E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 |
Part 1
To determine the safety and tolerability of ascending weekly doses and estimate the MTD of oral/enteral LMI070 in infants with type 1 SMA.
Part 2
To evaluate the safety and tolerability of multiple dose weekly regimens of oral/enteral LMI070 for 12 weeks in patients with type 1 SMA. |
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E.2.2 | Secondary objectives of the trial |
Part 1
-To evaluate LMI070 pharmacokinetics in serum after single and repeated doses of LMI070.
-To evaluate the effect of LMI070 on muscle by ultrasound.
-To evaluate the effect of LMI070 on growth parameters.
-To evaluate the effect of LMI070 on respiratory function
-To evaluate the effect of LMI070 on infant motor development.
In addition to the above for Part 2:
-To evaluate the efficacy of LMI070 on motor and developmental milestones
-To evaluate the efficacy of LMI070 on ulnar nerve compound action potential [CMAP] (optional) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Written informed consent must be obtained from the parent / guardian before any assessment is performed.
•Type 1 SMA, diagnosed clinically (symptom onset <6 months of age) and confirmed genetically (homozygous SMN1 gene deletion or mutation) plus SMN2 copy number of 2.
•Best supportive care in place and stable for at least 14 days before screening.
•Age at screening between 1 and 7 months, plus or minus 2 weeks.
•Must be able to demonstrate antigravity strength in both biceps.
•Must have or agree to have placement of feeding tube for enteral access via nasogastric (NG), nasojejunal (NJ), percutaneous gastrostomy (PEG), or percutaneous jejunostomy (PEJ) tube. |
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E.4 | Principal exclusion criteria |
•Use of other investigational drugs within 14 days.
•Neurologic, neuromuscular or genetic disorders other than SMA
•Anemia (Hgb < 8 g/dL), leukopenia (ANC < 2000/ml), or thrombocytopenia (< 100,000/mL).
•Hepatic dysfunction (AST or ALT > 1.5 x ULN; total bilirubin > ULN).
•Renal dysfunction (eGFR < 80 ml/min).
•Clinically significant abnormalities in hematology or clinical chemistry parameters, as assessed by the Site Investigator, at screening that would render the subject unsuitable for inclusion
•Hypoxemia (O2 saturation awake <92% or O2 saturation asleep <91%,without ventilation support) or requiring oral suctioning >2 per day
•Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period.
•Excluding SMA, any medically unstable condition including cardiomyopathy, hepatic dysfunction, kidney disorder, endocrine disorder, GI disorders, prematurity of <32 weeks gestation, metabolic disorders, severe respiratory compromise and significant brain abnormalities or injuries including hypoxic-ischemic encephalopathy.
•Ongoing medical condition that according to the Site Investigator would interfere with the conduct and assessments of the study. Examples are medical disability other than SMA that would interfere withthe assessment of safety or would compromise the ability of the subject to undergo study procedures including be assessed by CHOP-INTEND motor scale. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint for Part 1:
Physical Exam : Screening, D1 – D85 + EOS
Vital signs: Screening, D1 – D85 + EOS
ECG : Screening, D1, D8, D85 + EOS
Safety : Screening, Baseline, D3, D8, D15, D29, D43, D57, D71, D85 + EOS
Adverse Events: All Visits
Primary endpoint Part 2
Physical Exam – Screening, Baseline, D1 – D88 + EOS
Vital signs - Screening, Baseline, D1 – D88 + EOS
ECG - Screening, D1, D8, D88 + EOS
Safety – Screening, Baseline, D8, d15, D2, D29, D36, D43, D50, D57, D64, D71, D88 + EOS
Adverse Events – All Visits
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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) |
Secondary Endpoint Part 1
PK - D1 (Pre-dose + 1, 2, 4, 8 & 24 hours post-dose), D2, D3, D5, D8, D29, D43
Ultrasound : Baseline, D85 + EOS
Growth measurements : Screening, D1, D8-D85 + EOS
Respiratory function: Baseline, D8-D85 +EOS
CHOP-INTEND : Baseline, D36, D85 + EOS
Secondary Endpoint Part 2
PK : D1 (Pre-dose + 1, 2, 4, 8 & 24 hours post-dose), D2, D3, D5, D8, D29, D43, D57 (Pre-dose + 2, 4, 8 & 24 hours post-dose), D59, D62
Ultrasound : Baseline, D88 + EOS
Growth measurements : Screening, D1, D8-D57, D64, D71, D88 + EOS
Respiratory function - Baseline, D8-D57, D64, D71, D88 + EOS
CHOP-INTEND – Baseline, D15, D36, D57, D88 + EOS
CMAP – Baseline, D88 + EOS
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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 | 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 | No |
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
| 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 | 8 |
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 |
European Union |
United States |
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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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When the last subject completes their End of Study visit, and any repeat assessments associated with this visit have been documented and followed-up appropriately by the Investigator, or in the event of an early study termination decision, the date of that decision.
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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 | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |