E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Childhood Cerebral Adrenoleukodystrophy (CCALD) |
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E.1.1.1 | Medical condition in easily understood language |
CCALD is a rapidly progressive inflammatory demyelinating disorder characterized by a breakdown of the protective sheath called myelin, which surrounds and protects the nerve cells in the brain. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
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 |
Primary:
To evaluate the safety and pharmacokinetics of NV1205 in pediatric subjects diagnosed with CCALD.
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E.2.2 | Secondary objectives of the trial |
Exploratory:
To assess the effect of NV1205 on expression of the ABCD2 gene, levels of very long chain fatty acids (VLCFAs), beta oxidation rate of VLCFA, markers of lipid peroxidation, brain lesions as measured by magnetic resonance imaging (MRI), and brain metabolic status as measured by magnetic resonance spectroscopy (MRS).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Males ≥4 and <18 years of age
2. CCALD diagnosis confirmed by genetic testing
a. Genetic testing for CCALD diagnosis is not performed as part of the study screening assessments, and historic record is expected to be available to verify this requirement. However, if prior genetic verification of CCALD diagnosis was not done, or is not available, genetic testing must be performed to verify this eligibility requirement prior to initiating drug
3. Loes score of >0 and ≤15
4. Not eligible for HSCT, does not have access to HSCT, or opts not to receive HSCT, and is not expected to receive HSCT
5. VLCFA levels above normal limit in plasma or blood spot test
a. For subjects not on VLCFA lowering agents such as Lorenzo’s oil, a test within 3 months of enrollment is acceptable.
b. Patients on VLCFA lowering agents such as Lorenzo’s oil must stop the medication and have high VLCFA levels before enrollment
6. Signed informed consent by subject’s parent(s)/legally acceptable representative(s). In addition, signed children’s assent form according to local requirements.
7. Use of adequate contraception for subjects of reproductive potential during the study and for 93 days after the last dose of the study drug
a. Adequate contraception include vasectomy, true abstinence when this is in line with the preferred and usual lifestyle of the subject or consistent use of condom by subjects, or the use of effective contraceptive methods such as hormonal contraception, intrauterine device or hormone-releasing system, or bilateral tubal ligations by subject’s partners. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method are not acceptable methods of contraception.
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E.4 | Principal exclusion criteria |
1. Electrocardiographic (ECG) evidence of a previous myocardial infarction (MI) or ECG changes that likely represent cardiac ischemia, an unstable cardiac condition within the last 3 months (e.g., MI, revascularization, congestive heart failure, acute coronary syndrome), or ventricular tachycardia, unexplained syncope or syncope due to a cardiac etiology, long QT syndrome, or a family history of sudden cardiac death
2. History of cerebrovascular accident
3. QTcF >450 msec; significant ST-T wave changes that make interpretation of the QT interval challenging. PR >240 msec; resting heart rate <50 or >100 beats per minute
4. History of cancer within the past 5 years
5. Expected to initiate a major dietary change known to affect levels of VLCFA
6. Use of prohibited medications, including QTc prolonging drugs, oncologic chemotherapy for cancer treatment, metformin, statins, or Lorenzo's Oil within 14 days of first dose or at least 5.5 known half-lives of the relevant medication
7. Use of any investigational drug or procedures within 30 days of first dose of NV1205
8. Evidence of cataract development
9. Other significant medical conditions judged by the Investigator to preclude entry
10. HSCT recipient or receiving conditioning treatment for HSCT
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety Endpoints:
• Adverse events
• Thyroid function tests
• Liver function tests
• Markers of bone metabolism
• Hematology and chemistry laboratory tests
• 12 lead electrocardiogram (ECG) evaluation
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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) |
Pharmacodynamic (PD) Endpoints:
• Spectroscopically measured concentration of N-acetylaspartate (NAA), choline, and creatine in brain
• Plasma VLCFA
• Markers of oxidative stress in plasma and urine.
MRI and Clinical Endpoints:
• Brain MRI (Loes score) and presence of gadolinium-enhanced lesions
• Neurological function score
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | 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 | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Phase I/II, Open-Label, Dose Escalation Study of the Safety, PK and PD of NV1205 |
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E.7.2 | Therapeutic exploratory (Phase II) | No |
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 | 3 |
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 | 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 |
Argentina |
Australia |
Chile |
Colombia |
France |
Russian Federation |
Ukraine |
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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |