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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT05115110




Registration number
NCT05115110
Ethics application status
Date submitted
1/11/2021
Date registered
10/11/2021

Titles & IDs
Public title
A Study to Investigate the Safety and Efficacy of RO7204239 in Combination With Risdiplam (RO7034067) in Participants With Spinal Muscular Atrophy
Scientific 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
Secondary ID [1] 0 0
BN42644
Universal Trial Number (UTN)
Trial acronym
MANATEE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Spinal Muscular Atrophy (SMA) 0 0
Condition category
Condition code
Musculoskeletal 0 0 0 0
Other muscular and skeletal disorders
Neurological 0 0 0 0
Other neurological disorders
Other 0 0 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - RO7204239
Treatment: Drugs - Placebo
Treatment: Drugs - Risdiplam

Experimental: RO7204239 + Risdiplam - Participants who have not previously been treated with risdiplam will receive risdiplam for at least 8 weeks prior to randomization into a treatment group (Part 1 only). Participants that have been treated with risdiplam for at least 8 continuous weeks immediately prior to joining the study may be immediately randomized to combination therapy, or join the study run-in period (the period between screening and randomization to a treatment group) where they will continue to receive risdiplam monotherapy until randomization.

Participants enrolled in Part 1 will receive RO7204239 (low or high dose) + risdiplam for 24 weeks, followed by RO7204239 + risdiplam for 72 weeks.

Participants enrolled in Part 2 will receive risdiplam for 8 weeks and then treatment with RO7204239 + risdiplam for 72 weeks.

Once the treatment period has completed (Part 1 or Part 2), participants will have the option of treatment with RO7204239 + risdiplam for 2 additional years.

Active comparator: Placebo + Risdiplam - Participants who have not previously been treated with risdiplam will receive risdiplam for at least 8 weeks prior to randomization into a treatment group (Part 1 only). Participants that have been treated with risdiplam for at least 8 continuous weeks immediately prior to joining the study may be immediately randomized to combination therapy, or join the study run-in period (the period between screening and randomization to a treatment group) where they will continue to receive risdiplam monotherapy until randomization.

Participants enrolled in Part 1 will receive placebo (low or high dose-matched) + risdiplam for 24 weeks, followed by RO7204239 + risdiplam for 72 weeks.

Participants enrolled in Part 2 will receive risdiplam for 8 weeks and then treatment with placebo + risdiplam for 72 weeks.

Once the treatment period has completed (Part 1 or Part 2), participants will have the option of treatment with RO7204239 + risdiplam for 2 additional years.


Treatment: Drugs: RO7204239
RO7204239 will administered every 4 weeks (Q4W) by subcutaneous (SC) injection into the abdomen.

RO7204239 will be investigated at low- and high-dose in Part 1.

Treatment: Drugs: Placebo
Placebo will be administered Q4W by SC injection into the abdomen.

Treatment: Drugs: Risdiplam
Risdiplam will be administered orally once daily (QD) for the duration of the study.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Part 1 - Percentage of participants with adverse events (AEs)
Timepoint [1] 0 0
Up to 4.5 years
Primary outcome [2] 0 0
Part 1 - Incidence of relevant echocardiographic parameter z scores > 2
Timepoint [2] 0 0
Up to 4.5 years
Primary outcome [3] 0 0
Part 1 - Serum concentration of RO7204239
Timepoint [3] 0 0
Through Week 96
Primary outcome [4] 0 0
Part 1 - Time to maximum serum concentration (Cmax) of RO7204239
Timepoint [4] 0 0
Through Week 96
Primary outcome [5] 0 0
Part 1 - Area under the curve (AUC) of RO7204239
Timepoint [5] 0 0
Through Week 96
Primary outcome [6] 0 0
Part 1 - Trough concentration (Ctrough) of RO7204239
Timepoint [6] 0 0
Through Week 96
Primary outcome [7] 0 0
Part 1 - Plasma concentration of risdiplam
Timepoint [7] 0 0
Week 21
Primary outcome [8] 0 0
Part 1 - Plasma concentration of risdiplam metabolite (M1)
Timepoint [8] 0 0
Week 21
Primary outcome [9] 0 0
Part 1 - Cmax of risdiplam
Timepoint [9] 0 0
Week 21
Primary outcome [10] 0 0
Part 1 - AUC of risdiplam
Timepoint [10] 0 0
Week 21
Primary outcome [11] 0 0
Part 1 - Ctrough of risdiplam
Timepoint [11] 0 0
Week 21
Primary outcome [12] 0 0
Part 1 - Incidence of anti-drug antibodies (ADAs)
Timepoint [12] 0 0
Through Week 96
Primary outcome [13] 0 0
Part 1 - Change from baseline in serum concentration of total myostatin
Timepoint [13] 0 0
Through Week 85
Primary outcome [14] 0 0
Part 1 - Change from baseline in serum concentration of free latent myostatin
Timepoint [14] 0 0
Through Week 85
Primary outcome [15] 0 0
Part 1 - Change from baseline in serum concentration of mature myostatin
Timepoint [15] 0 0
Through Week 85
Primary outcome [16] 0 0
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
Timepoint [16] 0 0
Week 24 of combination treatment
Primary outcome [17] 0 0
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
Timepoint [17] 0 0
Week 24 of combination treatment
Primary outcome [18] 0 0
Part 2 - Change from baseline in Revised Hammersmith Scale (RHS) total score
Timepoint [18] 0 0
Week 72 of combination treatment (study Week 80)
Secondary outcome [1] 0 0
Part 2 - Change from baseline in Motor Function Measure (MFM) Domain 1 + Domain 2 (D1 + D2) score
Timepoint [1] 0 0
Week 72 of combination treatment (study Week 80)
Secondary outcome [2] 0 0
Part 2 - Change from baseline in MFM-32 total score
Timepoint [2] 0 0
Week 72 of combination treatment (study Week 80)
Secondary outcome [3] 0 0
Part 2 - Change from baseline in time taken to rise from the floor as measured by RHS Item 25
Timepoint [3] 0 0
Week 72 of combination treatment (study Week 80)
Secondary outcome [4] 0 0
Part 2 - Change from baseline in time taken to walk/run 10 meters as measured by RHS Item 19
Timepoint [4] 0 0
Week 72 of combination treatment (study Week 80)
Secondary outcome [5] 0 0
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
Timepoint [5] 0 0
Week 72 of combination treatment (study Week 80)
Secondary outcome [6] 0 0
Part 2 - Percentage of participants with adverse events (AEs)
Timepoint [6] 0 0
Up to 4.5 years
Secondary outcome [7] 0 0
Part 2 - Serum concentration of RO7204239
Timepoint [7] 0 0
Through Week 80
Secondary outcome [8] 0 0
Part 2 - Cmax of RO7204239
Timepoint [8] 0 0
Through Week 80
Secondary outcome [9] 0 0
Part 2 - AUC of RO7204239
Timepoint [9] 0 0
Through Week 80
Secondary outcome [10] 0 0
Part 2 - Ctrough of RO7204239
Timepoint [10] 0 0
Through Week 80
Secondary outcome [11] 0 0
Part 2 - Plasma concentration of risdiplam
Timepoint [11] 0 0
Week 32
Secondary outcome [12] 0 0
Part 2 - Plasma concentration of risdiplam metabolite (M1)
Timepoint [12] 0 0
Week 32
Secondary outcome [13] 0 0
Part 2 - Cmax of risdiplam
Timepoint [13] 0 0
Week 32
Secondary outcome [14] 0 0
Part 2 - AUC of risdiplam
Timepoint [14] 0 0
Week 32
Secondary outcome [15] 0 0
Part 2 - Ctrough of risdiplam
Timepoint [15] 0 0
Week 32
Secondary outcome [16] 0 0
Part 2 - Incidence of ADAs
Timepoint [16] 0 0
Through Week 80

Eligibility
Key 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)
Minimum age
2 Years
Maximum age
25 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
2/06/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
27/06/2026
Actual
Sample size
Target
259
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
Sydney Children's Hospital; CENTRE FOR CHILD HEALTH RESEARCH & INNOVATION (CHeRI) - Randwick
Recruitment postcode(s) [1] 0 0
2031 - Randwick
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Massachusetts
Country [2] 0 0
United States of America
State/province [2] 0 0
New York
Country [3] 0 0
United States of America
State/province [3] 0 0
Texas
Country [4] 0 0
Belgium
State/province [4] 0 0
Gent
Country [5] 0 0
Belgium
State/province [5] 0 0
Liège
Country [6] 0 0
Canada
State/province [6] 0 0
British Columbia
Country [7] 0 0
Canada
State/province [7] 0 0
Ontario
Country [8] 0 0
Canada
State/province [8] 0 0
Quebec
Country [9] 0 0
Croatia
State/province [9] 0 0
Zagreb
Country [10] 0 0
Italy
State/province [10] 0 0
Lazio
Country [11] 0 0
Italy
State/province [11] 0 0
Liguria
Country [12] 0 0
Italy
State/province [12] 0 0
Lombardia
Country [13] 0 0
Italy
State/province [13] 0 0
Marche
Country [14] 0 0
Japan
State/province [14] 0 0
Hyogo
Country [15] 0 0
Japan
State/province [15] 0 0
Kagoshima
Country [16] 0 0
Japan
State/province [16] 0 0
Tokyo
Country [17] 0 0
Netherlands
State/province [17] 0 0
Utrecht
Country [18] 0 0
Poland
State/province [18] 0 0
?ód?
Country [19] 0 0
Poland
State/province [19] 0 0
Gda?sk
Country [20] 0 0
Poland
State/province [20] 0 0
Pozna?
Country [21] 0 0
Poland
State/province [21] 0 0
Warszawa
Country [22] 0 0
Portugal
State/province [22] 0 0
Lisboa
Country [23] 0 0
Spain
State/province [23] 0 0
Barcelona
Country [24] 0 0
Spain
State/province [24] 0 0
Madrid
Country [25] 0 0
Spain
State/province [25] 0 0
Valencia
Country [26] 0 0
United Kingdom
State/province [26] 0 0
Birmingham
Country [27] 0 0
United Kingdom
State/province [27] 0 0
London
Country [28] 0 0
United Kingdom
State/province [28] 0 0
Oxford

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Hoffmann-La Roche
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clinical Trials
Address 0 0
Hoffmann-La Roche
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Reference Study ID Number: BN42644 https://forpatients.roche.com/
Address 0 0
Country 0 0
Phone 0 0
888-662-6728
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).
When will data be available (start and end dates)?
Available to whom?
Available for what types of analyses?
How or where can data be obtained?


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT05115110