| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Metachromatic Leukodystrophy | |
| E.1.1.1 | Medical condition in easily understood language | Metachromatic Leukodystrophy, is an inherited genetic disease affecting
mainly babies and young children, and more rarely also affecting
adolescents and adults. | |
| E.1.1.2 | Therapeutic area | Body processes [G] - Genetic Phenomena [G05] |
| MedDRA Classification |
| 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 | 10067609 | | E.1.2 | Term | Metachromatic leukodystrophy | | 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 | | - To evaluate the pharmacodynamic effect of OTL-200 in CSF and the brain of patients with LJ MLD as compared to baseline | |
| E.2.2 | Secondary objectives of the trial | -To evaluate the pharmacodynamic effect of OTL-200 in bone marrow and peripheral blood and on various brain metabolites in LJ MLD patients as compared to baseline, siblings and/or untreated historical controls
-To evaluate engraftment of OTL-200
-To evaluate the clinical efficacy of OTL-200 in LJ MLD participants as compared to baseline, untreated historical controls or siblings
-To evaluate the safety and tolerability of the HSPC-GT procedure and OTL-200 | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1.Documented biochemical and molecular diagnosis of MLD, based on ARSA activity below the normal range and identification of two disease causing ARSA alleles. Novel mutations will be analysed within silico prediction tool and excluded from being known common polymorphisms. In the case of a novel mutation(s), a 24-hour urine collection must show elevated sulfatide levels.
2. O/R or R/R genotype or a genotype recognized as associated with the LJ variant of MLD.
3. a) if symptomatic: age at disease onset between ≥7 and <17 years of age (i.e. before their 17th birthday) OR b) if pre-symptomatic: participant must be <17 years of age at treatment (i.e before their 17th birthday) AND must have a sibling with a diagnosis of late-juvenile MLD variant based on age at disease onset (≥7 and <17 years of age i.e before sibling's 17th birthday), with biochemical and molecular diagnosis.
4. Normal cognitive function as defined by an IQ≥ 85 on age appropriate cognitive scales.
5.a) If the participant is <7 years age (i.e before their 7th birthday): normal motor milestones achievement, normal gross motor function according to chronological age and normal neurological examination (if applicable based on the age of the subject, GMFC-MLD =0) OR b) If the participant is ≥7 years, normal gross motor function or mild gross motor function impairment, defined by a GMFC-MLD 0or 1 (i.e patient is able to walk independently).
6. If applicable, participant willing and capable of compliance with contraceptive requirements as detailed further in Protocol Section 7.1 Contraceptive use by men or women should be consistent with local regulations regarding he methods of contraception for those participating in clinical studies.
7. Participant (or if applicable, parent/legal guardian) providing signed informed consent as described in Section 17 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol. | |
| E.4 | Principal exclusion criteria | 1. Documented HIV infection (positive HIV RNA and/or anti-p24 antibodies).
2.Malignant neoplasia (except localised skin cancer) or a documented history of hereditary cancer syndrome. Participants with a prior successfully treated malignancy and a sufficient follow-up to exclude recurrence (based on oncologist opinion) can be included after discussion and approval by the OTL-MM.
3.Myelodysplasia, cytogenetic alterations characteristic of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) or other serious haematological disorders.
4.Patients currently enrolled in other interventional trials.
5.Has previously undergone allogeneic HSCT and has evidence of residual cells of donor origin.
6.Previous gene therapy.
7.Has symptomatic herpes zoster, not responsive to specific treatment
8.Evidence of active tuberculosis (TB)
9.Acute or chronic stable Hepatitis B (HBV)
10.Presence of positive Hepatitis C RNA test result at screening
11.End-organ dysfunction, severe active infection not responsive to treatment, or other severe disease or clinical condition which, in the judgement of the investigator, would make the participant inappropriate for entry into this study | |
| E.5 End points |
| E.5.1 | Primary end point(s) | Co-primary pharmacodynamic efficacy endpoints:
•Change in ARSA activity levels in CSF
•Change in neuronal metabolite ratio NAA: Cr in white matter regions of interest of the brain | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | | from baseline to 24 months post-treatment | |
| E.5.2 | Secondary end point(s) | Efficacy:
•Change in ARSA activity levels in CSF from baseline to multiple visits over time
•Change from baseline to multiple visits over time in neuronal metabolite ratio NAA: Cr in white matter regions of interest of the brain (may include but not limited to the centrum semiovale; parieto-occipital white matter)
•Change from baseline to 24 months and multiple visits over time in ARSA levels in total PBMC, CD14+ and CD15+
•Neuronal metabolite ratios at 24 months and multiple visits over time relative to baseline and compared to untreated historical controls / siblings in treated participants (may include but not limited to Cho:Cr, mIns:Cr, Lac: Cr, Cho: NAA, NAA: H2O, Cho: H2O, mIns: H2O, Lac: H2O) in white matter regions of interest (may include but not limited to the centrum semiovale; frontal, occipital, and parieto-occipital white matter).
•Engraftment as measured by %LV in BM progenitors (at D30 post gene therapy and at multiple visits over time)
oBrain MRI assessments at 24 months and at multiple visits over time as compared to baseline, untreated historical controls or siblings
oNeurocognitive assessments at 24 months and at multiple visits over time as compared to baseline, untreated historical controls or siblings
oFull neurological clinical examination (NCE) at 24 months and at multiple visits over time as compared to baseline, untreated historical controls or siblings
oGMFC-MLD at 24 months and at multiple visits over time as compared to baseline, untreated historical controls or siblings
oAssessment of NCV at 24 months and at multiple visits over time as compared to baseline, untreated historical controls or siblings
oVineland Adaptive Behavioural Scales at 24 months and at multiple visits over time as compared to baseline, untreated historical controls or siblings
Safety as measured by:
•Conditioning regimen related toxicity and AEs
•Non-conditioning related AEs
•Haematological reconstitution (ANC > 500/µL associated with evidence of BM recovery at day +60)
•Infusion related reactions
•Immunogenicity (e.g. anti-ARSA Antibodies)
•Abnormal Clonal Proliferation (ACP)
•Replication Competent Lentivirus
•Insertion Site analysis findings
| |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | Efficacy endpoints:
•Change in ARSA activity levels in CSF from baseline to multiple visits over time
•Change from baseline to multiple visits over time in neuronal metabolite ratio NAA: Cr
•Change from baseline to 24 months and multiple visits over time in ARSA levels in total PBMC and CD15+
•Engraftment as measured by %LV in BM progenitors (at D30 post gene therapy and at multiple visits over time)
All the others: at 24 months and at multiple visits over time
Safety: through the study | |
| 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 | No |
| 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) | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
