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Investigate Safety, Tolerability, PK, PD and Efficacy of Risdiplam (RO7034067) in Infants With Type1 Spinal Muscular Atrophy (FIREFISH)

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ClinicalTrials.gov Identifier: NCT02913482
Recruitment Status : Active, not recruiting
First Posted : September 23, 2016
Last Update Posted : June 5, 2019
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Brief Summary:
Open-label, multi-center clinical study is to assess the safety, tolerability, pharmacokinetic (PK), pharmacodynamics (PD), and efficacy of Risdiplam (RO7034067) in infants with Type 1 spinal muscular atrophy (SMA). The study consists of two parts, an exploratory dose finding part (Part 1) and a confirmatory part (Part 2) which will investigate Risdiplam (RO7034067) for 24-months at the dose selected in Part 1.

Condition or disease Intervention/treatment Phase
Muscular Atrophy, Spinal Drug: Risdiplam Phase 2 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Two Part Seamless, Open-label, Multicenter Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of RO7034067 in Infants With Type 1 Spinal Muscular Atrophy
Actual Study Start Date : December 24, 2016
Estimated Primary Completion Date : November 17, 2023
Estimated Study Completion Date : November 17, 2023


Arm Intervention/treatment
Experimental: Part 1 (Dose Finding): Risdiplam (RO7034067)
Participants will receive multiple ascending doses of Risdiplam (RO7034067), administered orally once daily for 4 weeks followed by open-label extension phase.
Drug: Risdiplam
Risdiplam will be administered orally.
Other Name: RO7034067

Experimental: Part 2 (Confirmatory): Risdiplam (RO7034067)
Participants will receive Risdiplam (RO7034067), administered orally at the dose defined in Part 1 of the study. Treatments will continue maximum up to 24-months.
Drug: Risdiplam
Risdiplam will be administered orally.
Other Name: RO7034067




Primary Outcome Measures :
  1. Recommended Part 2 Dose of Risdiplam [ Time Frame: 2 weeks ]
  2. Part 2: Percentage of Infants who are Sitting Without Support at 12-months of Treatment Assessed by the Gross Motor Scale of the Bayley Scales of Infant and Toddler development Third Edition (BSID-III) [ Time Frame: Month 12 ]

Secondary Outcome Measures :
  1. Percentage of Participants With Adverse Events (AE) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to 25 months ]
  2. Part 1: Maximum Plasma Concentration (Cmax) of Risdiplam [ Time Frame: Pre-dose (PrD) (Hour 0) and 2, 4, 6, hour post-dose (PoD) on Days 1, 28, 84, 364, 546, 728; PrD on Day 2; PrD and 4 hours PoD on Days 7, 14, 56, 119, 182, 245, 301, 427, 490, 609, 672 ]
  3. Part 2: Maximum Plasma Concentration (Cmax) of Risdiplam [ Time Frame: 2, 4, 6, hours PoD on Day 1; PrD (Hour 0) on Days 2, 14, 119, 245, 364, 427, 490, 609, 728; PrD and 2, 4, 6 hours PoD on Days 28, 56, 182, 301, 546, 672 ]
  4. Part 1: Area Under the Curve (AUC) of Risdiplam [ Time Frame: PrD (Hour 0) and 2, 4, 6, hour PoD on Days 1, 28, 84, 364, 546, 728; PrD on Day 2; PrD and 4 hours PoD on Days 7, 14, 56, 119, 182, 245, 301, 427, 490, 609, 672 ]
  5. Part 2: Area Under the Curve (AUC) of Risdiplam [ Time Frame: 2, 4, 6, hours PoD on Day 1; PrD (Hour 0) on Days 2, 14, 119, 245, 364, 427, 490, 609, 728; PrD and 2, 4, 6 hours PoD on Days 28, 56, 182, 301, 546, 672 ]
  6. Part 1: Concentration at the end of a Dosing Interval (Ctrough) of Risdiplam [ Time Frame: PrD (Hour 0) Days 1, 2, 7, 14, 28, 56, 84, 119, 364, 546 ]
  7. Part 2: Concentration at the end of a Dosing Interval (Ctrough) of Risdiplam [ Time Frame: PrD (Hour 0) on Days 2, 14, 28, 56, 119, 182, 301, 546, 672 ]
  8. Time to Death [ Time Frame: Baseline up to 25 Months ]
  9. Time to Permanent Ventilation [ Time Frame: Month 12, Month 24 ]
  10. Survival of Motor Neuron (SMN) Protein Levels in Blood [ Time Frame: Days 1, 14 (Part 1 only), 28, 119, 245, 364, 609, 728 ]
  11. Survival Motor Neuron (SMN) Messenger Ribonucleic Acid (mRNA) Levels in Blood [ Time Frame: Days 1, 14 (Part 1 only), 28, 245, 364, 609, 728 ]
  12. Change From Baseline in the Total Raw Score of the BSID-III Gross Motor Scale at Month 12 and 24 [ Time Frame: Baseline, Month 12, Month 24 ]
  13. Percentage of Infants who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 and 24 [ Time Frame: Month 12, Month 24 ]
  14. Percentage of Infants who Achieve Highest Motor Milestone as Assessed in the BSID-III Gross Motor Scale [ Time Frame: Month 12, Month 24 ]
  15. Percentage of Infants who Achieve a Score of 40 or Higher in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) at Month 12 [ Time Frame: Month 12 ]
  16. Percentage of Infants who Achieve a Reduction of At Least 30 Degrees in Phase Angle From Baseline, as Measured by Respiratory Plethysmography (RP) at Month 12 [ Time Frame: Baseline, Month 12 ]
  17. Time to Death or Permanent Ventilation, Whichever Occurred First [ Time Frame: Baseline up to 25 Months ]
  18. Percentage of Infants who are Alive Without Permanent Ventilation at Month 12 and 24 [ Time Frame: Month 12, Month 24 ]
  19. Percentage of Infants who are Sitting Without Support for 5 Seconds at 24-months [ Time Frame: Month 24 ]
  20. Percentage of Infants who Stand Alone as Assessed in Item 40 of the BSID-III Gross Motor Scale at Month 24 [ Time Frame: Month 24 ]
  21. Percentage of Infants who Walk Alone as Assessed in Item 42 of the BSID-III Gross Motor Scale at Month 24 [ Time Frame: Month 24 ]
  22. Percentage of Infants who are Sitting Without Support for 30 Seconds at 24-months [ Time Frame: Month 24 ]
  23. Percentage of Infants that are Crawling at 24 Months [ Time Frame: Month 24 ]
  24. Proportion of Infants Achieving an Increase of >/= 4 Points from Baseline CHOP-INTEND Score [ Time Frame: Baseline, 8 Months, 12 Months ]
  25. Proportion of Infants Achieving Head Control (Defined as a Score of >/= 3 for CHOP-INTEND Item 12) [ Time Frame: 8, 12, and 24 Months ]
  26. Proportion of Infants not Requiring Respiratory Support (Invasive or Non-Invasive) at 12 and 24 Months [ Time Frame: Months 12, Month 24 ]
  27. Proportion of Infants Able to Feed Orally at 12 and 24 Months [ Time Frame: Month 12, Month 24 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   1 Month to 7 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Clinical history, signs or symptoms attributable to Type 1 SMA with onset after 28 days but prior to the age of 3 months
  • Gestational age of 37 to 42 weeks
  • Confirmed diagnosis of 5q-autosomal recessive SMA
  • Participants has two survival motor neuron 2 (SMN2) gene copies, as confirmed by central testing
  • Body weight greater than or equal to (>=) third percentile for age, using appropriate country-specific guidelines
  • Receiving adequate nutrition and hydration (with or without gastrostomy) at the time of screening, in the opinion of the Investigator
  • Adequately recovered from any acute illness at the time of screening and considered well-enough to participate in the opinion of the Investigator

Exclusion Criteria:

  • Concomitant or previous participation in any investigational drug or device study within 90 days prior to screening or 5 half-lives, whichever is longer
  • Concomitant or previous administration of SMN2-targeting antisense oligonucleotide, SMN2 splicing modifier or gene therapy study
  • Any history of cell therapy
  • Hospitalization for pulmonary event within the last 2 months, or planned at the time of screening
  • Presence of clinically relevant electrocardiogram (ECG) abnormalities before study drug administration
  • Unstable gastrointestinal, renal, hepatic, endocrine or cardiovascular system diseases
  • Participants requiring invasive ventilation or tracheostomy
  • Participants requiring awake non-invasive ventilation or with awake hypoxemia (arterial oxygen saturation less than [<] 95 percent [%]) with or without ventilator support
  • Participants with a history of respiratory failure or severe pneumonia, and have not fully recovered their pulmonary function at the time of screening
  • Multiple or fixed contractures and/or hip subluxation or dislocation at birth
  • Presence of non-SMA related concurrent syndromes or diseases
  • 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
  • Any inhibitor of cytochrome P450 (CYP) 3A4 and/or any Organic Cation Transporter 2 (OCT-2) and multidrug and toxin extrusion (MATE) substrates taken within 2 weeks and/or any inducer of CYP3A4 taken within 4 weeks (or within 5-times the elimination half-life, whichever is longer) prior to dosing or participants (and the mother, if breastfeeding the infant) taking any nutrients known to modulate CYP3A activity and any known flavin containing monooxygenase (FMO) 1 or FMO3 inhibitors or substrates
  • Prior use (at any time in the participants lives) and/or anticipated need for quinolones (chloroquine and hydroxychloroquine), thioridazine, vigabatrin, retigabine, or any other drug known to cause retinal toxicity during the study. Infants exposed to chloroquine, hydroxycholoroquine, thioridazine, vigabatrin, retigabine or drugs with known retinal toxicity given to mothers during pregnancy (and lactation) should not be enrolled.
  • Recent history (less than 6 months) of ophthalmic disease that would interfere with the conduct of the study as assessed by an ophthalmologist
  • Therapeutic use, defined as use for 8 weeks or longer, of the following medications within 90 days prior to enrollment: riluzole, valproic acid, hydroxyurea, sodium phenylbutyrate, butyrate derivatives, creatine, carnitine, growth hormone, anabolic steroids, probenecid, agents anticipated to increase or decrease muscle strength, agents with known or presumed histone deacetylase (HDAC) inhibitory effect, medications known to or suspected of causing retinal toxicity (deferoxamine, topiramate, latanoprost, niacin, rosiglitazone, tamoxifen, canthaxanthine, sildenafil, and interferon) and medications with known phototoxicity liabilities (e.g., oral retinoids including over-the-counter [OTC] formulations, amiodarone, phenothiazines and use of minocycline)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02913482


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Locations
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United States, California
Stanford University Medical Center
Palo Alto, California, United States, 94304
United States, Illinois
Ann and Robert H. Lurie Children Hospital of Chicago
Chicago, Illinois, United States, 60611
United States, Massachusetts
Boston Childrens Hospital
Boston, Massachusetts, United States, 02115
United States, New York
Columbia University Medical Center; The Neurological Institute of New York
New York, New York, United States, 10032
Belgium
UZ Gent
Gent, Belgium, 9000
UZ Leuven Gasthuisberg
Leuven, Belgium, 3000
Chr de La Citadelle
Liège, Belgium, 4000
Brazil
Instituto de Puericultura E Pediatria Martagão Gesteira
Rio de Janeiro, RJ, Brazil, CEP 21941-912
Hospital das Clinicas - FMUSP; Neurologia
Sao Paulo, SP, Brazil, 05403-000
China
Peking University First Hospital
Beijing City, China, 100034
Children's Hospital of Fudan University
Shanghai, China, 201102
Croatia
Clinical Medical Center Zagreb; University Hospital Rebro Department of Paediatrics
Zagreb, Croatia, 10000
France
Hopital Femme Mere Enfant; Medecine Physique et Readaptation Pediatrique - L'ESCALE
Bron, France, 69677
Hopital Armand Trousseau
Paris, France, 75571
Italy
IRCCS Ospedale Pediatrico Bambino Gesù; U.O. Malattie Neuromuscolari e Neurodegenerative
Roma, Lazio, Italy, 00165
Policlinico Agostino Gemelli; Dipartimento di Neuropsichiatria Infantile
Roma, Lazio, Italy, 00168
IRCCS Istituto Giannina Gaslini; U.O.S.D. Centro di Miologia e Patologie Neurodegenerative
Genova, Liguria, Italy, 16147
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico; Unità Operativa Complessa di Neurologia
Milano, Lombardia, Italy, 20122
Fondazione IRCCS Istituto Neurologico "Carlo Besta"; UO di Neurologia dello Sviluppo
Milano, Lombardia, Italy, 20133
Japan
Fukuoka Children's Hospital
Fukuoka, Japan, 813-0017
Hiroshima University Hospital
Hiroshima, Japan, 734-8551
Hyogo College of Medicine Hospital
Hyogo, Japan, 663-8501
Kagoshima City Hospital
Kagoshima, Japan, 890-8760
Shiga Medical Center for Children
Shiga, Japan, 524-0022
Center Hospital of the National Center for Global Health and Medicine
Tokyo, Japan, 162-8655
Poland
Szpital Gdanskiego Uniwersytetu Medycznego; Clinic of developmental neurology
Gdańsk, Poland, 80-952
The Children's Memorial Health Institute Department of Neurology and Epileptology
Warszawa, Poland, 04-730
Russian Federation
Russian Children Neuromuscular Center of Veltischev
Moscow, Moskovskaja Oblast, Russian Federation, 125412
Saudi Arabia
King Faisal Specialist Hospital and Research Centre Building
Riyadh, Saudi Arabia, 11211
Serbia
Institute for Mother and Child Dr. Vukan Cupic
Belgrade, Serbia, 11000
Spain
Hospital Sant Joan De Deu
Esplugues De Llobregas, Barcelona, Spain, 08950
Hospital Universitari Vall d'Hebron; Area Genética Clínica y Molecular
Barcelona, Spain, 08035
Hospital Universitario Virgen del Rocio
Sevilla, Spain, 41013
Switzerland
Universitäts-Kinderspitalbeider Basel_Abteilung für Neuro- und Entwicklungspädiatrie
Basel, Switzerland, 4005
Turkey
Hacettepe University, School of Medicine; Pediatrics Department; Pediatrics Child Neurology Unit
Ankara, Turkey, 06100
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche

Additional Information:
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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02913482     History of Changes
Other Study ID Numbers: BP39056
2016-000778-40 ( EudraCT Number )
First Posted: September 23, 2016    Key Record Dates
Last Update Posted: June 5, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Atrophy
Muscular Atrophy
Muscular Atrophy, Spinal
Pathological Conditions, Anatomical
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Spinal Cord Diseases
Central Nervous System Diseases
Motor Neuron Disease
Neurodegenerative Diseases
Neuromuscular Diseases