Kinetics of Blood Platelets Transfused to Healthy Subjects

Study Overview
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Brief Summary
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The current phase 0 trial is preceding the phase 1/2 trial of a newly developed drug, NAITgam, for the prevention of fetal and neonatal alloimmune thrombocytopenia (FNAIT) - a rare, but potentially very severe bleeding condition in the fetus or newborn. FNAIT may occur in women whose blood platelets do not express HPA-1a. If the fetus has inherited HPA-1a from the father, the mother's immune system may be stimulated to produce HPA-1a antibodies if HPA-1a positive fetal blood platelets enter the maternal circulation during delivery. In a subsequent pregnancy, such antibodies will cross the placenta and may reduce the number of HPA-1a positive blood platelets in the fetus, which in turn may result in severe bleeding in the fetus or newborn. The phase 1/2 study of NAITgam will examine NAITgam's ability to eliminate HPA-1a positive blood platelets that has been transfused to healthy male subjects, whose blood platelet do not express HPA-1a. The ability to quickly eliminate transfused HPA-1a positive platelets is considered as a surrogate endpoint for NAITgam's ability to prevent formation of antibodies against HPA-1a after delivery of an HPA-1a positive child. The current phase 0 trial will examine the survival of blood platelets transfused to healthy male individuals without subsequent administration of NAITgam. The natural survival of transfused platelet, as determined in the phase 0 trial, will be compared with the survival of transfused HPA-1a positive platelets after administration of NAITgam in the phase 1/2 trial. The aim of the phase 0 trial is first, to determine the dose of blood platelet that should be transfused to the healthy subjects in the phase 1/2 trial; and secondly, to determine the optimal time point, after transfusion of platelets, for administration of NAITgam in the phase 1/2 trial. Eight to 24 healthy male subjects will be included in the phase 0 trial. After transfusion of platelets, blood samples will be collected at regular intervals to determine the proportion of transfused blood platelets. Differences between tissue type antigens between donor and recipient will be used to determine the proportion of transfused platelets. Survival of transfused platelets will be performed by flow cytometry - a method that can be used to quantify very small proportions of cells in the blood. Fluorochrome-conjugated monoclonal antibodies against HLA-A2 and HLA-A9 will be used for flow cytometric identification the transfused platelets.

Official Title
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An Open-label, Single Centre, Exploratory Trial Investigating the Kinetics of Platelets Transfused to Healthy, Male Subjects

Conditions
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Fetal and Neonatal Alloimmune Thrombocytopenia

Intervention / Treatment
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* Other: Platelet transfusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent must be obtained before any trial related procedures are performed Healthy, male subjects Age ≥18 and < 50 years old BMI < 30kg/mˆ2 HLA-A2 and/or HLA-A9 negative Exclusion Criteria: History of hypersensitivity to platelet concentrates or human plasma protein Subjects with known IgA deficiency and anti-IgA antibodies Blood donation received within 3 weeks Platelet counts < 150 × 10ˆ9/L or > 450 × 10ˆ9/L Any type of known platelet function disorder Treatment with non-steroidal anti-inflammatory drugs (NSAIDs, e.g. acetylsalicylic acid) or selective serotonin reuptake inhibitors within 7 days prior to Visit 1 Chronic or ongoing active infectious disease requiring systemic treatment including, but not limited to, chronic and renal infection, chronic chest infection with bronchiectasis, and tuberculosis Participation in any other interventional clinical trial during the trial period Subjects known or suspected of not being able to comply with this trial protocol (e.g. due to alcoholism, drug dependency or psychological disorder) Presence of HLA-antibodies class I (MFI level > 3000) Signs of previous or ongoing infection with HIV and/or Hepatitis B and/or C virus

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Platelet transfusion<br>HLA-A2 and/or HLA A9 negative healthy study subjects will be transfused with a small dose of platelets from an HLA-A2 and/or HLA-A9 positive donor. | Other: Platelet transfusion<br>* Transfusion of a platelet dose from 20 × 10ˆ9 to 100 × 10ˆ9.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Terminal elimination half live | Determination of the terminal elimination half live of a single platelet dose transfused to healthy male subjects | The terminal elimination half live of transfused platelets will be determined based on the survival of platelets within the first 5 days after trandfusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | The peak platelet concentration | Will be determined within the first 5 days after transfusion | 
| AUC | The area under the platelet concentration versus time curve | Will be determined within the first 5 days after transfusion | 
| Clearance | Natural clearance of platelets from the circulation | Will be determined within the first 5 days after transfusion |