Primary:The purpose of this study is to evaluate the safety, tolerability, orally administered LMI070 in patients with Type 1 SMA.pharmacokinetics (PK), pharmacodynamics (PD) and efficacy; and to estimate the Maximum Tolerated Dose (MTD) and optimal…
ID
Source
Brief title
Condition
- Neuromuscular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoints 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 endpoints 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
Secondary outcome
Secondary Endpoints 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 Endpoints 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
Background summary
Type I SMA (spinal muscular atrophy) is a fatal disease of infants who are
deficient in SMN (Survival Motor Neuron), a key survival protein for alpha
motor neurons in the spinal cord. Oral LMI070 has been shown to systemically
increase SMN production in animal models and
prolongs survival of a most severe mouse model bearing the SMA mutation. In
addition, an oral single dose of LMI070 in preclinical models has shown
upregulation of SMN protein in the spinal cord for up to 7 days. However,
because it has potential toxicity (cell cycle arrest) at high doses, it is
being introduced into human use in infant patients who may benefit most from it
despite the risks. The known risks (marrow suppression and GI disturbances) are
monitorable, manageable and reversible; based on preclinical studies, toxicity
can be controlled or can be mitigated by intermittent dosing.
Study objective
Primary:
The purpose of this study is to evaluate the safety, tolerability, orally
administered LMI070 in patients with Type 1 SMA.pharmacokinetics (PK),
pharmacodynamics (PD) and efficacy; and to estimate the Maximum Tolerated Dose
(MTD) and optimal orally administered LMI070 in patients with Type 1 SMA.
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 regimens of
oral/enteral LMI070 for 12 weeks in patients with Type 1 SMA.
Secondary:
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.
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)
Study design
This is phase II, open-label, multi-part, first-in-human proof of concept study
in infants with Type 1 spinal muscular atrophy, to evaluate safety,
tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of
orally administered LMI070.
Enrollment to this study is restricted to patients with Type 1 SMA with 2
copies of the SMN2 gene. In Part 1 of the study patients will be dosed once
weekly with LMI070 until MTD is determined. A Bayesian logistic regression
model (BLRM) with escalation overdose control (EWOC) will be used to determine
the dose levels used for each dose escalation. The decision to dose escalate
the next cohort will be made after safety data have been collected for 14 days
following the first dose (14-day DLT window). PK will be used to confirm
wash-out of LMI070 to avoid accumulation of the compound. The data will be used
to further develop the PK model. If PK data show the potential for
accumulation, the dosing frequency may be decreased; conversely, if drug
exposure is lower than predicted, dose frequency may be increased.
For Part 1, patients completing 13 weeks of treatment will be considered to
have completed the study. However, they may continue treatment if Novartis, the
investigator and the independent DMC agree that this is in the best interest of
the patient.
Part 2 of the study will enroll new patients into one of up to 3 weekly dosing
regimens (multiple doses per week) for 12 weeks to assess efficacy and safety.
Patients may continue treatment if Novartis, the investigator and the
independent DMC agree that this is in the best interest of the patient.
Intervention
Multiple doses oral/enteral LMI070.
Study burden and risks
Burden of participation is the risk of side effects of LMI070 and discomforts
of trial procedures.
Possible side effects of the study medication include:
- Vomiting & diarrhea
- Fatigue/lethargy
- Increased risk of infection
- Bleeding of the gastrointestinal tract
The following trial procedures may cause the following discomfort /risk:
- Blood sample collection: Fainting, pain and/or bruising. Rarely a small blood
clot or infection.
- For the administration of the medication a feeding tube may be inserted;
infection, bleeding, discomfort in the mouth, nose and stomach, coughing and
sneezing, reflux, skin irritation from tape/adhesive and restriction of the
airway
- CMAP (optinal); include nerve injury, infection, bleeding, pain and
discomfort in the immediate area around the arm
Intervention:
Physical examination: 15x
Head and chest circumference + BSA: 15x
Height, weight: 15x
Blood pressure, pulse, body temperature and respiratory rate: 19x
Urinalysis (overall health and biomarker research): 10x
Collection hair for biomarker research: 2x
Assess muscle function: 4x
ECG: 5x
Respiratory Function: 14x
Ultrasound: 3x
Tracking side effects in diary: During treatment period.
Blood sample collection: 17x
Optional:
CMAP: 3x
Additional blood collection immunogenicity: 1x
Except for medication which may be required to treat adverse events, and
continuation of standard of care medications prescribed for SMA, no medication
other than study drugs will be allowed from the first dosing until all of the
Study Completion evaluations have been conducted.
There is prohibited medication (chronic treatment for SMA) specified in Table
5.1 of the protocol (page 34).This medication could be considered confounding
to this study; therefore, these drugs could interfere with assessment of study
endpoints. None of these medications are assumed as standard treatment for SMA,
as this medication is not authorized for treatment of SMA.
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
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.
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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-002053-19-NL |
| ClinicalTrials.gov | NCT02268552 |
| CCMO | NL50648.000.14 |