E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Aicardi-Goutières Syndrome (AGS) |
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E.1.1.1 | Medical condition in easily understood language |
Aicardi-Goutières Syndrome (AGS) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 22.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10083189 |
E.1.2 | Term | Aicardi-Goutieres syndrome |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To demonstrate proof-of-mechanism for TPN-101 in AGS, as evidenced by reduction in interferon (IFN) score • To assess the safety and tolerability of TPN-101 in patients with (AGS) |
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E.2.2 | Secondary objectives of the trial |
• To assess PK of TPN-101 in plasma and CSF • To assess the PD effects of TPN-101 in blood and CSF • To assess effect of TPN-101 on cerebral blood flow • To assess clinical and functional status |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female participants of the following ages: a. Cohort 1: Adults (≥ 18 years of age) b. Cohort 2: Adolescents (12 to 17 years of age) c. Cohort 3: Children 5 to 11 years of age d. 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): a. Early onset encephalopathy with psychomotor delay, spasticity, extrapyramidal signs, and microcephaly, the latter appearing in the first year of life b. Calcifications particularly visible at basal ganglia level (putamen, pallidus, and thalamus), but also extending to the periventricular white matter c. Cerebral white matter abnormalities d. Cerebral atrophy e. 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.
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E.4 | Principal exclusion criteria |
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: 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; infection at the desired LP site; 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); severe deformity or abnormality of the lumbar spine; suspected non-communicating hydrocephalus or intracranial mass; 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: a. 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 b. Clinically significant abnormality on 12-lead ECG prior to study drug administration, confirmed by repeat testing c. Total alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2× ULN, confirmed by repeat testing d. Total bilirubin > 1.2 × the ULN (unless due to Gilbert’s syndrome) e. Serum creatinine > 168 μmol/L (1.9 mg/dL), confirmed by repeat testing f. Hemoglobin less than 7.5 g/dL or absolute neutrophil cell count of < 1500/μL g. Positive blood screen for HIV or hepatitis B surface antigen h. Positive urine drug screen
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E.5 End points |
E.5.1 | Primary end point(s) |
• Reduction in innate immune signaling, as assessed by the expression of 24 ISG, used to calculate an IFN score in whole blood. • Incidence and severity of treatment-emergent adverse events (TEAEs) with TPN-101 administered for up to 48 weeks in patients with AGS.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Concentrations of TPN-101 in plasma and cerebrospinal fluid (CSF) • L1 expression including L1 RNA • INF status in blood and CSF, including IFN-alpha, IFN-gamma, as well as by measuring antiviral protective capacity (IFN activity) in patient serum and CSF, and genome-wide RNA-Seq expression analysis in whole blood • Other inflammatory biomarkers in blood and CSF, (e.g., neopterin) • Neurodegeneration biomarkers, including NfL, UCHL-1, tau, and GFAP in blood and CSF • Brain magnetic resonance imaging (MRI) including arterial spin labeling for measurement of cerebral blood flow • Clinical and functional status, as measured by Vineland-3, AGS Scale, Caregiver Diary Score, BSID III, WPPSI-IV, WISC-V, WAIS-IV, GMFM-88, and classification according to 5 systems: GMFCS, MACS, CFCS, EDACS, and VFCS
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 48 and monitored throughout the study |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Disease-related biomarkers, Survival |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
France |
Italy |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |