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Investigate Safety, Tolerability, PK, PD and Efficacy of Risdiplam (RO7034067) in Infants With Type1 Spinal Muscular Atrophy (FIREFISH)

Primary Purpose

Muscular Atrophy, Spinal

Status

Active

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Risdiplam

About this trial

This is an interventional treatment trial for Muscular Atrophy, Spinal

Eligibility Criteria

1 Month - 7 Months (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Clinical history, signs or symptoms attributable to Type 1 SMA with onset after 28 days but prior to the age of 3 months
Gestational age of 37 to 42 weeks
Confirmed diagnosis of 5q-autosomal recessive SMA
Participants has two survival motor neuron 2 (SMN2) gene copies, as confirmed by central testing
Body weight greater than or equal to (>=) third percentile for age, using appropriate country-specific guidelines
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

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 SMN2-targeting antisense oligonucleotide, 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
Presence of clinically relevant electrocardiogram (ECG) abnormalities before study drug administration
Unstable gastrointestinal, renal, hepatic, endocrine or cardiovascular system diseases
Participants requiring invasive ventilation or tracheostomy
Participants requiring awake non-invasive ventilation or with awake hypoxemia (arterial oxygen saturation less than [<] 95 percent [%]) with or without ventilator support
Participants 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
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
Any inhibitor of cytochrome P450 (CYP) 3A4 and/or any Organic Cation Transporter 2 (OCT-2) and multidrug and toxin extrusion (MATE) substrates taken within 2 weeks and/or any inducer of CYP3A4 taken within 4 weeks (or within 5-times the elimination half-life, whichever is longer) prior to dosing or participants (and the mother, if breastfeeding the infant) taking any nutrients known to modulate CYP3A activity and any known flavin containing monooxygenase (FMO) 1 or FMO3 inhibitors or substrates
Prior use (at any time in the participants lives) and/or anticipated need for quinolones (chloroquine and hydroxychloroquine), thioridazine, vigabatrin, retigabine, or any other drug known to cause retinal toxicity during the study. Infants exposed to chloroquine, hydroxycholoroquine, 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
Therapeutic use, defined as use for 8 weeks or longer, of the following medications within 90 days prior to enrollment: riluzole, valproic acid, hydroxyurea, sodium phenylbutyrate, butyrate derivatives, creatine, carnitine, growth hormone, anabolic steroids, probenecid, agents anticipated to increase or decrease muscle strength, agents with known or presumed histone deacetylase (HDAC) inhibitory effect, medications known to or suspected of causing retinal toxicity (deferoxamine, topiramate, latanoprost, niacin, rosiglitazone, tamoxifen, canthaxanthine, sildenafil, and interferon) and medications with known phototoxicity liabilities (e.g., oral retinoids including over-the-counter [OTC] formulations, amiodarone, phenothiazines and use of minocycline)

Sites / Locations

Stanford University Medical Center
Ann and Robert H. Lurie Children Hospital of Chicago
Boston Childrens Hospital
Columbia University Medical Center; The Neurological Institute of New York
UZ Gent
UZ Leuven Gasthuisberg
Chr de La Citadelle
Instituto de Puericultura E Pediatria Martagão Gesteira
Hospital das Clinicas - FMUSP_X; Neurologia
Peking University First Hospital
Children's Hospital of Fudan University
Clinical Medical Center Zagreb; University Hospital Rebro Department of Paediatrics
Hopital Femme Mere Enfant; Medecine Physique et Readaptation Pediatrique ? L?ESCALE
Hopital Armand Trousseau
IRCCS Ospedale Pediatrico Bambino Gesù; U.O. Malattie Neuromuscolari e Neurodegenerative
Policlinico Agostino Gemelli; Dipartimento di Neuropsichiatria Infantile
IRCCS Istituto Giannina Gaslini; U.O.S.D. Centro di Miologia e Patologie Neurodegenerative
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico; Unità Operativa Complessa di Neurologia
Fondazione IRCCS Istituto Neurologico ?Carlo Besta?; UO di Neurologia dello Sviluppo
Hyogo Medical University Hospital
Szpital Gdanskiego Uniwersytetu Medycznego; Clinic of developmental neurology
The Children?s Memorial Health Institute Department of Neurology and Epileptology
Russian Children Neuromuscular Center of Veltischev
King Faisal Specialist Hospital and Research Centre Building
Institute for Mother and Child Dr. Vukan Cupic
Hospital Sant Joan De Deu
Hospital Universitari Vall d'Hebron; Area Genética Clínica y Molecular
Hospital Universitario Virgen del Rocio
Universitäts-Kinderspital (UKBB) Neuropädiatrie
Hacettepe University, School of Medicine; Pediatrics Department; Pediatrics Child Neurology Unit
Hospital Yeditepe University Kozyatagi; Pediatry
Ams of Ukraine; Inst. of Neurology, Psychiatry & Narcology

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Part 1 (Dose Finding): Risdiplam (RO7034067)

Part 2 (Confirmatory): Risdiplam (RO7034067)

Arm Description

Participants will receive multiple ascending doses of risdiplam (RO7034067), administered orally once daily for a minimum of 4 weeks to select the dose for Part 2. During the first year of treatment, most participants will switch to the Part 2 dose. During the second year of treatment, all Part 1 participants will be receiving the Part 2 dose. They will thereafter enter a 3-year open-label extension phase and continue to receive risdiplam at the same dose.

Participants will receive risdiplam (RO7034067), administered orally once daily at the dose defined in Part 1 of the study, for a duration of 24 months. They will thereafter enter a 3-year open-label extension phase and continue to receive risdiplam at the same dose.

Outcomes

Primary Outcome Measures

Part 1: Selected Part 2 Dose of Risdiplam

All safety, tolerability, PK and PD data available up to the clinical cut-off date of 5 January 2018, plus data that became available prior to the database snapshot on 6 February 2018 were included in the Internal Monitoring Committee (IMC) review. The IMC was responsible for selecting the dose for Part 2 of the study (pivotal dose). An external Independent Data Monitoring Committee (iDMC) reviewed data from Part 1 and confirmed the dose-selection decision of the IMC. The dose for Part 2 selected by the IMC was a dose that: 1.Was judged to be safe and well-tolerated, based on all available safety data from Part 1 and as confirmed by the iDMC; 2. Resulted in an exposure at steady-state below the exposure cap (mean value) of AUC0-24h,ss 2000 ng*h/mL (adjusted for free-fraction, if required); 3. Resulted in an SMN protein increase that was expected to be clinically relevant.

Part 2: Percentage of Infants Who Are Sitting Without Support for at Least 5 Seconds as Assessed by Item 22 of the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development Third Edition (BSID-III) at Month 12

The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 22 is not considered achieved if the infant sits alone for less than 5 seconds before losing balance and falling over, or if the infant uses his or her arms to prop him- or herself up. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.

Secondary Outcome Measures

Part 2: Percentage 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

The CHOP-INTEND instrument was developed to evaluate motor function in infants with SMA from the ages of 1.4 to 37.9 months. It consists of 16 items, where each item assesses a specific motor task graded on a scale of 0 to 4, where zero is no response and 4 is a complete response. The total score ranges from 0 to 64, with higher scores consistent with better motor function. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.

Part 2: Percentage of Infants Achieving an Increase of >/= 4 Points in Their CHOP-INTEND Score From Baseline at Months 8 and 12

Part 2: Percentage of Infants Achieving Head Control (Defined as a Score of >/= 3 for CHOP-INTEND Item 12) at Months 8, 12 and 24

Part 2: Change From Baseline in the Total Raw Score of the BSID-III Gross Motor Scale at Months 12 and 24

The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). In this study the gross motor scale was assessed in a modified way compared with the standard administration. A total raw score was calculated by summing the item scores to give a maximum possible score of 72.

Part 2: Percentage of Infants Who Achieve the Attainment Levels of a Subset of Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 8

The HINE was designed to evaluate infants between 2 months and 24 months of age. It is a simple and standardized instrument that includes 26 items assessing different aspects of neurological examinations, such as cranial nerves, posture, movements, tone, and reflexes. In this study, Module 2 of the HINE (HINE-2) was assessed. The HINE-2 evaluates 8 developmental milestones (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking) scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform a task and a score of 2, 3, or 4 (depending on the task) indicating full milestone development. The total score is calculated by summing the item scores to give a maximum possible score of 26. This measure represents subset numbers at Month 8 for head control, ability to kick and rolling milestones only.

Part 2: Percentage 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

Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24

Part 2: Percentage of Motor Milestone Responders as Assessed by HINE-2 at Months 12 and 24

The HINE-2 evaluates 8 developmental milestones scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform a task and a score of 2, 3, or 4 (depending on the task) indicating full milestone development. The total score is calculated by summing the item scores to give a maximum possible score of 26. For the motor milestone responder definition, an improvement in a motor milestone is defined as at least a 2-point increase in ability to kick (or maximal score) or a 1-point increase in head control, rolling, sitting, crawling, standing, or walking. Worsening is similarly defined as a 2-point decrease in ability to kick (or lowest score) or a 1-point decrease in head control, rolling, sitting, crawling, standing, or walking. Voluntary grasp is excluded from the definition. An infant is classified as a responder if more motor milestones show improvement than show worsening. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.

Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24

The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). This specific measure included 6 milestones: Item 9 'Controls head while upright for 15 seconds', Item 14 'Rolls from side to back', Item 22 'Sits without support for 5 seconds', Item 30 'Crawls on stomach', Item 40 'Stands alone' and Item 42 'Walks alone'. Reported here is the percentage of participants for whom the reported item was the highest item achieved out of these six items by Months 12 and 24.

Part 2: Percentage of Infants Who Are Sitting Without Support for at Least 5 Seconds as Assessed by Item 22 of the BSID-III Gross Motor Scale at Month 24

Part 2: Percentage of Infants Who Are Sitting Without Support for at Least 30 Seconds as Assessed by Item 26 of the BSID-III Gross Motor Scale at Month 24

The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 26 is not considered achieved if the infant sits alone for less than 30 seconds before losing balance and falling over, or if the infant uses his or her arms to prop him- or herself up. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.

Part 2: Percentage of Infants Who Are Standing Alone as Assessed by Item 40 of the BSID-III Gross Motor Scale at Month 24

The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Reported here is the percentage of participants who achieved item 40 'Stands alone' at Month 24. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.

Part 2: Percentage of Infants Who Are Walking Alone as Assessed by Item 42 of the BSID-III Gross Motor Scale at Month 24

The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Reported here is the percentage of participants who achieved item 42 'Walks alone' at Month 24. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.

Part 2: Time to Death

The median time to event was estimated using Kaplan-Meier methodology. 90% CI was estimated using the method of Brookmeyer and Crowley.

Part 2: Time to Death or Permanent Ventilation

Permanent ventilation is defined as >/=16 hours of non-invasive ventilation per day or intubation for >21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. The median time to event was estimated using Kaplan-Meier methodology. 90% CI was estimated using the method of Brookmeyer and Crowley.

Part 2: Time to Permanent Ventilation

Part 2: Percentage of Infants Who Are Alive Without Permanent Ventilation at Months 12 and 24

Permanent ventilation is defined as >/=16 hours of non-invasive ventilation per day or intubation for >21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation.

Part 2: Percentage of Infants Who Are Alive at Months 12 and 24

Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation.

Part 2: Percentage of Infants Who Are Without Permanent Ventilation at Months 12 and 24

Permanent ventilation is defined as >/=16 hours of non-invasive ventilation per day or intubation for >21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation.

Part 2: Percentage of Infants Who Achieve a Reduction of At Least 30 Degrees in Phase Angle From Baseline, as Measured by Respiratory Plethysmography (RP) at Month 12

RP measures the degree of synchrony between abdominal and thoracic cage-driven breathing. The weakness of intercostal muscles leads to asynchrony of the thorax with the diaphragm, resulting in inefficient and paradoxical breathing patterns. The degree of synchrony between the movement of the chest wall and abdomen during the respiratory cycle can be expressed as the phase angle between the two compartments and measured by placing two RP bands around the thorax and abdomen. In paradoxical breathing, the phase angle is reversed compared with the normal ventilation cycle. A phase angle of 0° indicates perfect in-phase movement, while a value of 180° indicates completely out-of-phase movement between the two compartments. In this measure, 8 or more valid breaths were used to determine the phase angle at each visit; the calculation was not performed if fewer than 8 valid breaths had been measured. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.

Part 2: Percentage of Infants Not Requiring Respiratory Support (Invasive or Non-Invasive) at Months 12 and 24

90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.

Part 2: Percentage of Infants Able to Feed Orally at Months 12 and 24

Able to feed orally includes participants fed orally and participants fed via a combination of oral and tube feeding. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.

Part 1 and Part 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

An adverse event (AE) is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.

Part 2: Number of Participants With AEs and SAEs Leading to Treatment Discontinuation

Part 2: Number of Participants With AEs and SAEs Leading to Treatment Modification/Interruption

Part 2: Anthropometric Examination of Weight Measured in Kilograms

Anthropometric examination included weight, height, head circumference and chest circumference.

Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeters

Anthropometric examination included weight, height, head circumference and chest circumference.

Part 2: Maximum Plasma Concentration (Cmax) of Risdiplam

Part 2: Area Under the Curve (AUC) of Risdiplam

Part 2: Concentration at the End of a Dosing Interval (Ctrough) of Risdiplam

Survival Motor Neuron (SMN) Protein Levels in Blood

Survival Motor Neuron (SMN) Messenger Ribonucleic Acid (mRNA) Levels in Blood

Full Information

NCT ID

NCT02913482

First Posted

September 21, 2016

Last Updated

October 5, 2023

Sponsor

Hoffmann-La Roche

1. Study Identification

Unique Protocol Identification Number

NCT02913482

Brief Title

Investigate Safety, Tolerability, PK, PD and Efficacy of Risdiplam (RO7034067) in Infants With Type1 Spinal Muscular Atrophy

Acronym

FIREFISH

Official Title

A Two Part Seamless, Open-label, Multicenter Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of Risdiplam (RO7034067) in Infants With Type 1 Spinal Muscular Atrophy

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

December 23, 2016 (Actual)

Primary Completion Date

November 14, 2019 (Actual)

Study Completion Date

November 17, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Hoffmann-La Roche

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Open-label, multi-center clinical study is to assess the safety, tolerability, pharmacokinetic (PK), pharmacodynamics (PD), and efficacy of Risdiplam (RO7034067) in infants with Type 1 spinal muscular atrophy (SMA). The study consists of two parts, an exploratory dose finding part (Part 1) and a confirmatory part (Part 2) which will investigate Risdiplam (RO7034067) for 24-months at the dose selected in Part 1.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Muscular Atrophy, Spinal

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2, Phase 3

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

62 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Part 1 (Dose Finding): Risdiplam (RO7034067)

Arm Type

Experimental

Arm Description

Arm Title

Part 2 (Confirmatory): Risdiplam (RO7034067)

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Risdiplam

Other Intervention Name(s)

RO7034067, Evrysdi

Intervention Description

Risdiplam will be administered orally.

Primary Outcome Measure Information:

Title

Part 1: Selected Part 2 Dose of Risdiplam

Description

Time Frame

Minimum of 2 weeks at steady state exposure

Title

Description

Time Frame

Month 12

Secondary Outcome Measure Information:

Title

Part 2: Percentage 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

Description

Time Frame

Month 12

Title

Part 2: Percentage of Infants Achieving an Increase of >/= 4 Points in Their CHOP-INTEND Score From Baseline at Months 8 and 12

Description

Time Frame

Month 8, Month 12

Title

Part 2: Percentage of Infants Achieving Head Control (Defined as a Score of >/= 3 for CHOP-INTEND Item 12) at Months 8, 12 and 24

Description

Time Frame

Month 8, Month 12, Month 24

Title

Part 2: Change From Baseline in the Total Raw Score of the BSID-III Gross Motor Scale at Months 12 and 24

Description

The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). In this study the gross motor scale was assessed in a modified way compared with the standard administration. A total raw score was calculated by summing the item scores to give a maximum possible score of 72.

Time Frame

Baseline, Month 12, Month 24

Title

Part 2: Percentage of Infants Who Achieve the Attainment Levels of a Subset of Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 8

Description

Time Frame

Month 8

Title

Part 2: Percentage 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

Description

Time Frame

Month 12

Title

Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24

Description

Time Frame

Month 24

Title

Part 2: Percentage of Motor Milestone Responders as Assessed by HINE-2 at Months 12 and 24

Description

Time Frame

Month 12, Month 24

Title

Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24

Description

The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). This specific measure included 6 milestones: Item 9 'Controls head while upright for 15 seconds', Item 14 'Rolls from side to back', Item 22 'Sits without support for 5 seconds', Item 30 'Crawls on stomach', Item 40 'Stands alone' and Item 42 'Walks alone'. Reported here is the percentage of participants for whom the reported item was the highest item achieved out of these six items by Months 12 and 24.

Time Frame

Month 12, Month 24

Title

Part 2: Percentage of Infants Who Are Sitting Without Support for at Least 5 Seconds as Assessed by Item 22 of the BSID-III Gross Motor Scale at Month 24

Description

Time Frame

Month 24

Title

Part 2: Percentage of Infants Who Are Sitting Without Support for at Least 30 Seconds as Assessed by Item 26 of the BSID-III Gross Motor Scale at Month 24

Description

The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 26 is not considered achieved if the infant sits alone for less than 30 seconds before losing balance and falling over, or if the infant uses his or her arms to prop him- or herself up. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.

Time Frame

Month 24

Title

Part 2: Percentage of Infants Who Are Standing Alone as Assessed by Item 40 of the BSID-III Gross Motor Scale at Month 24

Description

The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Reported here is the percentage of participants who achieved item 40 'Stands alone' at Month 24. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.

Time Frame

Month 24

Title

Part 2: Percentage of Infants Who Are Walking Alone as Assessed by Item 42 of the BSID-III Gross Motor Scale at Month 24

Description

The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Reported here is the percentage of participants who achieved item 42 'Walks alone' at Month 24. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.

Time Frame

Month 24

Title

Part 2: Time to Death

Description

The median time to event was estimated using Kaplan-Meier methodology. 90% CI was estimated using the method of Brookmeyer and Crowley.

Time Frame

Up to 24 months (up to the Clinical Cut-off Date [CCOD] of 12 November 2020)

Title

Part 2: Time to Death or Permanent Ventilation

Description

Time Frame

Up to 24 months (up to the CCOD of 12 November 2020)

Title

Part 2: Time to Permanent Ventilation

Description

Time Frame

Up to 24 months (up to the CCOD of 12 November 2020)

Title

Part 2: Percentage of Infants Who Are Alive Without Permanent Ventilation at Months 12 and 24

Description

Permanent ventilation is defined as >/=16 hours of non-invasive ventilation per day or intubation for >21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation.

Time Frame

Month 12, Month 24

Title

Part 2: Percentage of Infants Who Are Alive at Months 12 and 24

Description

Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation.

Time Frame

Month 12, Month 24

Title

Part 2: Percentage of Infants Who Are Without Permanent Ventilation at Months 12 and 24

Description

Permanent ventilation is defined as >/=16 hours of non-invasive ventilation per day or intubation for >21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation.

Time Frame

Month 12, Month 24

Title

Part 2: Percentage of Infants Who Achieve a Reduction of At Least 30 Degrees in Phase Angle From Baseline, as Measured by Respiratory Plethysmography (RP) at Month 12

Description

Time Frame

Month 12

Title

Part 2: Percentage of Infants Not Requiring Respiratory Support (Invasive or Non-Invasive) at Months 12 and 24

Description

90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.

Time Frame

Month 12, Month 24

Title

Part 2: Percentage of Infants Able to Feed Orally at Months 12 and 24

Description

Able to feed orally includes participants fed orally and participants fed via a combination of oral and tube feeding. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.

Time Frame

Month 12, Month 24

Title

Part 1 and Part 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Description

Time Frame

From first dose of risdiplam up to a minimum of 24 months (CCOD of 12 November 2020)

Title

Part 2: Number of Participants With AEs and SAEs Leading to Treatment Discontinuation

Description

Time Frame

From first dose of risdiplam up to a minimum of 24 months (CCOD of 12 November 2020)

Title

Part 2: Number of Participants With AEs and SAEs Leading to Treatment Modification/Interruption

Description

Time Frame

From first dose of risdiplam up to a minimum of 24 months (CCOD of 12 November 2020)

Title

Part 2: Anthropometric Examination of Weight Measured in Kilograms

Description

Anthropometric examination included weight, height, head circumference and chest circumference.

Time Frame

Month 12, Month 24

Title

Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeters

Description

Anthropometric examination included weight, height, head circumference and chest circumference.

Time Frame

Month 12, Month 24

Title

Part 2: Maximum Plasma Concentration (Cmax) of Risdiplam

Time Frame

Day 1: predose, 2, 4, 6, 24 hours; Days 14, 119, 245, 364, 427, 490, 609, 728: predose, 4 hours; Days 28, 56, 182, 301, 546, 672: predose, 2, 4, 6 hours

Title

Part 2: Area Under the Curve (AUC) of Risdiplam

Time Frame

Day 1: predose, 2, 4, 6, 24 hours; Days 14, 119, 245, 364, 427, 490, 609, 728: predose, 4 hours; Days 28, 56, 182, 301, 546, 672: predose, 2, 4, 6 hours

Title

Part 2: Concentration at the End of a Dosing Interval (Ctrough) of Risdiplam

Time Frame

Predose on Days 2, 14, 28, 56, 119, 182, 301, 546, 672

Title

Survival Motor Neuron (SMN) Protein Levels in Blood

Time Frame

Days 1, 14 (Part 1 only), 28, 119, 245, 364, 609, 728

Title

Survival Motor Neuron (SMN) Messenger Ribonucleic Acid (mRNA) Levels in Blood

Time Frame

Days 1, 14 (Part 1 only), 28, 245, 364, 609, 728

10. Eligibility

Sex

All

Minimum Age & Unit of Time

1 Month

Maximum Age & Unit of Time

7 Months

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Clinical history, signs or symptoms attributable to Type 1 SMA with onset after 28 days but prior to the age of 3 months Gestational age of 37 to 42 weeks Confirmed diagnosis of 5q-autosomal recessive SMA Participants has two survival motor neuron 2 (SMN2) gene copies, as confirmed by central testing Body weight greater than or equal to (>=) third percentile for age, using appropriate country-specific guidelines 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 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 SMN2-targeting antisense oligonucleotide, 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 Presence of clinically relevant electrocardiogram (ECG) abnormalities before study drug administration Unstable gastrointestinal, renal, hepatic, endocrine or cardiovascular system diseases Participants requiring invasive ventilation or tracheostomy Participants requiring awake non-invasive ventilation or with awake hypoxemia (arterial oxygen saturation less than [<] 95 percent [%]) with or without ventilator support Participants 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 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 Any inhibitor of cytochrome P450 (CYP) 3A4 and/or any Organic Cation Transporter 2 (OCT-2) and multidrug and toxin extrusion (MATE) substrates taken within 2 weeks and/or any inducer of CYP3A4 taken within 4 weeks (or within 5-times the elimination half-life, whichever is longer) prior to dosing or participants (and the mother, if breastfeeding the infant) taking any nutrients known to modulate CYP3A activity and any known flavin containing monooxygenase (FMO) 1 or FMO3 inhibitors or substrates Prior use (at any time in the participants lives) and/or anticipated need for quinolones (chloroquine and hydroxychloroquine), thioridazine, vigabatrin, retigabine, or any other drug known to cause retinal toxicity during the study. Infants exposed to chloroquine, hydroxycholoroquine, 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 Therapeutic use, defined as use for 8 weeks or longer, of the following medications within 90 days prior to enrollment: riluzole, valproic acid, hydroxyurea, sodium phenylbutyrate, butyrate derivatives, creatine, carnitine, growth hormone, anabolic steroids, probenecid, agents anticipated to increase or decrease muscle strength, agents with known or presumed histone deacetylase (HDAC) inhibitory effect, medications known to or suspected of causing retinal toxicity (deferoxamine, topiramate, latanoprost, niacin, rosiglitazone, tamoxifen, canthaxanthine, sildenafil, and interferon) and medications with known phototoxicity liabilities (e.g., oral retinoids including over-the-counter [OTC] formulations, amiodarone, phenothiazines and use of minocycline)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Clinical Trials

Organizational Affiliation

Hoffmann-La Roche

Official's Role

Study Director

Facility Information:

Facility Name

Stanford University Medical Center

City

Palo Alto

State/Province

California

ZIP/Postal Code

94304

Country

United States

Facility Name

Ann and Robert H. Lurie Children Hospital of Chicago

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60611

Country

United States

Facility Name

Boston Childrens Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02115

Country

United States

Facility Name

Columbia University Medical Center; The Neurological Institute of New York

City

New York

State/Province

New York

ZIP/Postal Code

10032

Country

United States

Facility Name

UZ Gent

City

Gent

ZIP/Postal Code

9000

Country

Belgium

Facility Name

UZ Leuven Gasthuisberg

City

Leuven

ZIP/Postal Code

3000

Country

Belgium

Facility Name

Chr de La Citadelle

City

Liège

ZIP/Postal Code

4000

Country

Belgium

Facility Name

Instituto de Puericultura E Pediatria Martagão Gesteira

City

Rio de Janeiro

State/Province

ZIP/Postal Code

CEP 21941-912

Country

Brazil

Facility Name

Hospital das Clinicas - FMUSP_X; Neurologia

City

Sao Paulo

State/Province

ZIP/Postal Code

05403-000

Country

Brazil

Facility Name

Peking University First Hospital

City

Beijing City

ZIP/Postal Code

100034

Country

China

Facility Name

Children's Hospital of Fudan University

City

Shanghai

ZIP/Postal Code

201102

Country

China

Facility Name

Clinical Medical Center Zagreb; University Hospital Rebro Department of Paediatrics

City

Zagreb

ZIP/Postal Code

10000

Country

Croatia

Facility Name

Hopital Femme Mere Enfant; Medecine Physique et Readaptation Pediatrique ? L?ESCALE

City

Bron

ZIP/Postal Code

69677

Country

France

Facility Name

Hopital Armand Trousseau

City

Paris

ZIP/Postal Code

75571

Country

France

Facility Name

IRCCS Ospedale Pediatrico Bambino Gesù; U.O. Malattie Neuromuscolari e Neurodegenerative

City

Roma

State/Province

Lazio

ZIP/Postal Code

00165

Country

Italy

Facility Name

Policlinico Agostino Gemelli; Dipartimento di Neuropsichiatria Infantile

City

Roma

State/Province

Lazio

ZIP/Postal Code

00168

Country

Italy

Facility Name

IRCCS Istituto Giannina Gaslini; U.O.S.D. Centro di Miologia e Patologie Neurodegenerative

City

Genova

State/Province

Liguria

ZIP/Postal Code

16147

Country

Italy

Facility Name

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico; Unità Operativa Complessa di Neurologia

City

Milano

State/Province

Lombardia

ZIP/Postal Code

20122

Country

Italy

Facility Name

Fondazione IRCCS Istituto Neurologico ?Carlo Besta?; UO di Neurologia dello Sviluppo

City

Milano

State/Province

Lombardia

ZIP/Postal Code

20133

Country

Italy

Facility Name

Hyogo Medical University Hospital

City

Hyogo

ZIP/Postal Code

663-8501

Country

Japan

Facility Name

Szpital Gdanskiego Uniwersytetu Medycznego; Clinic of developmental neurology

City

Gda?sk

ZIP/Postal Code

80-952

Country

Poland

Facility Name

The Children?s Memorial Health Institute Department of Neurology and Epileptology

City

Warszawa

ZIP/Postal Code

04-730

Country

Poland

Facility Name

Russian Children Neuromuscular Center of Veltischev

City

Moscow

State/Province

Moskovskaja Oblast

ZIP/Postal Code

125412

Country

Russian Federation

Facility Name

King Faisal Specialist Hospital and Research Centre Building

City

Riyadh

ZIP/Postal Code

11211

Country

Saudi Arabia

Facility Name

Institute for Mother and Child Dr. Vukan Cupic

City

Belgrade

ZIP/Postal Code

11000

Country

Serbia

Facility Name

Hospital Sant Joan De Deu

City

Esplugues De Llobregas

State/Province

Barcelona

ZIP/Postal Code

08950

Country

Spain

Facility Name

Hospital Universitari Vall d'Hebron; Area Genética Clínica y Molecular

City

Barcelona

ZIP/Postal Code

08035

Country

Spain

Facility Name

Hospital Universitario Virgen del Rocio

City

Sevilla

ZIP/Postal Code

41013

Country

Spain

Facility Name

Universitäts-Kinderspital (UKBB) Neuropädiatrie

City

Basel

ZIP/Postal Code

4005

Country

Switzerland

Facility Name

Hacettepe University, School of Medicine; Pediatrics Department; Pediatrics Child Neurology Unit

City

Ankara

ZIP/Postal Code

06100

Country

Turkey

Facility Name

Hospital Yeditepe University Kozyatagi; Pediatry

City

Atasehir- Istanbul

ZIP/Postal Code

34752

Country

Turkey

Facility Name

Ams of Ukraine; Inst. of Neurology, Psychiatry & Narcology

City

Kharkov

ZIP/Postal Code

61068

Country

Ukraine

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

Citations:

PubMed Identifier

36244364

Citation

Masson R, Mazurkiewicz-Beldzinska M, Rose K, Servais L, Xiong H, Zanoteli E, Baranello G, Bruno C, Day JW, Deconinck N, Klein A, Mercuri E, Vlodavets D, Wang Y, Dodman A, El-Khairi M, Gorni K, Jaber B, Kletzl H, Gaki E, Fontoura P, Darras BT; FIREFISH Study Group. Safety and efficacy of risdiplam in patients with type 1 spinal muscular atrophy (FIREFISH part 2): secondary analyses from an open-label trial. Lancet Neurol. 2022 Dec;21(12):1110-1119. doi: 10.1016/S1474-4422(22)00339-8. Epub 2022 Oct 14.

Results Reference

derived

PubMed Identifier

35906608

Citation

Cances C, Vlodavets D, Comi GP, Masson R, Mazurkiewicz-Beldzinska M, Saito K, Zanoteli E, Dodman A, El-Khairi M, Gorni K, Gravestock I, Hoffart J, Scalco RS, Darras BT; ANCHOVY Working Group. Natural history of Type 1 spinal muscular atrophy: a retrospective, global, multicenter study. Orphanet J Rare Dis. 2022 Jul 29;17(1):300. doi: 10.1186/s13023-022-02455-x.

Results Reference

derived

PubMed Identifier

34320287

Citation

Darras BT, Masson R, Mazurkiewicz-Beldzinska M, Rose K, Xiong H, Zanoteli E, Baranello G, Bruno C, Vlodavets D, Wang Y, El-Khairi M, Gerber M, Gorni K, Khwaja O, Kletzl H, Scalco RS, Fontoura P, Servais L; FIREFISH Working Group. Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls. N Engl J Med. 2021 Jul 29;385(5):427-435. doi: 10.1056/NEJMoa2102047.

Results Reference

derived

PubMed Identifier

33626251

Citation

Baranello G, Darras BT, Day JW, Deconinck N, Klein A, Masson R, Mercuri E, Rose K, El-Khairi M, Gerber M, Gorni K, Khwaja O, Kletzl H, Scalco RS, Seabrook T, Fontoura P, Servais L; FIREFISH Working Group. Risdiplam in Type 1 Spinal Muscular Atrophy. N Engl J Med. 2021 Mar 11;384(10):915-923. doi: 10.1056/NEJMoa2009965. Epub 2021 Feb 24.

Results Reference

derived

Links:

URL

http://roche-sma-clinicaltrials.com

Description

roche-sma-clinicaltrials.com provides information about the Roche Firefish clinical trial NCT02913482 and molecule being investigated in SMA.

Learn more about this trial

Investigate Safety, Tolerability, PK, PD and Efficacy of Risdiplam (RO7034067) in Infants With Type1 Spinal Muscular Atrophy

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