| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | |
| E.1.1.1 | Medical condition in easily understood language | | A genetic condition that affects the nervous system and causes severe physical and learning disabilities | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| 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 evaluate the safety and tolerability of multiple-ascending doses of GTX-102 administered by intrathecal (IT) injection to patients with AS | |
| E.2.2 | Secondary objectives of the trial | To evaluate the pharmacokinetics (PK) of GTX-102 in plasma and cerebrospinal fluid (CSF) of patients with AS
| |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1. Signed informed consent from parent(s) or legal guardian(s)
2. Documented genetic confirmation of full maternal UBE3A gene deletion causing AS in the region of 15q11.2-q13 including class I, II or III)
3. Age 4 to 17 years inclusive at screening
4. Stable seizure control (defined as clinically stable with no changes in antiepileptic medications over the prior 1 month before the screening visit, other than weight associated dose adjustments)
5. Able to ambulate independently, or with an assistive device (note, a child whose primary means of mobility is by wheelchair is excluded from the study)
6. Platelet count, prothrombin time / international normalized ratio, and partial thromboplastin time within 1.2 x the normal limits
7. Normal renal function with serum creatinine and spot urine protein ≤ 1.4 x ULN
8. Normal hepatic function with total bilirubin, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase ≤ 1.4 x ULN. Exception: levels ≤ 2 × ULN are acceptable if due to AEDs or Gilbert syndrome
9. Willing and able to comply with scheduled visits, drug administration plan, laboratory
tests, study restrictions, and all study procedures, including LP procedure.
10. Able to tolerate the anesthetic regimen, if required for LP procedure
11. a) A female patient is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
• Female of non-childbearing potential (ie, pre-menarche)
• Female of childbearing potential who agrees to remain abstinent (refrain from heterosexual intercourse) or use acceptable contraceptive methods during the treatment period and for at least 3 months after the final dose of GTX-102
b) A male patient is eligible to participate if he agrees to remain abstinent (refrain from heterosexual intercourse) or use acceptable contraceptive methods during the treatment period and for at least 3 months after the final dose of GTX-102 | |
| E.4 | Principal exclusion criteria | 1. Any change in medications (excluding AEDs) or diet/supplements intended to treat symptoms of AS (eg, sleeping aids, supplements, dietary change including ketogenic or low-glycemic index diet, other) over the prior 1 month before screening.
2. Any bleeding or platelet disorder
3. Any clinically significant cardiovascular, endocrine, hepatic, renal, pulmonary, gastrointestinal, neurologic, malignant, metabolic, psychiatric, or other condition that, in the judgment of the Investigator, will pose a safety risk, will make the patient unsuitable for participation in, and/or unable to complete the study procedures.
4. Any laboratory abnormality, that, in the Investigator’s opinion, could adversely affect the safety of the patient, make it unlikely that the course of treatment or follow up would be completed, or impair the assessment of study result
5. Known positive for hepatitis B virus, hepatitis C virus, or human immunodeficiency virus
6. Any active infection
7. Bone, spine, bleeding, or other disorder that exposes the patient to risk of injury or unsuccessful lumbar puncture
8. Drugs that increase the risk of bleeding (eg, heparin, low molecular weight heparin, platelet inhibitors).
9. Any prior use of gene therapy
10. Use of any investigational drugs in the past 6 months or within 5 half-lives, whichever period is greater (with the exception of prior GTX-102)
11. Known hypersensitivity to any oligonucleotide, as demonstrated by an immunemediated
reaction (eg, pneumonitis, hepatitis, nephritis, neuritis, or other system inflammation), or a systemic allergic reaction such as signs and symptoms of anaphylaxis, urticaria, clinically significant rash
12. Patient is pregnant or lactating
13. Any medical condition that would require intubation for the anesthesia procedure | |
| E.5 End points |
| E.5.1 | Primary end point(s) | Incidence of treatment-emergent adverse events (TEAEs) and serious TEAEs (SAEs),
discontinuations due to TEAEs, AESIs, and the severity of TEAEs
Changes in physical and neurological examinations, vital signs, laboratory tests (chemistry, hematology, coagulation markers, urinalysis), electrocardiogram (ECG), and CSF protein levels and other potential safety biomarkers which may include, but are not limited to neurofilament-light, phosphorylated Neurofilaments-heavy (pNFheavy), brain-derived neurotrophic factor (BDNP), glial fibrillary acidic protein (GFAP),
ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and matrix metalloproteinase 9
(MMP-9)
| |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | Loading Phase: Day 1, 2, 16, 30, 44, 58, 72, 86 and 128
Maintenance Phase: Day 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, 365, 393 and EOS | |
| E.5.2 | Secondary end point(s) | Plasma PK of GTX-102
GTX-102 concentrations in CSF
| |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | Loading Phase
-Plasma PK of GTX-102: Day 2, 58
-GTX-102 concentrations in CSF: Day 2, 30, 58, 86
Maintenance Phase
-Plasma PK of GTX-102: Day 1, 85, 169, 253, 337
-GTX-102 concentrations in CSF: Day 1, 85, 169, 253, 337
| |
| 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 | No |
| 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 | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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.8.3 | The trial involves single site in the Member State concerned | No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| 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 | | Australia | | Canada | | Israel | | United States | | France | | Germany | | Spain | | United Kingdom | |
| 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 | | Patients may continue on GTX-102 during the Maintenance phase of the study until GTX-102 is commercially available, intolerable toxicity occurs, the parent/legal guardian withdraws consent, or the study is terminated. | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
