A Study of Risdiplam (RO7034067) in Adult and Pediatric Participants With Spinal Muscular Atrophy

Phase 2

Completed

Conditions: Spinal Muscular Atrophy

Interventions: Drug: Risdiplam

Registration Number: NCT03032172

Lead Sponsor: Hoffmann-La Roche

Brief Summary: This is a multi-center, exploratory, non-comparative, and open-label study to investigate the safety, tolerability, PK, and PK/PD relationship of risdiplam in adults, children and infants with Spinal Muscular Atrophy (SMA) previously enrolled in Study BP29420 (Moonfish) with the splicing modifier RO6885247 or previously treated with nusinersen, olesoxime or AVXS-101.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 174

Inclusion Criteria

Confirmed diagnosis of 5q-autosomal recessive SMA
Previous enrollment in Study BP29420 (Moonfish) with the splicing modifier RO6885247 or previous treatment with any of the following: 1.) Nusinersen (defined as having received >= 4 doses of nusinersen, provided that the last dose was received >= 90 days prior to screening) or 2.) Olesoxime (provided that the last dose was received <= 12 months and >= 90 days prior to screening) or 3.) AVXS-101 (provided that the time of treatment was >= 12 months prior to screening)
Adequately recovered from any acute illness at the time of screening and considered well enough to participate in the opinion of the Investigator
For women of childbearing potential: negative blood pregnancy test at screening, agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating eggs for at least 28 days after the final dose of study drug
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm
For participants aged 2 years or younger at screening: 1.) Parent or caregiver of participant is willing to consider nasogastric, naso-jejunal or gastrostomy tube placement, as recommended by the Investigator, during the study to maintain safe hydration, nutrition and treatment delivery; 2.) Parent or caregiver of participant is willing to consider the use of non-invasive ventilation, as recommended by the Investigator during the study

Exclusion Criteria

Inability to meet study requirements
Concomitant participation in any investigational drug or device study
Previous participation in any investigational drug or device study within 90 days prior to screening, or 5 half-lives of the drug, whichever is longer with the exception of studies of olesoxime, AVXS-101, or nusinersen
Any history of gene or cell therapy, with the exception of AVXS-101
Unstable gastrointestinal, renal, hepatic, endocrine, or cardiovascular system diseases as considered to be clinically significant by the Investigator
Inadequate venous or capillary blood access for the study procedures, in the opinion of the Investigator
For patients aged < 2 years, hospitalization for a pulmonary event within 2 months prior to screening and pulmonary function not fully recovered at the time of screening
Lactating women
Suspicion of regular consumption of drugs of abuse
For adults and adolescents only, positive urine test for drugs of abuse or alcohol at screening or Day -1 visit
Presence of clinically significant electrocardiogram (ECG) abnormalities before study drug administration from average of triplicate measurement or cardiovascular disease
History of malignancy if not considered cured
For participants aged > 6 years, significant risk for suicidal behavior, in the opinion of the Investigator as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)
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
Recently initiated treatment for spinal muscular atrophy (within <6 weeks prior to enrollment) with oral salbutamol or another beta 2-adrenergic agonist taken orally
Any prior use of chloroquine, hydroxychloroquine, retigabin, vigabatrin or thioridazine, is not allowed
Ascertained or presumptive hypersensitivity (e.g., anaphylactic reaction) to risdiplam or to the constituents of its formulation
Concomitant disease or condition that could interfere with, or treatment of which might interfere with, the conduct of the study, or that would, in the opinion of the Investigator, pose an unacceptable risk to the participant in this study
Recent history (less than one year) of ophthalmological diseases
Any prior use of an inhibitor or inducer of FMO1 or FMO3 taken within 2 weeks (or within 5 elimination half-lives, whichever is longer) prior to dosing

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Risdiplam	Risdiplam	Participants will receive multiple doses of risdiplam orally once daily for 24 months. After 24-month treatment, participants will be offered the opportunity to enter the open-label extension (OLE) phase for 3 years.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events (AEs)	Baseline up to 5 years	An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Number of Participants Who Discontinued Treatment Due to AEs	Baseline up to 5 years	An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Participants who discontinued treatment due to AEs are reported here.
Number of Participants With Shift in Puberty Status From Baseline	Baseline, Week 52, 104, 156, 208 and 260	Tanner staging of sexual development is a scale used to assess physical maturation as children transition through adolescence into adulthood. Scale defines physical development based on the following characteristics: pubic hair, penis, and testes development in boys; and pubic hair and breast development in girls. It consists of 5 stages, Stage I (prepubertal) to Stage V (mature adult). Participants under 9 years at screening began Tanner staging assessments at 1st visit following their 9th birthday. Tanner data are presented in three categories: Normal (expected stage of puberty based on participant's age at post-baseline visit), Delayed (pubertal development is behind expectations for age at post-baseline visit), \& Missing (participant did not attend scheduled visit). Tanner staging assessments were scheduled for participants aged 9-17 years but were also conducted in some older participants, up to age 22. Shift in puberty status from baseline to each week has been represented here.
Number of Participants With Protocol-defined Neurological Conditions (NC)	Baseline up to Week 260	Neurological examination was performed by asking questions to the participants and/or their caregiver, as well as observing the participants' behavior in general and while performing certain tasks. Questions and tasks were adapted to the age and motor ability of the participant. For very young participants, observing reaction to a sound, speech development, shifting attention to a newly introduced toy, observing the participant interact with the parent/caregiver \& for older participants examination of social interaction (school, friends, activities, job as appropriate), memory (e.g., with short word recall), reasoning \& language, drawing, etc. Participants with neurological conditions besides those expected with SMA and those expected with SMA are reported.
Number of Participants With Emergence or Worsening of Symptoms as Assessed Using Columbia Suicide Severity Rating Scale (C-SSRS)	Up to approximately 5 years	C-SSRS was used to assess the lifetime suicidality of a participant (baseline) as well as any new instances of suicidality (since last visit). The interview prompts recollection of suicidal ideation (SI), including the intensity of the ideation, behavior and attempts with actual/potential lethality. A modified and reduced version (pediatric version) was used for children (aged 6-11 years). Categories have binary responses (yes/no) \& include: Wish to be Dead; Non-specific Active Suicidal Thoughts; Active SI with Any Methods (Not Plan) without Intent to Act; Active SI with Some Intent to Act, without Specific Plan; Active SI with Specific Plan \& Intent, Preparatory Acts \& Behavior; Aborted Attempt; Interrupted Attempt; Actual Attempt (non-fatal); Completed Suicide. SI or behavior is indicated by a "yes" answer to any of the listed categories. A score of 0 is assigned if no suicide risk is present. A score of 1 or higher indicates SI or behavior.
Anthropometric Examination: Change From Baseline in Weight	Baseline up to Week 260	Weight was measured at baseline, Weeks 65, 91, and every 13 weeks thereafter for participants 2-17 years and at every visit for participants \<2 years. Per protocol, height was not measured at Day 7, Weeks 8, 17, 35, and thus not collected for all participants. No participants in the RO6885247 arm attended the Weeks 65, 169, 195, and 247 visit; none in the AVXS-101 arm attended the Week 247 visit. Symptom-directed height/weight assessments were done at clinically indicated visits as needed.
Anthropometric Examination: Change From Baseline in Height	Baseline up to Week 260	Height of all participants able to stand was measured while standing using a stadiometer, with at least 3 independent measurements, which were averaged. Participants unable to stand during the measurement, height was derived from measurement of ulna length. For very young children, height was measured with child in a lying position using an inflexible length board with fixed headboard \& movable footboard. Height was measured: baseline, Weeks 13,39,52,78 \& 104 for participants 2-17 years; Weeks 52 \& 104 for \>17 years \& every visit for participants \<2 years. After Week 104, measurements occurred every 26 weeks. Per protocol, height was not measured at Weeks 2,4,17,26,35,43,61,65,87,91,96,117,143,169,195,221 \&247 \& thus not collected for all participants. No participants \<17 years in RO6885247, Olesoxime, or AVXS-101 arms attended the Week 260 visit \& no participants in RO6885247 arm attended Week 39. Symptom-directed height assessments were done at clinically indicated visits as needed.
Anthropometric Examination: Change From Baseline in Head Circumference	Baseline up to Week 208	Head circumference for participants aged \< 5 years was measured to the nearest 0.1 cm using a flexible, non-stretchable tape. Head circumference was measured around the widest part of the head from the most prominent point on the back of the head (occiput) to the most prominent part of the forehead between the eyebrows. The measurement was repeated three times, and the largest measurement was recorded. Head circumference was assessed for participants \< 5 years of age. Since all participants in the RO6885247 and Olesoxime arms were \> 5 years, data were not collected for these arms. Head circumference was not collected at Weeks 35 and 61 (AVXS-101 arm) and Weeks 87, 182, and 208 (Nusinersen arm) because the protocol only required this measurement for participants \< 5 years of age. At these timepoints, neither of the participants \< 5 years attended the visit, and other participants may have been \> 5 years of age.
Maximum Plasma Concentration (Cmax) of Risdiplam	Predose on Weeks 2, 4, 13, 26, 39, 52, 65, 91 and post-dose on Weeks 1, 4, 13, 52, 91 and 104	As pre-specified in the protocol, the PK data were not to be compared between participants who received different prior treatments (RO6885247, nusinersen, olesoxime and AVXS-101) received before entering this study, but to analyze the PK parameters of risdiplam. Hence, PK data have been presented in a single arm group irrespective of prior therapies received by the participants in previous studies.
Area Under the Concentration-Time Curve (AUC0-24h) of Risdiplam	24 hours Postdose at Year 2 Visit	As pre-specified in the protocol, the PK data were not to be compared between participants who received different prior treatments (RO6885247, nusinersen, olesoxime and AVXS-101) received before entering this study, but to analyze the PK parameters of risdiplam. Hence, PK data have been presented in a single arm group irrespective of prior therapies received by the participants in previous studies.
Plasma Trough Concentration (Ctrough) of Risdiplam	Predose at Year 5 visit	As pre-specified in the protocol, the PK data were not to be compared between participants who received different prior treatments (RO6885247, nusinersen, olesoxime and AVXS-101) received before entering this study, but to analyze the PK parameters of risdiplam. Hence, PK data have been presented in a single arm group irrespective of prior therapies received by the participants in previous studies.

Secondary Outcome Measures

Name	Time	Method
Survival of Motor Neuron (SMN) Protein Levels in Blood	Baseline and Year 5	SMA is caused by a homozygous deletion or mutation of the SMN 1 gene, which encodes SMN, an essential protein expressed in both neuronal and non-neuronal cells. In humans, there are two SMN genes, the SMN1 gene and its paralog SMN2. Risdiplam directly targets the underlying molecular deficiency of the disease and promotes the inclusion of exon 7 to generate full-length SMN2 mRNA, which therefore increases the production of functional SMN protein. As pre-specified in the protocol, the PD data were not to be compared between participants who received different prior treatments, but to analyze the PD parameters of risdiplam. Hence, PD data have been presented in a single arm group irrespective of prior therapies received by the participants in previous studies.

Trial Locations

Locations (24): Stanford University Medical Center
🇺🇸
Palo Alto, California, United States
Hôpital Necker-Enfants Malades
🇫🇷
Paris, France
Hopital des Enfants
🇫🇷
Toulouse, France
Nemours Children's Hospital
🇺🇸
Orlando, Florida, United States
Boston Childrens Hospital
🇺🇸
Boston, Massachusetts, United States
Columbia University Medical Center
🇺🇸
New York, New York, United States
UZ Gent
🇧🇪
Ghent, Belgium
UZ Leuven Gasthuisberg
🇧🇪
Leuven, Belgium
Hopital Femme Mere Enfant
🇫🇷
Bron, France
Hopital Roger Salengro
🇫🇷
Lille, France
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Stanford University Medical Center
🇺🇸Palo Alto, California, United States