Clinical trial NCT05115110: A Study to Investigate the Safety and Efficacy of RO7204239 in Combination With Risdiplam (RO7034067) in Participants With Spinal Muscular Atrophy
Official title: A Two-Part, Seamless, Multi-Center, Randomized, Placebo-Controlled, Double-Blind Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of RO7204239 in Combination With Risdiplam (RO7034067) in Patients With Spinal Muscular Atrophy
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Spinal Muscular Atrophy (SMA)
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2021-11-10
Enrollment: 259
Sex: ALL
Minimum age (years): 2
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Risdiplam works by helping the body produce more survival motor neuron (SMN) protein throughout the body. This means fewer motor neurons - nerve cells that pass impulses from nerves to muscles to cause movement - are lost, which may improve how well muscles work in people with SMA. RO7204239 is an investigational anti-myostatin antibody that is designed to target myostatin. Myostatin plays an important role in the regulation of skeletal muscle size by controlling growth. Inhibiting myostatin may help muscles grow in size and strength. RO7204239 in combination with risdiplam, which is designed to increase the amount of SMN protein throughout the body, has the potential to further improve motor function and clinical outcomes for people living with SMA.

This trial will study the safety and efficacy of RO7204239 in combination with risdiplam in patients with spinal muscular atrophy (SMA). The trial has two parts; Part 1 is the dose-finding part in SMA patients that are either ambulant (aged 2-10 years) or non-ambulant (aged 5-10 years) within separate cohorts, and Part 2 is the pivotal part in SMA patients aged 2-25 years that are ambulant.


Eligibility criteria: Inclusion Criteria:

* Age at screening: Part 1 Cohorts A (ambulant participants), B (ambulant participants), and D (non-ambulant participants): 5-10 years, inclusive; Part 1 Cohort C (ambulant participants): 2-4 years, inclusive; Part 2 (ambulant participants): 2-25 years, inclusive
* Participants who have a confirmed genetic diagnosis of 5q-autosomal recessive SMA
* Symptomatic SMA disease, as per investigator's clinical judgement
* Participants who have received previous SMA disease-modifying therapies may be included provided that: Onasemnogene abeparvovec was received at least 90 days prior to screening. Participants should be tapered off steroids prior to receiving risdiplam. In addition, participants should have normal levels of liver function tests, coagulatory parameters, platelets, and troponin-I at 90 days after administration of onasemnogene abeparvovec or at least 1 month after tapering off corticosteroids, whichever comes later; Nusinersen last dose was received at least 90 days prior to screening; Risdiplam is switched to the investigational medicinal product (IMP) provided by the site

Inclusion Criteria for Part 1 Cohorts A, B, and C and Part 2 only:

* Participants who are ambulant, where ambulant is defined as able to walk/run unassisted (i.e., without the use of assistive devices such as canes, walking sticks, crutches, walkers, person/hand-held assistance, braces, orthoses, over the malleoli insoles or any other type of support) 10 meters in ≤ 30 seconds as measures by the Timed 10-Meter Walk/Run Test \[10MWRT\] at screening

Inclusion Criteria for Part 1 Cohort D only:

* Participants who are able to sit, defined by: A score of 3 on Item 9 of the MFM32 (sitting without upper limb support while maintaining contact between the two hands for 5 seconds); A score of at least 2 on Item 10 of the MFM32 (while seated, leaning forward to touch a tennis ball and sitting back again, either with or without upper limb support)
* Participants who are able to raise a standardized plastic cup with a 200g weight in it to the mouth, using both hands if necessary, defined by a score of 3 on the entry item of the Revised Upper Limb Module (RULM)

Exclusion Criteria:

* Concomitant or 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 those who have completed a risdiplam study, or participated in a nusinersen or onasemnogene abeparvovec study
* Receiving or have received previous administration of anti-myostatin therapies
* Any history of cell therapy
* Hospitalization for a pulmonary event within the last 2 months or planned hospitalization at the time of screening
* Past surgery for scoliosis or hip fixation in the 6 months preceding screening or planned within the next 9 months (Part 1) or 21 months (Part 2)
* Unstable gastrointestinal, renal, hepatic, endocrine, or cardiovascular system diseases considered to be clinically significant
* Clinically significant ECG abnormalities at screening from average of triplicate measurement, abnormal findings at echocardiography, or cardiovascular disease indicating a safety risk for participants at the time of screening
* Any major illness within 1 month before screening
* Received any multidrug and toxin extrusion (MATE1/2K) substrates within 2 weeks before screening
* Hereditary fructose intolerance
* Used any of the following medications within 90 days prior to screening: riluzole, valproic acid, hydroxyurea, sodium phenylbutyrate, butyrate derivatives, creatine, carnitine, growth hormone, anabolic steroids, probenecid, acetyl cholinesterase inhibitors, agents that could potentially increase or decrease muscle strength, and agents with known or presumed histone deacetylase (HDAC) inhibitory effect
* Clinically significant abnormalities in laboratory test results at the time of screening
* Ascertained or presumptive hypersensitivity to RO7204239 or risdiplam, or to the constituents of its formulations
* Clinically relevant history of anaphylactic reaction requiring inotropic support
* Any abnormal skin conditions, pigmentation or lesions in the area intended for SC injection (abdomen) and that would prevent visualization of potential injection site reactions to RO7204239
* Immobilization, surgical procedures, fracture, or trauma to the upper or lower limbs within 90 days prior to screening

Exclusion Criteria for Part 1 Cohorts A and B only:

* Participants with contraindications for MRI scan (including, but not restricted to, claustrophobia, pacemaker, artificial heart valves, cochlear implants, presence of foreign metal objects in heart or body, including spinal rods, intracranial vascular clips, insulin pumps, etc.), difficulties maintaining a prolonged supine position, or any other clinical history or examination finding that would pose a potential hazard in combination with MRI

Exclusion Criteria for Part 1 Cohort D only:

* Participants who are unable to adopt the correct position to endure adequate quality of DXA scan acquisition, as determined by the DXA scan technologist
* Participants who have contractures at screening that would interfere with DXA scan acquisition or functional assessments, as confirmed by the DXA scan technologist and clinical evaluator
* For participants able to take steps only: Able to walk unassisted (i.e., without the use of assistive devices such as canes, walking sticks, crutches, walkers, person/hand held assistance, braces, orthoses, over the malleoli insoles or any other type of support) 10 meters in ≤ 30 seconds as measured by the timed 10MWRT at screening
* Participants who have severe scoliosis (curvature \> 40°) at screening based on the participant's most recent X-ray as performed per standard of care or scoliosis that would interfere with functional assessments, as confirmed by the clinical evaluator. An X-ray is not required if it is not clinically indicated (e.g., in participants with mild scoliosis)
* Participants who require invasive ventilation, tracheostomy, or the use of noninvasive ventilation (e.g., bilevel positive airway pressure) during the daytime

Primary outcomes:
measure: Part 1 - Percentage of participants with adverse events (AEs)
timeFrame: Up to 4.5 years
measure: Part 1 - Incidence of relevant echocardiographic parameter z scores > 2
timeFrame: Up to 4.5 years
measure: Part 1 - Serum concentration of RO7204239
timeFrame: Through Week 96
measure: Part 1 - Time to maximum serum concentration (Cmax) of RO7204239
timeFrame: Through Week 96
measure: Part 1 - Area under the curve (AUC) of RO7204239
timeFrame: Through Week 96
measure: Part 1 - Trough concentration (Ctrough) of RO7204239
timeFrame: Through Week 96
measure: Part 1 - Plasma concentration of risdiplam
timeFrame: Week 21
measure: Part 1 - Plasma concentration of risdiplam metabolite (M1)
timeFrame: Week 21
measure: Part 1 - Cmax of risdiplam
timeFrame: Week 21
measure: Part 1 - AUC of risdiplam
timeFrame: Week 21
measure: Part 1 - Ctrough of risdiplam
timeFrame: Week 21
measure: Part 1 - Incidence of anti-drug antibodies (ADAs)
timeFrame: Through Week 96
measure: Part 1 - Change from baseline in serum concentration of total myostatin
timeFrame: Through Week 85
measure: Part 1 - Change from baseline in serum concentration of free latent myostatin
timeFrame: Through Week 85
measure: Part 1 - Change from baseline in serum concentration of mature myostatin
timeFrame: Through Week 85
measure: Part 1 - Percent change from baseline in the contractile area of skeletal muscle in the dominant thigh muscles as assessed by magnetic resonance imaging (MRI) in participants aged at least 5 years
timeFrame: Week 24 of combination treatment
measure: Part 1 - Percent change from baseline in the contractile area of skeletal muscle in the dominant calf muscles as assessed by MRI in participants aged at least 5 years
timeFrame: Week 24 of combination treatment
measure: Part 2 - Change from baseline in Revised Hammersmith Scale (RHS) total score
timeFrame: Week 72 of combination treatment (study Week 80)
Secondary outcomes:
measure: Part 2 - Change from baseline in Motor Function Measure (MFM) Domain 1 + Domain 2 (D1 + D2) score
timeFrame: Week 72 of combination treatment (study Week 80)
measure: Part 2 - Change from baseline in MFM-32 total score
timeFrame: Week 72 of combination treatment (study Week 80)
measure: Part 2 - Change from baseline in time taken to rise from the floor as measured by RHS Item 25
timeFrame: Week 72 of combination treatment (study Week 80)
measure: Part 2 - Change from baseline in time taken to walk/run 10 meters as measured by RHS Item 19
timeFrame: Week 72 of combination treatment (study Week 80)
measure: Part 2 - Percent change from baseline in lean mass as assessed by full body dual energy X-ray absorptiometry (DXA) scan in participants aged at least 5 years
timeFrame: Week 72 of combination treatment (study Week 80)
measure: Part 2 - Percentage of participants with adverse events (AEs)
timeFrame: Up to 4.5 years
measure: Part 2 - Serum concentration of RO7204239
timeFrame: Through Week 80
measure: Part 2 - Cmax of RO7204239
timeFrame: Through Week 80
measure: Part 2 - AUC of RO7204239
timeFrame: Through Week 80
measure: Part 2 - Ctrough of RO7204239
timeFrame: Through Week 80
measure: Part 2 - Plasma concentration of risdiplam
timeFrame: Week 32
measure: Part 2 - Plasma concentration of risdiplam metabolite (M1)
timeFrame: Week 32
measure: Part 2 - Cmax of risdiplam
timeFrame: Week 32
measure: Part 2 - AUC of risdiplam
timeFrame: Week 32
measure: Part 2 - Ctrough of risdiplam
timeFrame: Week 32
measure: Part 2 - Incidence of ADAs
timeFrame: Through Week 80
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: Denton
country: United States
facility: Neurology & Neuromuscular Care Center
state: Texas
city: Randwick
country: Australia
facility: Sydney Children's Hospital
state: New South Wales
city: Gent
country: Belgium
facility: UZ Gent
city: Liège
country: Belgium
facility: Chr de La Citadelle
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital
state: British Columbia
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: McGill University Health Centre - Glen Site
state: Quebec
city: Zagreb
country: Croatia
facility: Clinical Hospital Centre Zagreb
city: Roma
country: Italy
facility: 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 Istituto Neurologico ?Carlo Besta?
state: Lombardia
city: Milano
country: Italy
facility: Asst Grande Ospedale Metropolitano Niguarda
state: Lombardia
city: Ancona
country: Italy
facility: Ospedali Riuniti Torrette di Ancona
state: Marche
city: Hyogo
country: Japan
facility: Kobe University Hospital
city: Kagoshima
country: Japan
facility: Kagoshima University Hospital
city: Tokyo
country: Japan
facility: Center Hospital of the National Center for Global Health and Medicine
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: ?ód?
country: Poland
facility: Instytut Centrum Zdrowia Matki Polki
city: Gda?sk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Pozna?
country: Poland
facility: Uniwersytecki Szpital Kliniczny w Poznaniu
city: Warszawa
country: Poland
facility: Klinika Neurologii I Wydzialu Lekarskiego WUM w Warszawie
city: Warszawa
country: Poland
facility: Instytut Pomnik Centrum Zdrowia Dziecka
city: Lisboa
country: Portugal
facility: CHULC, E.P.E. - Hospital Dona Estefania
city: Lisboa
country: Portugal
facility: Hospital de Santa Maria
city: Esplugues De Llobregas
country: Spain
facility: Hospital Sant Joan De Deu
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Valencia
country: Spain
facility: Hospital Universitario la Fe
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
city: London
country: United Kingdom
facility: Great Ormond Street Hospital For Children
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: