Clinical trial NCT03032172: A Study of Risdiplam (RO7034067) in Adult and Pediatric Participants With Spinal Muscular Atrophy
Official title: An Open-Label Study to Investigate the Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics of Risdiplam (RO7034067) in Adult and Pediatric Patients With Spinal Muscular Atrophy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Spinal Muscular Atrophy
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2017-01-26
Enrollment: 174
Sex: ALL
Minimum age (years): 6
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) with Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events Scale, V 4.0
timeFrame: Baseline up to 5 years
measure: Percentage of Participants With Emergence or Worsening of Symptoms As Assessed Using Columbia Suicide Severity Rating Scale (C-SSRS) (Adult Version for Adults and Adolescents, Pediatric Version for Patients Aged 6-11 Years)
timeFrame: Baseline up to 5 years
measure: Percentage of Participants With Protocol Defined Clinically Significant Changes in Ophthalmological Assessments
timeFrame: Baseline up to 5 years
measure: Percentage of Participants With Protocol Defined Clinically Significant Changes in Neurological Assessments
timeFrame: Baseline up to 5 years
measure: Tanner Staging Among all Participants Aged From 9 to 17 Years
timeFrame: Baseline up to 5 years
measure: Mean Plasma Concentration of Risdiplam
timeFrame: Up to 2 years
measure: Maximum Plasma Concentration (Cmax) of Risdiplam
timeFrame: Up to 2 years
measure: Area Under the Plasma Concentration Versus Curve (AUC) of Risdiplam
timeFrame: Up to 2 years
measure: Concentration of Risdiplam at the End of Dosing Interval (Ctrough)
timeFrame: Up to 2 years
measure: Mean Plasma Concentration of Risdiplam Metabolite
timeFrame: Up to 2 years
measure: Cmax of Risdiplam Metabolite
timeFrame: Up to 2 years
measure: AUC of Risdiplam Metabolite
timeFrame: Up to 2 years
measure: Ctrough of Risdiplam Metabolite
timeFrame: Up to 2 years
Secondary outcomes:
measure: SMN messenger Ribonucleic Acid (mRNA) Level in Blood
timeFrame: Up to 2 years
measure: SMN Protein Levels in Blood
timeFrame: Up to 2 years
Other outcomes:
Locations:
city: Orlando
country: United States
facility: Nemours Children's Hospital
state: Florida
city: Boston
country: United States
facility: Boston Childrens Hospital
state: Massachusetts
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Gent
country: Belgium
facility: UZ Gent
city: Leuven
country: Belgium
facility: UZ Leuven Gasthuisberg
city: Bron
country: France
facility: Hopital Femme Mere Enfant
city: Lille
country: France
facility: Hopital Roger Salengro
city: Montpellier
country: France
facility: CHRU de Montpellier, Hopital Gui de Chauliac
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Roma
country: Italy
facility: IRCCS Ospedale Pediatrico Bambino Gesù
state: Lazio
city: Roma
country: Italy
facility: Policlinico Agostino Gemelli
state: Lazio
city: Genova
country: Italy
facility: IRCCS Istituto Giannina Gaslini
state: Liguria
city: Milano
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
state: Lombardia
city: Messina
country: Italy
facility: UOSD Malattie Neurodegenerative
state: Sicilia
city: Utrecht
country: Netherlands
facility: UMC Utrecht
city: Warszawa
country: Poland
facility: Klinika Neurologii I Wydzialu Lekarskiego WUM w Warszawie
city: Basel
country: Switzerland
facility: Universitäts-Kinderspital (UKBB) Neuropädiatrie
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
city: London
country: United Kingdom
facility: UCL Institute of Child Health & Great Ormond Street Hospital for Children
city: Newcastle upon Tyne
country: United Kingdom
facility: The Newcastle upon Tyne Hospitals NHS Foundation Trust
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: