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| ID | Type | Description | Link |
|---|---|---|---|
| U01HD082806-03 | U.S. NIH Grant/Contract | View source |
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Results from other clinical trials on AGS established baricitinib as standard of care treatment. Thanks to the knowledge gained in the clinical treatment of AGS, a clinical trial around the effects of RTI in AGS is no longer relevant at this time.
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| Name | Class |
|---|---|
| Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | NIH |
| National Human Genome Research Institute (NHGRI) | NIH |
| Gilead Sciences | INDUSTRY |
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The overall objectives are to explore the safety and efficacy of Reverse Transcriptase Inhibitors Tenofovir (TDF)/ Emtricitabine (FTC) administered in AGS affected children 2 to 18 years of age.
The investigators propose that a trial to assess the proof of principle that antiretroviral therapy through a drug combination of Tenofovir (TDF) and Emtricitabine (FTC) can decrease endogenous retroelement accumulation, and alter interferon signaling in Aicardi Goutières Syndrome (AGS) patients is reasonable and warranted at this time, based on existing in vitro and animal data. Additionally, this trial will further the investigators understanding of this disorder, measuring for the first time retroelements in human participants, exploring the retroviral burden in cerebrospinal fluid (CSF), the Interferon (IFN) signaling response, as well as evaluating antigen targets of autoimmunity and cytokines. If successful, this approach will clearly demonstrate the need for a larger trial of antiretrovirals in AGS with more clinically relevant outcomes.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| TDF/FTC then Placebo | Experimental | This is a double-blind, placebo-controlled, 2 arm, cross-over trial involving 34 children with clinical findings and molecular confirmation of Aicardi Goutieres Syndrome, who also have an abnormal interferon signature. For arm 1, half of the patients will receive TDF/FTC (a combination of Tenofovir [TDF] and Emtricitabine [FTC]) for the first 6 months of the study. There will be a one month washout period before starting on placebo for 6 months. |
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| Placebo then TDF/FTC | Experimental | For arm 2, half of the patients will receive placebo for the first 6 months of the study. There will be a one month washout period before starting on TDF/FTC (a combination of Tenofovir [TDF] and Emtricitabine [FTC]) for 6 months. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tenofovir (TDF) and Emtricitabine (FTC) | Drug | Tenofovir (TDF): a nucleotide reverse transcriptase inhibitor (NtRTI) an acyclic nucleotide analog of adenosine 5'-monophosphate. This is used in children as young as age 2. Emtricitabine (FTC): a nucleoside reverse transcriptase inhibitor (NRTI), a synthetic analog of cytidine which binds at the active site of the reverse transcriptase. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in interferon activation as measured by interferon response genes | The investigators propose to measure genes in the IFN stimulatory pathway in AGS patients, as a measure of disease activity and as a possible biomarker of therapeutic activity. Current data suggests that IFN related genes remain elevated in the late teens in AGS affected subjects, making it a more reliable measure of disease activity than IFN alpha. Validation of this preliminary data includes serial measurements in blood across several time points, to assess for variability. | From Baseline to 13 months |
| Measure | Description | Time Frame |
|---|---|---|
| Determination of immune cell composition in CSF | The investigators will pursue immunophenotyping of CSF cells in AGS subjects. Immunophenotyping and target antigens will further understanding of end organ damage in AGS. Additionally, this may provide biomarkers for therapeutic outcome and disease activity. | From Baseline to 13 months |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Adeline Vanderver, MD | Children's Hospital of Philadelphia | Principal Investigator |
| William Gahl, MD. PhD | National Institute of Health Genome Research Institute | Principal Investigator |
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| ID | Term |
|---|---|
| D000068698 | Tenofovir |
| D000069480 | Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination |
| D000068679 | Emtricitabine |
| ID | Term |
|---|---|
| D063065 | Organophosphonates |
| D009943 | Organophosphorus Compounds |
| D009930 | Organic Chemicals |
| D000225 | Adenine |
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| Emerson Resources |
| UNKNOWN |
| National Institutes of Health (NIH) | NIH |
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| Placebo | Other | Placebo for Tenofovir and Placebo for Emtricitabine |
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| Determination of immune cell composition in blood |
The investigators will pursue immunophenotyping of peripheral blood monocytes in AGS participants. Immunophenotyping and target antigens will further our understanding of end organ damage in AGS. Additionally, this may provide biomarkers for therapeutic outcome and disease activity. |
| From Baseline to 13 months |
| Accumulation of endogenous retroelements as measured in circulating immune cells | Performed by assays from previously collected samples | From Baseline to 13 months |
| Accumulation of endogenous retroelements as measured in circulating CSF | Performed by assays from previously collected samples | From Baseline to 13 months |
| Change in presence of non-specific and specific autoantibodies in blood | Performed by assays from previously collected samples | From Baseline to 13 months |
| Changes in Adverse Events - Safety monitoring laboratory tests | Patient monitoring for adverse effects | From Baseline to 13 months and as clinically warranted |
| Changes in total days hospitalized for disease-related illnesses. | Assess the effects of the treatment | Baseline - 13 months |
| D011687 |
| Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D003841 | Deoxycytidine |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D003853 | Deoxyribonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D004338 | Drug Combinations |
| D004364 | Pharmaceutical Preparations |