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

• Register: EUCTR
• Last refreshed on: 5 June 2018
• Main ID: EUCTR2016-000778-40-DE
• Date of registration: 21/07/2016
• Prospective Registration: Yes
• Primary sponsor: F. Hoffmann-La Roche Ltd
• Public title: A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of RO7034067 in Infants with Type1 Spinal Muscular Atrophy
• Scientific title: 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
• Date of first enrolment: 05/01/2017
• Target sample size: 64
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-000778-40
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: yes; Other trial design description: 2 part design; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no; Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Brazil, Canada, China, Croatia, France, Germany, Italy, Japan, Lebanon, Poland, Russian Federation, Saudi Arabia, Serbia, Spain, Switzerland, Turkey, Ukraine, United Kingdom, United States

Contacts

• Name: Trial Information Support Line-TISL
• Affiliation: F.Hoffmann-La Roche Ltd

• Name: Trial Information Support Line-TISL
• Affiliation: F.Hoffmann-La Roche Ltd

Key inclusion & exclusion criteria

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
- Infant 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
Are the trial subjects under 18? yes
Number of subjects for this age range: 64
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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 Administration of a SMN2 targeting antisense oligonucleotide or SMN2 splicing modifier or gene therapy either in a clinical study or as part of medical care.
- 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, (at any time in the patients' life) and/or, anticipated need for quinolones (chlororquine and hydroxychloroquine), thioridazine, hydroxychloroquine, vigabatrin, retigabine, or any other drug known to cause retinal toxicity during the study. Infants exposed to chloroquine, hydroxychloroquine, thioridazine, vigabatrin, retigabine or drugs with known retinal toxicity given to mothers during pregnancy (and lactation) should not be enrolled.
- Recent history (less than 6 months) of ophthalmic disease that would interfere with the conduct of the study as assessed by an ophthalmologist


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Type 1 Spinal Muscular Atrophy (SMA)
MedDRA version: 20.1 Level: PT Classification code 10041582 Term: Spinal muscular atrophy System Organ Class: 10010331 - Congenital, familial and genetic disorders

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Intervention(s)

Product Name: RO7034067
Product Code: RO7034067/F06 with solvent (RO7034067/F08)
Pharmaceutical Form: Powder and solvent for oral solution
INN or Proposed INN: n/a
Current Sponsor code: RO7034067/F06
Other descriptive name: RO7034067
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-

Product Name: RO7034067
Product Code: RO7034067/F07 with solvent (RO7034067/F09)
Pharmaceutical Form: Powder and solvent for oral solution
INN or Proposed INN: n/a
Current Sponsor code: RO7034067/F07
Other descriptive name: RO7034067
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 120-

Product Name: RO7034067
Product Code: RO7034067 / F12
Pharmaceutical Form: Powder for oral solution
INN or Proposed INN: n/a
Current Sponsor code: RO7034067/F12
Other descriptive name: RO7034067
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-

Product Name: RO7034067
Product Code: RO7034067 / F13
Pharmaceutical Form: Powder for oral solution
INN or Proposed INN: n/a
Current Sponsor code: RO7034067 / F13
Other descriptive name: RO7034067
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 60-

Primary Outcome(s)

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

Secondary Objective: To assess:
•Safety and tolerability of RO7034067
•Pharmacokinetics of RO7034067
•Pharmacodynamic effects of RO7034067
•Effect on motor development milestones
•Effect on sitting without support and further motor development
milestones
•Impact of treatment with RO7034067 on time to event (death,
permanent ventilation)
•Change from baseline in the total raw score of the BSID-III gross
motor scale
•To assess the 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)
•Who achieve an increase of at least 4 points on their CHOP-INTEND
score from baseline
•Who achieve head control
•Who achieve a reduction of at least 30 degrees in phase angle
(respiratory inductance plethysmography)
•Who are alive without permanent ventilation
•Who do not require invasive or non-invasive respiratory support

Main Objective: 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

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. Vital signs abnormalities
5. Anthropometric and ophthalmological examination
Part 1
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)

Secondary Outcome(s)

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 an increase of at least 4 points in
their CHOP-INTEND score from baseline at Month 8 and Month 12
8. Proportion of infants who achieve head control at Month 8, Month 12,
and Month 24
9. Proportion of infants who achieve a reduction of at least 30 degrees in
their phase angle from baseline, as measured by respiratory inductance
plethysmography, at Month 12
10. Time to permanent ventilation (from enrollment)
11. Proportion of infants who are alive at Month 12 and 24
12. Proportion of infants who are alive without permanent ventilation at
Month 12 and 24
13. Proportion of infants who do not require invasive or non-invasive
respiratory support at Month 12 and Month 24
14. Ability to swallow and to feed orally at Month 12 and Month 24

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. Month 8 and 12
8. Month 8, Month 12 and 24

9. Baseline and Month 12
10. Up to 2 years
11-14. At Month 12 and 24

Secondary ID(s)

BP39056

Source(s) of Monetary Support

F. Hoffmann-La Roche Ltd