Clinical Trials Register

Summary
EudraCT Number:	2014-002053-19
Sponsor's Protocol Code Number:	CLMI070X2201
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-07-31
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Bulgarian Drug Agency

A.2

EudraCT number

2014-002053-19

A.3

Full title of the trial

An open-label multi-part first-in-human study of oral LMI070 in infants with Type 1 spinal muscular atrophy

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Clinical trial of LMI070 given by mouth to Type I SMA infant patients.

A.3.2

Name or abbreviated title of the trial where available

CLMI070X2201

A.4.1

Sponsor's protocol code number

CLMI070X2201

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02268552

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Novartis Pharma Services AG
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Pharma Services AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Pharma GmbH
B.5.2	Functional name of contact point	Medizinischer Infoservice (MCC)
B.5.3	Address:
B.5.3.1	Street Address	Roonstrasse 25
B.5.3.2	Town/ city	Nürnberg
B.5.3.3	Post code	90429
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49 1802 232300
B.5.5	Fax number	+49 911 27312160
B.5.6	E-mail	infoservice.novartis@novartis.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	LMI070
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not established
D.3.9.3	Other descriptive name	LMI070
D.3.9.4	EV Substance Code	SUB166489
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Spinal Muscular Atrophy

E.1.1.1

Medical condition in easily understood language

motor neuron 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	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10051203
E.1.2	Term	Spinal muscular atrophy congenital
E.1.2	System Organ Class	100000004850

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: Determine the safety and tolerability of ascending weekly doses and estimate the MTD of branaplam in infants with Type 1 SMA.
Part 2: Evaluate the safety and tolerability of ascending weekly doses of branaplam for 52 weeks in patients with Type 1 SMA.

E.2.2

Secondary objectives of the trial

Part 1:
- To evaluate branaplam pharmacokinetics in plasma after single and repeated doses of branaplam.
- To evaluate the effect of branaplam on growth parameters
- To evaluate the effect of branaplam on respiratory function
- To evaluate the effect of branaplam on infant motor development
- To evaluate the efficacy of LMI070 on ulnar and peroneal nerve compound motor action potential [CMAP]

In addition to the above for Part 2:
- To evaluate the efficacy of branaplam on motor and developmental milestones
- To evaluate the efficacy of branaplam on the ability to sit without support.
- To evaluate the efficacy of LMI070 on ulnar and peroneal nerve compound motor action potential [CMAP]

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Common for both Parts 1 and 2:
- Type 1 SMA, diagnosed clinically, with symptom onset <6 months of age and genetic confirmation of mutations in both alleles of the SMN1 gene, and with SMN2 copy number of 2.
- Best supportive care in place and stable for at least 14 days before screening.
- Must be able to demonstrate antigravity strength in both biceps. At birth gestational age >32 weeks and body weight at birth >2 kg.
- Must live within 2 hours drive of study center. Clearance should be obtained from the site investigator and sponsor if the patient
resides more than 2 hours ground travel from the study center

Specific for Part 1
- Age at screening between 1 and 7 months
- 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 for administration of branaplam (for patients in whom branaplam
cannot be administered orally ; NG tube may be removed between doses).

Specific for Part 2
- Type 1 SMA, diagnosed with genetic confirmation of mutations in both alleles of the SMN1 gene, and with SMN2 copy number of 2.
- Impossibility / inappropriateness of treatment with nusinersen for one of the following conditions: unavailability of the drug, clinical choice (motivations expressed by the attending physician) or choice of the patient / caregiver.
- Age at screening up to 180 days of age
- 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 for administration of branaplam (for the first administration only and for patients in whom branaplam cannot be administered orally; NG tube may be removed between doses).
- Minimum CHOP INTEND score of 15 at baseline
- Must be able to swallow solid and liquid even if feeding is used to support nutrition intake and must be in the 5th percentile for length or weight on the international growth curves and must be proportional in height and weight.

E.4

Principal exclusion criteria

Common for both Parts 1 and 2:
- Neurologic, or neuromuscular conditions other than SMA.
- Anemia, leukopenia, neutropenia or thrombocytopenia
- Hepatic dysfunction
- Age adjusted renal dysfunction
- Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period.
- 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.
- Current diagnosis of cardiac and/or vascular abnormalities or ECG abnormalities
- Acute or ongoing medical condition that, according to the Site Investigator and discussed with sponsor, would interfere with the conduct and assessments of the study. Examples are medical disability other than SMA that would interfere with the assessment of safety or would compromise the ability of the subject to undergo study procedures including be assessed by CHOP INTEND motor scale, changes in hematologic parameters or gastrointestinal dysfunction that would compromise the ability of adequate assessment of safety

Specific for Part 1
- Use of other investigational drugs within 14 days.
- Intractable seizure disorder (other than inactive febrile seizures).
- Persistent (in the opinion of the Investigator) hypoxemia (O2 saturation awake <92% or O2 saturation asleep <91%, without ventilation support) or requiring oral suctioning >2 per day.

Specific for Part 2
- Use of gene transfer at any time or other investigational drugs within 14 days.
- Patients who have received nusinersen at any time prior to screening
- Intractable epilepsy
- Persistent (in the opinion of the Investigator) hypoxemia (O2 saturation awake <92% or O2 saturation asleep <91%, without ventilation support).

E.5 End points

E.5.1

Primary end point(s)

Part 1 Safety & Tolerability [Time Frame: 13 Weeks]:
To evaluate the effect of branaplam on the following;
- Number of adverse events reported at all dose levels
- Changes from baseline in existing and newly reported findings on physical examination
- Changes from baseline in hematology, blood chemistry and urinalysis results at all dose levels
- Changes from baseline in vital signs at all dose levels
- Changes from baseline on existing or newly reported ophthalmologic findings at all dose levels
- Changes from baseline on existing or newly reported cardiac function at all dose levels
- Changes from baseline in existing and newly reported neurological findings at all dose levels
- Changes from baseline in existing and newly reported neurophysiological findings at all dose levels

Part 2 Safety & Tolerability [Time Frame: 52Weeks]:
To evaluate the effect of branaplam on the following;
- Number of adverse events reported at all dose levels
- Changes from baseline in existing and newly reported findings on physical examination
- Changes from baseline in hematology, blood chemistry and urinalysis results at all dose levels
- Changes from baseline in vital signs at all dose levels
- Changes from baseline on existing or newly reported ophthalmologic findings at all dose levels
- Changes from baseline on existing or newly reported cardiac function at all dose levels
- Changes from baseline in existing and newly reported neurological findings at all dose levels
- Changes from baseline in existing and newly reported neurophysiological findings at all dose levels

E.5.1.1

Timepoint(s) of evaluation of this end point

See Above

E.5.2

Secondary end point(s)

Part 1:
- Changes in Growth Parameters from baseline [Time Frame: Screening, Day 1, Day 8 to Day 85. Extended treatment periods: every 4 weeks and at the End of Study]
- Changes in respiratory function from baseline [Time Frame: Baseline, Day 8 to Day 85. Extended treatment periods: every 4 weeks and at the End of Study]
- Changes in Infant motor development from baseline [Time Frame: Baseline, Day 36, Day 85. Extended treatment periods: every 6 to 7 weeks and at the End of Study]
- Collect pharmacokinetic data from single and repeated dosing [Time Frame: Parts 1 and 2: Day 1 (Pre-dose + 1, 2, 4, 8 & 24 hours post-dose), Days 2, 3, 5, 8, 29. Part 1: Day 43. Part 2: Day 57, 57, 92 (Predose + 4 & 24 hours post-dose), 94, 99, 274 (Pre-dose + 4 & 24 hours post-dose), 276, 281]

In addition to the above for Part 2:
- Changes in motor and developmental milestones from baseline [Time Frame: Baseline, Day 15, Day 36, Day 57, Day 88 + End of Study]
- Changes in Ulnar Nerve Compound Motor Action Potential (CMAP) from baseline [Time Frame: Baseline, Day 88 + End of Study]
- Changes from baseline on the ability to site without support [Time Frame: 52 weeks]

E.5.2.1

Timepoint(s) of evaluation of this end point

See above

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

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

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

Belgium

Bulgaria

Czech Republic

Denmark

Germany

Hungary

Italy

Poland

Russian Federation

United States

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

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.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

infants

F.3.3.7

Others

Information not present in EudraCT

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Patients will initially be dosed for 13 weeks, however dosing may be extended if recommended by the independent DMC.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-09-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-10-04

P. End of Trial
P.	End of Trial Status	Completed

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IMP with orphan designation in the indication
Orphan Designation Number:
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