ISRCTN15569205终止2 期
A phase 2a study of TPN-101 in patients with Aicardi-Goutières Syndrome (AGS)
适应症
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 16
研究概览
简要总结
暂无简介。
研究设计
- 研究类型
- Interventional
入排标准
- 性别
- All
入选标准
- •1. Male or female participants of the following ages:
- •1.1. Cohort 1: Adults (=18 years of age)
- •1.2. Cohort 2: Adolescents (12 to 17 years of age)
- •1.3. Cohort 3: Children 5 to 11 years of age
- •1.4. Cohort 4: Children <5 years of age and >=6 kg in weight
- •2. Molecular diagnosis of AGS due to biallelic mutations in 1 of the following 5 genes: TREX1, RNASEH2A, RNASEH2B, RNASEH2C, or SAMHD1, or due to a recognized dominant mutation in TREX1.
- •3. IFN score in peripheral blood >2 standard deviations above the mean score of healthy controls measured on 3 occasions, approximately 2 weeks apart, during the 6-week Screening Period. The IFN score, determined on a Nanostring panel, is the median fold change in expression of a panel of 24 interferon-stimulated genes (ISGs) compared with the median IFN score of healthy controls.
- •4. Clinical syndrome consistent with AGS diagnosis based on clinical, CSF, and radiological findings. The following are examples of such findings (none of these are required for inclusion):
- •4.1. Early onset encephalopathy with psychomotor delay, spasticity, extrapyramidal signs, and microcephaly, the latter appearing in the first year of life
- •4.2. Calcifications particularly visible at basal ganglia level (putamen, pallidus, and thalamus), but also extending to the periventricular white matter
- •4.3. Cerebral white matter abnormalities
- •4.4. Cerebral atrophy
- •4.5. Important systemic symptoms in the early stages of the disease including irritability, feeding and sleeping difficulties, unexplained fevers, and the appearance of chilblain-like skin lesions on the fingers, toes, and ears
- •5. Women of childbearing potential (WOCBP) must be surgically sterilized (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), or agree to use highly effective methods of contraception, e.g., combined (estrogen and progestogen containing) or progestogen-only hormonal contraception associated with inhibition of
- •ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized partner (provided that the partner is the sole sexual partner of the WOCBP trial participant and that the vasectomized partner has received medical assessment of the surgical success); or sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments), from Screening through 3 months after the last dose of the study medication. Women who are pregnant or breastfeeding are not eligible for enrollment.
- •6. Has a reliable caregiver to accompany the patient to all study visits. Caregiver must have frequent contact with patient and be willing to monitor the patient's health and concomitant medications throughout the study.
排除标准
- •1. Mutation in IFIH1, ADAR1, LSM11, or RNU7-1.
- •2. Pre-/perinatal infections, in particular the TORCH complex (toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus)
- •3. Presence of other significant neurological disorders; brain tumor or other space-occupying lesion; history of severe head injury
- •4. Clinically significant intercurrent illness, medical condition (e.g., hematological, endocrine, cardiovascular, renal, hepatic, or gastrointestinal disease) or medical history (including neurological or mental illness) that would jeopardize the safety of the patient, limit participation, or compromise the interpretation of the data derived from the patient
- •5. Autoimmune disease requiring treatment or management (quiescent rheumatoid arthritis, psoriasis, treated autoimmune thyroiditis, or controlled Type 1 diabetes are acceptable)
- •6. History of human immunodeficiency virus (HIV), hepatitis B, or any active infection during Screening, unless the patient will have been symptom-free for at least 30 days prior to study drug administration. Patients with treated hepatitis C with no laboratory evidence of active disease and liver enzymes <2 × upper limit of normal (ULN) are allowed
- •7. History of cancer within 5 years of Screening, with the exception of fully treated non-melanoma skin cancers
- •8. Receipt of an experimental agent within 30 days or 5 half-lives prior to Screening, whichever is longer
- •9. Prior treatment with an immunomodulator other than a JAK inhibitor within 6 months of Screening; patients taking JAK inhibitors for AGS must have been on a stable dose for one month prior to Screening
- •10. Current treatment with a nucleoside reverse transcriptase inhibitor (NRTI) or other antiviral drug
- •11. Receipt of systemic corticosteroids within 30 days prior to Screening
- •12. Any vaccination within 30 days prior to Screening
- •13. Any major surgery within 30 days of Screening or any planned major surgery during the study
- •14. For patients who agree to the optional lumbar puncture (LP), any contraindication to undergoing an LP including, but not limited to:
- •14.1. Inability to tolerate an appropriately flexed position for the time necessary to perform an LP; international normalized ratio (INR) >1.4 or other coagulopathy; platelet count of <120,000/µL
- •14.2. Infection at the desired LP site
- •14.3. Taking anti-platelet or anti-coagulant medication within 30 days of Screening (Note: low dose aspirin is permitted but should be stopped 5 days prior to the LP)
- •14.4. Severe deformity or abnormality of the lumbar spine
- •14.5. Suspected non-communicating hydrocephalus or intracranial mass
- •14.6. Prior history of spinal mass or trauma
- •15. History of any significant drug allergy (such as anaphylaxis or
- •hepatotoxicity)
- •16. Physical and laboratory test findings, including the following:
- •16.1. Evidence of organ dysfunction or any clinically significant deviation from normal physical examination or vital signs that are not specific to AGS and that could interfere with the conduct of the study, the interpretation of the data, or increase patient risk, in the opinion of the investigator
- •16.2. Clinically significant abnormality on 12-lead ECG prior to study drug administration, confirmed by repeat testing
- •16.3. Total alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2× ULN, confirmed by repeat testing
- •16.4. Total bilirubin >1.2 × the ULN (unless due to Gilbert's syndrome)
- •16.5. Serum creatinine >168 µmol/L (1.9 mg/dL), confirmed by repeat testing
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