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

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ClinicalTrials.gov Identifier: NCT02913482
Recruitment Status : Recruiting
First Posted : September 23, 2016
Last Update Posted : August 2, 2018
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 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 RO7034067 for 24-months at the dose selected in Part 1.

Condition or disease Intervention/treatment Phase
Muscular Atrophy, Spinal Drug: RO7034067 Phase 2 Phase 3

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 : September 2, 2019
Estimated Study Completion Date : September 1, 2020


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

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




Primary Outcome Measures :
  1. Recommended Part 2 Dose of RO7034067 [ 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 RO7034067 [ 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 RO7034067 [ 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 RO7034067 [ 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 RO7034067 [ 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 RO7034067 [ 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 RO7034067 [ 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 ]


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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


Contacts
Contact: Reference Study ID Number: BP39056 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. and Canada) global-roche-genentech-trials@gene.com

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Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche

Additional Information:
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: August 2, 2018
Last Verified: July 2018

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

Additional relevant MeSH terms:
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