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

NCT03032172 | Completed Phase 2 Results DMC FDA Drug

• 3 other identifiers: BP390542016-004184-392023-506739-14-00
• Study Type: interventional
• Target: 174
• Locations: 9 countries
• Sites: 24

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.

Conditions

Spinal Muscular Atrophy

Outcome Measures

Primary Outcomes (11)

• Number of Participants With Adverse Events (AEs)

  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.

  Baseline up to 5 years

• Number of Participants Who Discontinued Treatment Due to AEs

  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.

  Baseline up to 5 years

• Number of Participants With Shift in Puberty Status From Baseline

  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.

  Baseline, Week 52, 104, 156, 208 and 260

• Number of Participants With Protocol-defined Neurological Conditions (NC)

  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.

  Baseline up to Week 260

• Number of Participants With Emergence or Worsening of Symptoms as Assessed Using Columbia Suicide Severity Rating Scale (C-SSRS)

  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.

  Up to approximately 5 years

• Anthropometric Examination: Change From Baseline in Weight

  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.

  Baseline up to Week 260

• Anthropometric Examination: Change From Baseline in Height

  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.

  Baseline up to Week 260

• Anthropometric Examination: Change From Baseline in Head Circumference

  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.

  Baseline up to Week 208

• Maximum Plasma Concentration (Cmax) of Risdiplam

  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.

  Predose on Weeks 2, 4, 13, 26, 39, 52, 65, 91 and post-dose on Weeks 1, 4, 13, 52, 91 and 104

• Area Under the Concentration-Time Curve (AUC0-24h) of Risdiplam

  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.

  24 hours Postdose at Year 2 Visit

• Plasma Trough Concentration (Ctrough) of Risdiplam

  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.

  Predose at Year 5 visit

Secondary Outcomes (1)

• Survival of Motor Neuron (SMN) Protein Levels in Blood

  Baseline and Year 5

Study Arms (1)

Risdiplam

EXPERIMENTAL

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.

Drug: Risdiplam

Interventions

Risdiplam DRUG

Risdiplam will be administered orally once daily.

Also known as: RO7034067

Risdiplam

Eligibility Criteria

• Age: 6 Months - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (24)

Stanford University Medical Center

Palo Alto, California, 94304, United States

Location

Nemours Children's Hospital

Orlando, Florida, 32827, United States

Location

Boston Childrens Hospital

Boston, Massachusetts, 02115, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

UZ Gent

Ghent, 9000, Belgium

Location

UZ Leuven Gasthuisberg

Leuven, 3000, Belgium

Location

Hopital Femme Mere Enfant

Bron, 69677, France

Location

Hopital Roger Salengro

Lille, 59037, France

Location

CHRU de Montpellier, Hopital Gui de Chauliac

Montpellier, 34295, France

Location

Hôpital Necker-Enfants Malades

Paris, 75015, France

Location

Hopital des Enfants

Toulouse, 31059, France

Location

Universitätsklinikum Essen

Essen, 45147, Germany

Location

Universitätsklinikum Freiburg

Freiburg im Breisgau, 79106, Germany

Location

IRCCS Ospedale Pediatrico Bambino Gesù

Rome, Lazio, 00165, Italy

Location

Policlinico Agostino Gemelli

Rome, Lazio, 00168, Italy

Location

IRCCS Istituto Giannina Gaslini

Genoa, Liguria, 16147, Italy

Location

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, Lombardy, 20122, Italy

Location

UOSD Malattie Neurodegenerative

Messina, Sicily, 98125, Italy

Location

UMC Utrecht

Utrecht, 3584 CX, Netherlands

Location

Klinika Neurologii I Wydzialu Lekarskiego WUM w Warszawie

Warsaw, 02-097, Poland

Location

Universitäts-Kinderspital (UKBB) Neuropädiatrie

Basel, 4005, Switzerland

Location

Birmingham Heartlands Hospital

Birmingham, B9 5SS, United Kingdom

Location

UCL Institute of Child Health & Great Ormond Street Hospital for Children

London, WC1N 1EH, United Kingdom

Location

The Newcastle upon Tyne Hospitals NHS Foundation Trust

Newcastle upon Tyne, NE1 4LP, United Kingdom

Location

Related Publications (1)

• Cleary Y, Kletzl H, Grimsey P, Heinig K, Ogungbenro K, Silber Baumann HE, Frey N, Aarons L, Galetin A, Gertz M. Estimation of FMO3 Ontogeny by Mechanistic Population Pharmacokinetic Modelling of Risdiplam and Its Impact on Drug-Drug Interactions in Children. Clin Pharmacokinet. 2023 Jun;62(6):891-904. doi: 10.1007/s40262-023-01241-7. Epub 2023 May 6.

  PMID: 37148485 DERIVED

Related Links

• roche-sma-clinicaltrials.com provides information about the Roche Jewelfish clinical trial NCT03032172 and molecule being investigated in SMA.

MeSH Terms

Conditions

Muscular Atrophy, Spinal

Interventions

Risdiplam

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; Neuromuscular Diseases

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800 821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 24, 2017
• First Posted: January 26, 2017
• Study Start: March 3, 2017
• Primary Completion: February 7, 2025
• Study Completion: February 7, 2025
• Last Updated: October 1, 2025
• Results First Posted: October 1, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share

Locations

CH (1); GB (3); IT (5); US (4); BE (2); FR (5); DE (2); NL (1); PL (1)