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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 62
- 试验地点
- 32
- 主要终点
- 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
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Month 至 7 Months（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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)
研究组 & 干预措施
Part 1 (Dose Finding): Risdiplam (RO7034067)
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.
干预措施: Risdiplam (Drug)
Part 2 (Confirmatory): Risdiplam (RO7034067)
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.
干预措施: Risdiplam (Drug)
结局指标
主要结局
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
时间窗: 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.
Part 1: Selected Part 2 Dose of Risdiplam
时间窗: Minimum of 2 weeks at steady state exposure
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.
次要结局
- Part 2: Anthropometric Examination of Weight Measured in Kilograms(Month 12, Month 24)
- Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeters(Month 12, Month 24)
- Part 2: Percentage of Infants Achieving an Increase of >/= 4 Points in Their CHOP-INTEND Score From Baseline at Months 8 and 12(Month 8, 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(Month 24)
- Part 2: Time to Death or Permanent Ventilation(Up to 24 months)
- Part 2: Percentage of Infants Able to Feed Orally at Months 12 and 24(Month 12, Month 24)
- Part 2: Number of Participants With AEs and SAEs Leading to Treatment Modification/Interruption(From first dose up to 30 days after last dose of risdiplam (up to 60 months))
- Part 2: Maximum Plasma Concentration (Cmax) of Risdiplam(Day 1: 2, 4, 6, 24 hours post dose; Days 14, 119, 245, 364, 427, 490, 609, 728: predose ; Days 28, 56, 182, 301, 546, 672: predose, 2, 4, 6 hours post dose)
- Part 2: Concentration at the End of a Dosing Interval (Ctrough) of Risdiplam at Year 5(Predose at Year 5)
- Part 2: Change From Baseline in the Total Raw Score of the BSID-III Gross Motor Scale at Months 12 and 24(Baseline, Month 12, 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(Month 12)
- Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24(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(Month 24)
- Part 2: Percentage of Infants Who Are Walking Alone as Assessed by Item 42 of the BSID-III Gross Motor Scale at Month 24(Month 24)
- Part 2: Time to Death(Up to 24 months)
- 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(Month 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(Month 8, 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(Month 8)
- Part 2: Percentage of Motor Milestone Responders as Assessed by HINE-2 at Months 12 and 24(Month 12, Month 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(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(Month 24)
- Part 2: Time to Permanent Ventilation(Up to 24 months)
- Part 2: Percentage of Infants Who Are Alive Without Permanent Ventilation at Months 12 and 24(Month 12, Month 24)
- Part 2: Percentage of Infants Who Are Alive at Months 12 and 24(Month 12, Month 24)
- Part 2: Percentage of Infants Who Are Without Permanent Ventilation at Months 12 and 24(Month 12, Month 24)
- Part 1 and Part 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)(From first dose up to 30 days after last dose of risdiplam (up to 60 months))
- Part 2: Number of Participants With AEs and SAEs Leading to Treatment Discontinuation(From first dose up to 30 days after last dose of risdiplam (up to 60 months))
- Part 2: Area Under the Curve (AUC) From 0 to 24 Hours of Risdiplam at Year 5 Visit(Year 5 visit: pre-dose)
- Part 2: Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood(Days 1, 28, 119, 245, 364, 609, 728, 819 and 1820)
- 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(Month 12)
- Part 2: Percentage of Infants Not Requiring Respiratory Support (Invasive or Non-Invasive) at Months 12 and 24(Month 12, Month 24)