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

• Register: ClinicalTrials.gov
• Last refreshed on: 8 January 2024
• Main ID: NCT02913482
• Date of registration: 21/09/2016
• Prospective Registration: Yes
• Primary sponsor: Hoffmann-La Roche
• Public title: Investigate Safety, Tolerability, PK, PD and Efficacy of Risdiplam (RO7034067) in Infants With Type1 Spinal Muscular Atrophy FIREFISH
• Scientific 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
• Date of first enrolment: December 23, 2016
• Target sample size: 62
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/ct2/show/NCT02913482
• Study type: Interventional
• Study design: Allocation: Non-Randomized. Intervention model: Sequential Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 2

Countries of recruitment

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

Contacts

• Name: Clinical Trials
• Affiliation: Hoffmann-La Roche

Key inclusion & exclusion 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)



Age minimum: 1 Month
Age maximum: 7 Months
Gender: All

Health Condition(s) or Problem(s) studied

Muscular Atrophy, Spinal

Intervention(s)

Drug: Risdiplam

Primary Outcome(s)

Part 1: Selected Part 2 Dose of Risdiplam [Time Frame: Minimum of 2 weeks at steady state exposure]

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 [Time Frame: Month 12]

Secondary Outcome(s)

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

Part 1 and Part 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [Time Frame: From first dose of risdiplam up to a minimum of 24 months (CCOD of 12 November 2020)]

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]

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

Part 2: Percentage of Infants Not Requiring Respiratory Support (Invasive or Non-Invasive) at Months 12 and 24 [Time Frame: Month 12, Month 24]

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 [Time Frame: Month 12]

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 [Time Frame: Month 24]

Part 2: Percentage of Infants Able to Feed Orally at Months 12 and 24 [Time Frame: Month 12, 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 [Time Frame: Month 24]

Part 2: Anthropometric Examination of Weight Measured in Kilograms [Time Frame: Month 12, Month 24]

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]

Part 2: Change From Baseline in the Total Raw Score of the BSID-III Gross Motor Scale at Months 12 and 24 [Time Frame: Baseline, Month 12, Month 24]

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 [Time Frame: Month 8]

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 [Time Frame: Month 8, Month 12, Month 24]

Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeters [Time Frame: Month 12, Month 24]

Part 2: Time to Death [Time Frame: Up to 24 months (up to the Clinical Cut-off Date [CCOD] of 12 November 2020)]

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]

Part 2: Number of Participants With AEs and SAEs Leading to Treatment Modification/Interruption [Time Frame: From first dose of risdiplam up to a minimum of 24 months (CCOD of 12 November 2020)]

Part 2: Percentage of Motor Milestone Responders as Assessed by HINE-2 at Months 12 and 24 [Time Frame: Month 12, Month 24]

Part 2: Time to Death or Permanent Ventilation [Time Frame: Up to 24 months (up to the CCOD of 12 November 2020)]

Part 2: Time to Permanent Ventilation [Time Frame: Up to 24 months (up to the CCOD of 12 November 2020)]

Part 2: Number of Participants With AEs and SAEs Leading to Treatment Discontinuation [Time Frame: From first dose of risdiplam up to a minimum of 24 months (CCOD of 12 November 2020)]

Part 2: Percentage of Infants Who Are Alive at Months 12 and 24 [Time Frame: Month 12, Month 24]

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

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 [Time Frame: Month 12]

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

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 [Time Frame: Month 24]

Part 2: Percentage of Infants Who Are Without Permanent Ventilation at Months 12 and 24 [Time Frame: Month 12, Month 24]

Survival Motor Neuron (SMN) Protein Levels in Blood [Time Frame: Days 1, 14 (Part 1 only), 28, 119, 245, 364, 609, 728]

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 [Time Frame: Month 12]

Survival Motor Neuron (SMN) Messenger Ribonucleic Acid (mRNA) Levels in Blood [Time Frame: Days 1, 14 (Part 1 only), 28, 245, 364, 609, 728]

Part 2: Percentage of Infants Who Are Alive Without Permanent Ventilation at Months 12 and 24 [Time Frame: Month 12, Month 24]

Secondary ID(s)

BP39056

2016-000778-40

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 08/01/2021
• URL: https://clinicaltrials.gov/ct2/show/results/NCT02913482