| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | spinocerebellar ataxia types 1, 3 and Huntington’s disease | |
| E.1.1.1 | Medical condition in easily understood language | | spinocerebellar ataxia types 1 or 3 and Huntington’s disease | |
| 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 | 23.0 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10057660 | | E.1.2 | Term | Spinocerebellar ataxia | | E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders | |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10070668 | | E.1.2 | Term | Huntington's disease | | E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders | |
| 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 | | Primary: To evaluate the safety and tolerability of multiple doses of intrathecal lumbar bolus administrations of VO659 in participants with clinically manifest SCA1, SCA3, or Huntington’s disease (HD). | |
| E.2.2 | Secondary objectives of the trial | Secondary: To characterise the CSF and blood pharmacokinetic (PK) profile of single and multiple doses of intrathecal lumbar bolus administrations of VO659 in participants with clinically manifest SCA1, SCA3 or HD.
Exploratory:
• To assess the pharmacodynamic (PD) profile of single and multiple doses of intrathecal lumbar bolus administrations of VO659, including target engagement and off-target effects based on biochemical biomarkers, and MRI neuroimaging assessments in participants with clinically manifest SCA1, SCA3 or HD.
• To assess effects on clinical outcome assessments of intrathecal lumbar bolus administrations of VO659 in participants with clinically manifest SCA1, SCA3 or HD | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1. Provide written informed consent (signed and dated).
2. Is ≥25 and ≤60 years of age inclusive, of any gender, at the time of signing the informed consent.
3. Have SCA1, SCA3 or HD meeting one of the following criteria:
a. SCA1 and SCA3: mild to moderate disease with a Scale for Assessment and Rating of Ataxia (SARA) score of ≥3 and ≤18
b. HD: early manifest, Stage I disease with a Total Functional Capacity (TFC) Score of ≥11 and ≤13 and a Unified Huntington’s Disease Rating Scale (UHDRS) Diagnostic Confidence Level (DCL) of 4.
4. Have genetically confirmed disease, defined by increased cytosine, adenine, and guanine (CAG) repeat length in the disease-causing allele by direct DNA testing. For each indication the requirements are:
a. SCA1: ≥41 contiguous, uninterrupted CAG repeats in ATXN1
b. SCA3: ≥61 repeats in ATXN3
c. HD: ≥36 CAG repeats in HTT.
5. Have good general health, in the opinion of the investigator, apart from having SCA1, SCA3, or HD.
6. Body weight of ≥50 kg and body mass index (BMI) within the range of 18-32 kg/m2 (inclusive).
7. Is willing to follow contraceptive requirements per local regulations regarding the methods of contraception for those participating in clinical trials. In case local regulations deviate from the contraception methods listed in Section 10.4, local regulations apply and will be described in the Informed Consent Form (ICF). | |
| E.4 | Principal exclusion criteria | 1. Have any condition that would prevent participation in trial assessments.
2. Have acute infection or febrile illness at the time of each dosing, or ongoing systemic antiviral or antimicrobial therapy that will not be completed at least three days prior to dosing.
3. Have one or more pathogenic mutation(s) in another polyQ disease gene, i.e., ATXN2, CACNA1A, ATXN7, TBP, AR, and ATN1, plus either ATXN3 and HTT (for patients with SCA1), ATXN1 and HTT (for participants with SCA3), or ATXN1 and ATXN3 (for participants with HD), in addition to the disease-causing mutation in the ATXN1 (patients with SCA1), ATXN3 (patients with SCA3) or HTT (patients with HD) gene.
Pathogenic mutations are defined as: ≥41 contiguous, uninterrupted CAG repeats in ATXN1; ≥61 repeats in ATXN3; ≥36 CAG repeats in HTT; ≥38 CAG repeats in AR; ≥48 CAG repeats in ATN1; ≥33 CAG repeats in ATXN2; ≥34 CAG repeats in ATXN 7; ≥20 CAG repeats in CACNA1A; ≥41CAG repeats in TBP.
4. Have clinical diagnosis of moderate or severe chronic migraines or history of the post-lumbar-puncture headache of moderate or severe intensity requiring hospitalisation or blood patch.
5. Have a brain, spinal or systemic disorder that would interfere with the LP process, CSF circulation, or safety assessments.
6. Have history of bleeding diathesis or coagulopathy, platelet count less than the lower limit of normal unless stable and assessed by the investigator and the Medical Monitor to be not clinically significant.
7. Have a history of any malignancy or obligatory precancerous condition of any organ system, except cervical carcinoma of Stage 1B or less, or non-invasive basal cell or squamous cell skin carcinoma that has been successfully treated.
8. Have inherited or acquired immunodeficiency, including human immunodeficiency virus (HIV) infection.
9. Have positive serology for hepatitis B surface antigen (HbsAg) or active hepatitis C infection.
10. Have any known history of hypersensitivity or allergies to the antisense oligonucleotide (AON) (VO659) or any excipient contained in the IMP.
11. Have any significant (moderate or severe) acute or chronic liver or kidney disease.
12. Have deviations of any of the following laboratory parameters at screening:
• Aspartate aminotransferase (AST) >2.0 x Upper Limit of normal range (ULN)
• Alanine aminotransferase (ALT) >2.0 x ULN
• Total bilirubin >1.5 x ULN
• Platelets <100,000/µl (i.e., <100 x 10^9/L)
• Estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m2 based on the modification of diet in renal disease (MDRD) formula
13. Have uncompensated cardiovascular disorder, any past or present cardiac arrhythmia, QTcF values on screening ECG of >450 ms for males and > 470 ms for females , familial history of long QT syndrome or sudden unexpected death.
14. Have a history of uncontrolled hypokalaemia or hypomagnesaemia.
15. Have a history of hospitalisation for any major medical or surgical procedure involving general anaesthesia within 6 weeks of screening or planned during the trial.
16. Have clinical evidence of acute COVID-19 or confirmed presence of COVID-19 / SARS-CoV-2 infection at any time during the screening period or have long-term neurological consequences of COVID-19 / SARS-CoV-2 infection that have not resolved or stabilised at the time of screening.
17. Have a history of attempted suicide, suicidal ideation with a plan that required hospital admission and/or change in level of care within 12 months prior to screening. For patients with (i) a suicide ideation score ≥4 on the Columbia Suicide Severity Rating Scale (C-SSRS) within the last 12 months, or (ii) suicidal behaviours within the last 12 months (as measured by the answer “Yes” on any of the C-SSRS Suicidal Behaviour Items), a risk assessment should be done by an appropriately-qualified mental health professional (e.g., a psychiatrist or licensed clinical psychologist) to assess whether it is safe for the patient to participate in the trial.
18. Have a history of psychosis, bipolar disorder or schizophrenia and patients deemed to be at significant risk of an acute depressive episode, confusional state or violent behaviour.
19. Have medical, psychiatric, or other conditions that, in the judgement of the investigator, may compromise the patient’s ability to understand the patient information sheet, to give informed consent, to comply with all trial requirements, or to complete the trial.
See protocol for additional exclusion criteria on "prior/concomitant therapy", "prior concurrent clinical trial experience", "other exclusions", "exclusion criteria to be checked before each IMP administration" | |
| E.5 End points |
| E.5.1 | Primary end point(s) | Primary endpoints:
1. Incidence and dose relationships of treatment-related:
o AEs,
o Serious adverse events (SAEs),
o Adverse events of special interest (AESI),
o Severe events (NCI-CTCAE Grade 3 or higher).
2. Changes in clinical safety parameters including physical and neurological examinations, vital signs, body weight, ECG, cardiac monitoring, suicidal ideation and behaviour risk monitoring by the Columbia Suicide Severity Rating Scale (C-SSRS), and review of structural MRI scans
3. Changes in laboratory safety parameters in blood (haematology, haemostasis, clinical chemistry), CSF (cell counts, protein, glucose), and urine (urinalysis).
4. Adverse changes in clinical status based on exploratory clinical, biochemical and neuroimaging assessments | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | 1. All visits
2. All visits except D3 of all doses and PDV2
3. All visits except D3 of all doses and PDV2
4. All visits | |
| E.5.2 | Secondary end point(s) | Secondary endpoints:
1. The CSF concentration-time profile of VO659, including the derived PK parameter of elimination half-life (t1/2), if possible.
2. The plasma concentration-time profile of VO659, including the derived PK parameters such as the area under the curve (AUC), maximum plasma concentration (Cmax), t1/2
3. Changes in mutant ATXN1 (in participants with SCA1) mutant ATXN3 (in participants with SCA3) or mutant HTT (in participants with HD) in CSF and blood
4. Changes in total ATXN1, total ATXN3, total HTT in CSF and blood
5. Changes in biomarkers indicative of neurodegeneration, such as NfL, total tau, GFAP, and UCH-L1 in CSF and the blood
6. Changes in biomarkers indicative of inflammation, such as C3a, IL-1β, IL-6, TNFα and YKL-40 (CH3-L1) in CSF and the blood
7. Changes in neuroimaging outcomes, such as the volume of whole brain and brain regions of interest (including but not limited to the cerebellum, pons, brainstem, and striatum), diffusion MRI, quantitative MRI for iron content (R2* mapping), MRS (optional, only at select trial sites), and OCT (only at select trial sites)
8. Changes in clinical outcome measures, such as SARA, 9-HPT, FARS (part I & II), INAS (participants with SCA1 or SCA3); UHDRS TFC, FAS, IS, TMS/DCL (participants with HD), MoCA, SDMT, CGI-S, and CGI-C (all participants).
9. Changes in Patient-reported outcomes, such as PGI-S and PGI-C | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | 1. D1 of all doses, PDV1, PDV3, PDV4, ED
2. D1, D2, D8 of dose 1 and 4; D1 and D8 of dose 2 and 3; PDV1, PDV3, PDV4, ED
3. D-1, D2, D8 of all doses, PDV1, PDV3, PDV4, ED
4. D-1, D2, D8 of all doses, PDV1, PDV3, PDV4, ED
5. D-1, D2, D8 of all doses, PDV1, PDV3, PDV4, ED
6. D-1, D2, D8 of all doses, PDV1, PDV3, PDV4, ED
7. Screening, PDV1, PDV4, ED
8. Screening, D-1, PDV1, PDV4, ED
9. D-1, PDV1, PDV4, ED | |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description | |
| 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 | 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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 | | United Kingdom | | Denmark | | France | | Germany | | Italy | | Netherlands | | Poland | | Spain | |
| 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 | | The date of the last visit of the last participant in the trial or the last scheduled procedure shown in the SoA (Table 1 of protocol) for the last participant in the trial globally, whichever occurs last. | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 22 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
