks may be included in the FU Study.
Note: These inclusion criteria were changed as of 1/1/2008. Prior to this date, infants with birth weights between 401 and 1500 grams who were admitted to NRN NICUs within 14 days of birth were included in the database.
OTHER: No Intervention
Infant, Newborn, Infant, Low Birth Weight, Infant, Small for Gestational Age, Infant, Premature
NICHD Neonatal Research Network, Extremely Low Birth Weight (ELBW), Prematurity, Neurodevelopmental Outcome, Follow up studies
Phase 1 Dose-escalating Study of MM-398 (Irinotecan Sucrosofate Liposome Injection) Plus Intravenous Cyclophosphamide in Recurrent or Refractory Pediatric Solid Tumors
- cancer@cchmc.org
ALL
12 months to 20 years old
PHASE1
NCT02013336
Inclusion Criteria:
* Histologically or cytologically-confirmed Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, or osteosarcoma
* Disease progression after prior therapy in locally advanced or metastatic setting
* Measurable or evaluable disease based on the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) criteria
* Age 12 months to \<21 years
* Adequate bone marrow reserves, hepatic function, and renal function
* Recovered from effects of any prior surgery or cancer therapy
* Patients 18 years or older will provide written consent. A parent or legal guardian of a patient \<18 years of age will provide informed consent and patients 11 to 18 years of age will provide written assent or as per participating institutional policy.
Exclusion Criteria:
* Clinically significant gastrointestinal disorders
* NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure
* Active infection or unexplained fever
* Known hypersensitivity to any of the components of MM-398 or other liposomal products
* Recent Investigational therapy
* Pregnant or breast feeding; females of child-bearing potential must test negative for pregnancy at the time of enrollment DRUG: MM-398 (Irinotecan Sucrosofate Liposome Injection) plus cyclophosphamide
Recurrent or Refractory Solid Tumors, Ewing Sarcoma, Rhabdomyosarcoma, Neuroblastoma, Osteosarcoma
pediatric, MM-398, cyclophosphamide, irinotecan
Venetoclax Combined With Vyxeos (CPX-351) for Participants With Relapsed or Refractory Acute Leukemia
- cancer@cchmc.org
ALL
1 year to 39 years old
PHASE1
NCT03826992
Inclusion Criteria:
* Ages 1 Year to 39 Years
* Diagnosis of one of the following:
* Acute myeloid leukemia (AML), any subtype except
* Patients with acute promyelocytic leukemia (APML) are NOT eligible
* Patients with ML-DS are NOT eligible
* Myeloid sarcoma
* Acute leukemia of ambiguous lineage (ALAL)
* Acute undifferentiated leukemia (AUL)
* T/myeloid mixed phenotype acute leukemia (MPAL)
* B/myeloid MPAL
* MPAL with KMT2A-rearrangement MPAL with t (9;22) are NOT eligible
* T-cell acute lymphoblastic leukemia (T ALL)
* Early thymocyte precursor (ETP) ALL
* KMT2A-rearranged ALL
* Disease Status
* Relapsed/Refractory AML, MPA, and AUL
* Untreated therapy related AML
* Relapsed/Refractory KMT2A-rearranged ALL, T-cell ALL, ETEP ALL
* Karnofsky/Lanksy performance level score of greater than or equal to 50 percent.
* Prior therapy requirements
* Fully recovered from acute toxicities of Hematopoietic Stem Cell Transplant (HSCT) or Anthracycline Exposure
* 14 days must have elapsed since the completion of systemic cytotoxic therapy other than hydroxyurea, decitabine or azacitidine
* 2 weeks must have elapsed for local palliative radiotherapy (RT); 6 months must have elapsed if prior craniospinal RT or if 50% radiation of pelvis, and at least 6 weeks must have elapsed if other substantial bone marrow radiation
* Adequate renal, liver, cardiac, and central nervous system (CNS) function
Exclusion Criteria:
* Diagnosis of one of the following:
* Myeloid Leukemia associated with Down Syndrome (ML-DS)
* Acute Promyelocytic Leukemia (APML)
* Acute leukemia with CNS status 3 involvement
* Philadelphia chromosome t(9;22) positive leukemia (Ph+ ALL, AML, MPAL, or AUL)
* Fanconi Anemia, Shwachman-Diamond syndrome, or any other bone marrow failure syndrome or DNA repair disorder
* Wilson's Disease or other copper-metabolism disorder
* Pregnant or breastfeeding
* Uncontrolled infection
* Received greater than 13.6 Gray (Gy) prior radiation to the mediastinum
* Receipt of growth factors within 7 days prior to enrollment
* Currently receiving another investigational drug
* Currently receiving anti-cancer agents (with the exception of intrathecal (IT) agents or hydroxyurea)
* Unable to comply with the safety monitoring requirements of the study DRUG: Vyxeos, DRUG: Venetoclax
Leukemia
relapsed, refractory, Vyxeos, Venetoclax, acute myeloid leukemia, acute myeloid leukemia, childhood, mixed-lineage leukemia (MLL), AML, CPX-351, Venclexta, Histone-lysine N-methyltransferase 2A (KmT2A)
Phase I/II Trial of Lentiviral Gene Transfer for SCID-X1 With Low Dose Targeted Busulfan Conditioning
Joan Moore - joan.moore@cchmc.org
MALE
0 years to 5 years old
PHASE1
NCT03311503
Inclusion Criteria:
\- 1. Diagnosis of SCID-X1 based on immunophenotype and lack of T cell function (proliferation to PHA \<10% of the lower limit of normal for the laboratory) AND confirmed by a mutation in IL2RG 2. Lack of an HLA identical (A, B, C, DR, DQ) related donor 3. Age 5 years old or younger 4. Signed informed consent 5. Documentation of willingness to follow up for 15 years post-infusion as currently required by the FDA 6. If the patient has previously undergone allogeneic transplant, lack of donor T cell engraftment must be documented.
7\. Age at least 8 weeks by the time of busulfan administration
Exclusion Criteria:
• Patients with an active, therapy-resistant infection. Infections that are known to be highly morbid in SCID patients will be considered active and therapy-resistant if the infectious agent is repeatedly isolated despite a minimum of 2 weeks of appropriate therapy and is associated with significant organ dysfunction (including but not limited to abnormalities listed below).
• Mechanical ventilation including continuous positive airway pressure
• Abnormal liver function defined by AST and ALT \>10 times the upper range of normal OR Bilirubin \>2 mg/dL
• Shortening fraction on echocardiogram \<25% or ejection fraction \<50%
• Renal failure defined as glomerular filtration rate \<30 ml/min/1.73 m2 or dialysis dependence
• Uncontrolled seizure disorder
• Encephalopathy
• Documented coexistence of any disorder known to affect DNA repair
• Diagnosis of active malignant disease other than EBV-associated lymphoproliferative disease
• Patients with evidence of infection with HIV-1
• Major (life-threatening) congenital anomalies. Examples of "major (life-threatening) congenital anomalies" include, but are not limited to: unrepaired cyanotic heart disease, hypoplastic lungs, anencephaly or other major central nervous system malformations, other severe non-repairable malformations of the gastrointestinal or genitourinary tracts that significantly impair organ function.
• Other conditions which in the opinion of the P.I. or co-investigators, contra-indicate collection and/or infusion of transduced cells or indicate patient's inability to follow the protocol. These may include for example clinical ineligibility to receive anesthesia, severe deterioriation of clinical condition of the patient after collection of bone marrow but before infusion of transduced cells, or documented refusal or inability of the family to return for scheduled visits. There may be other unforeseen rare circumstances that would result in exclusion of the patient, such as sudden loss of legal guardianship \-
BIOLOGICAL: autologous CD34+ cell transduced with G2SCID vector
Severe Combined Immunodeficiency, X Linked, Gene Therapy
lentiviral, Gene therapy, busulfan