Clinical Trials Register

Summary
EudraCT Number:	2016-000778-40
Sponsor's Protocol Code Number:	BP39056
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-08-16
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2016-000778-40

A.3

Full title of the trial

A TWO PART SEAMLESS, OPEN-LABEL, MULTICENTER STUDY TO INVESTIGATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS AND EFFICACY OF RO7034067 IN INFANTS WITH TYPE1 SPINAL MUSCULAR ATROPHY

A.3.1

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

A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of RO7034067 in Infants With Type1 Spinal Muscular Atrophy

A.4.1

Sponsor's protocol code number

BP39056

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	F. Hoffmann-La Roche Ltd
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	F. Hoffmann-La Roche Ltd
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	F.Hoffmann-La Roche Ltd
B.5.2	Functional name of contact point	Trial Information Support Line-TISL
B.5.3	Address:
B.5.3.1	Street Address	Grenzacherstrasse 124
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4070
B.5.3.4	Country	Switzerland
B.5.6	E-mail	global.rochegenentechtrials@roche.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.3.1	Product name	RO7034067
D.3.2	Product code	RO7034067/F06 with solvent (RO7034067/F08)
D.3.4	Pharmaceutical form	Powder and solvent for 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	n/a
D.3.9.2	Current sponsor code	RO7034067/F06
D.3.9.3	Other descriptive name	RO7034067
D.3.9.4	EV Substance Code	SUB179686
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
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.IMP: 2
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.3.1	Product name	RO7034067
D.3.2	Product code	RO7034067/F07 with solvent (RO7034067/F09)
D.3.4	Pharmaceutical form	Powder and solvent for 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	n/a
D.3.9.2	Current sponsor code	RO7034067/F07
D.3.9.3	Other descriptive name	RO7034067
D.3.9.4	EV Substance Code	SUB179686
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	120
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

Type 1 Spinal Muscular Atrophy (SMA)

E.1.1.1

Medical condition in easily understood language

SMA is a muscular disease that affects child's muscular development leading to muscle weakness and progressive loss of movement. Type 1 children are usually diagnosed before 6 months of age.

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	19.0
E.1.2	Level	PT
E.1.2	Classification code	10041582
E.1.2	Term	Spinal muscular atrophy
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

Part 1
•To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of RO7034067 in infants with Type 1 SMA and to select the dose for Part 2

Part 2
•To assess the efficacy of RO7034067 measured as the proportion of infants sitting without support after 12 months of treatment

E.2.2

Secondary objectives of the trial

•To assess:Safety and tolerability of RO7034067,Pharmacokinetics of RO7034067,Pharmacodynamic effects of RO7034067
•To assess at 12 months of treatment with RO7034067 the effect on motor development milestones
•To assess at 24 months of treatment with RO7034067 the effect on sitting without support and further motor development milestones
•To assess the proportion of infants who achieve a score of 40 or higher in the Childrens Hospital of Philadelphia Infant Test of Neuromuscular Disorders scale at 12 months of treatment
•To assess the proportion of infants who achieve a reduction of 30 degrees in phase angle (respiratory inductance plethysmography) at 12 months of treatment
•To assess at 12 and 24 months of treatment the proportion of infants who are alive without permanent ventilation
•To assess the impact of treatment with RO7034067 on time to event (death, permanent ventilation)
•To assess the effect at 12 and 24 months of treatment with RO7034067 on muscle electrophysiology

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Males and females aged between 28 days (1 month) of life and 210 days (7 months) (inclusive) at enrollment
- A legally authorized representative must be able to consent for the patient according to International Conference on Harmonisation and local regulations
- Gestational age of 37 to 42 weeks
- Confirmed diagnosis of 5q-autosomal recessive SMA, including:
•Genetic confirmation of homozygous deletion or compound heterozygosity predictive of loss of function of the survival motor neuron 1 (SMN1) gene
•Clinical history, signs or symptoms attributable to Type 1 SMA, i.e., hypotonia, absent deep tendon reflexes and/or tongue fasciculations with onset after the age of 28 days, but prior to the age of 3 months (inclusive), and inability to sit independently (without support) at the time of screening
- Patient has two SMN2 gene copies, as confirmed by central testing
- Body weight >= 3rd percentile for age, using appropriate country-specific guidelines (for the first infant only > 7 kg)
- Receiving adequate nutrition and hydration (with or without gastrostomy) at the time of screening, in the opinion of the Investigator
- Adequately recovered from any acute illness at the time of screening and considered well-enough to participate in the opinion of the Investigator

E.4

Principal exclusion criteria

- Concomitant or previous participation in any investigational drug or device study within 90 days prior to screening or 5 half-lives, whichever is longer
- Concomitant or previous participation in a SMN2 targeting antisense oligonucleotide or SMN2 splicing modifier or gene therapy study
- Any history of cell therapy
- Hospitalization for pulmonary event within the last 2 months, or planned at the time of screening
- Unstable gastrointestinal, renal, hepatic, endocrine or cardiovascular system diseases
- Inadequate venous or capillary blood access for the study procedures
- Patients requiring invasive ventilation or tracheostomy
- Patients requiring awake non-invasive ventilation or with awake hypoxemia (arterial oxygen saturation < 95%) with or without ventilator support
- Patients with a history of respiratory failure or severe pneumonia, and have not fully recovered their pulmonary function at the time of screening
- Multiple or fixed contractures and/or hip subluxation or dislocation at birth
- Presence of non-SMA related concurrent syndromes or diseases
- Confirmed (2 consecutive measurements) systolic blood pressure or diastolic blood pressure outside the 95th percentile for age; resting heart rate < 70 bpm or > 170 bpm
- Presence of clinically relevant electrocardiogram (ECG) abnormalities before study drug administration
- History of malignancy if not considered cured
- Any major illness within one month before the screening examination or any febrile illness within one week prior to screening and up to first dose administration
- Taking any nutrients known to modulate cytochrome [CYP] 3A activity within 2 weeks prior to administration of study drugs
- The infant (and the mother, if breastfeeding the infant):
• Any inhibitor of CYP3A4 taken within 2 weeks (or within 5 times the elimination half life, whichever is longer) prior to dosing, including but not limited to ketoconazole, miconazole, itraconazole, fluconazole, erythromycin, clarithromycin, ranitidine, cimetidine
• Any inducer of CYP3A4 taken within 4 weeks (or within 5 times the elimination half-life, whichever is longer) prior to dosing, including but not limited to rifampicin, rifabutin, glucocorticoids, carbamazepine, phenytoin, phenobarbital, St. John's wort
• Any organic cation transporter-2 and multidrug and toxic compound extrusion substrates shall be avoided
• Any known flavin containing monooxygenase (FMO) 1 or FMO3 inhibitors or substrates
- Clinically significant abnormalities in laboratory test results
- Ascertained or presumptive hypersensitivity to RO7034067 or the constituents of its formulation
- Prior use, anticipated need for hydroxychloroquine, vigabatrin, retigabine, or any other drug known to cause retinal toxicity during the study
- Recent history (less than 6 months) of ophthalmic disease that would interfere with the conduct of the study as assessed by an ophthalmologist

E.5 End points

E.5.1

Primary end point(s)

Part 1 and 2: Safety
1. Incidence and severity of adverse events (AE) and serious adverse events
2. Incidence of treatment discontinuations due to AE
3. Incidence of abnormal laboratory and ECG values
4. Clinically significant vital signs abnormalities
5. Anthropometric and ophthalmological examination

Pharmacokinetics
6.Plasma concentrations of RO7034067, and its metabolite(s)

Pharmacodynamic
7. Assessment of SMN protein in blood
8.Assessment of SMN messenger ribonucleic acid (mRNA) in blood

Part 2: Efficacy
9.Proportion of infants who are sitting without support at 12 months of treatment assessed by the Gross Motor Scale of the Bayley Scales of Infant and Toddler development – Third Edition (BSID-III)

E.5.1.1

Timepoint(s) of evaluation of this end point

1-4. Up to 2 years
5. Screening (D [Day] -30 to D -2), D56, D119, D182, D245, D301, D364, D427, D490, D546, D609, D672, D728
6. D1, D2, D7, D14, D28, D56, D84, D119, D182, D245, D301, D364, D427, D490, D546, D609, D672, D728
7. D1, D14, D28, D119, D245, D364, D609, D728
8. D1, D14, D28, D245, D364, D609, D728
9. At Month 12

E.5.2

Secondary end point(s)

Part 2
1. Plasma concentrations of RO7034067 and its metabolite(s)
2. Assessment of SMN protein in blood
3. Assessment of SMN mRNA in blood
4. Change from baseline in the Total Raw Score of the BSID-III gross motor scale at Month 12 and 24
5. Proportion of infants who achieve the attainment levels of the motor milestones assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 and 24
6. Proportion of infants who achieve a score of 40 or higher in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) at Month 12
7. Proportion of infants who achieve a reduction of 30 degrees in their phase angle from baseline, as measured by respiratory inductance plethysmography, at Month 12
8. Proportion of infants who achieve an increase of at least 0.3 millivolt from baseline in their compound muscle action potential negative peak amplitude at Month 12 and 24
9. Time to permanent ventilation (from enrollment)
10. Proportion of infants who are alive without permanent ventilation at Month 12 and 24

E.5.2.1

Timepoint(s) of evaluation of this end point

1. D1, D2, D14, D28, D56, D119, D182, D245, D301, D364, D427, D490, D546, D609, D672, D728
2. D1, D28, D119, D245, D364, D609, D728
3. D1, D28, D245, D364, D609, D728
4. Baseline, Month 12 and 24
5. Month 12 and 24
6. Month 12
7. Baseline and Month 12
8. Baseline, Month 12 and 24
9. Up to 2 years
10. At Month 12 and 24

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

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

genetic testing

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

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

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

2 part design

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

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

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

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

The end of this study is defined as the date when the last patient last visit (LPLV) occurs.
The study will continue until RO7034067 is commercially available in the infant’s country, or as per local regulation, or per the Sponsor’s decision to terminate RO7034067 development. However, the study will not exceed 4 years (or less as per country specific requirements) after the last infant is enrolled in the study.

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

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

informed consent for study participation will be obtained from parents or legal guardian

F.3.3.7

Others

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)

Post-trial access to study drug (SD) to eligible patients is offered free of charge according to the Roche Global Policy. A patient will be eligible to receive SD after the end of study if all of these conditions are met:patient has a life-threatening or severe medical condition and requires continued SD treatment for his or her well-being/no appropriate alternative treatments available/patient and his or her doctor comply with and satisfy any legal or regulatory requirements that apply to them

G. Investigator Networks to be involved in the Trial

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-10-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-09-15

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-12-04

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