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A Study of DNL310 in Pediatric Subjects With Hunter Syndrome

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04251026
Recruitment Status : Recruiting
First Posted : January 31, 2020
Last Update Posted : September 3, 2020
Sponsor:
Information provided by (Responsible Party):
Denali Therapeutics Inc.

Brief Summary:

This is a multicenter, multiregional, open-label study to assess the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of DNL310, an investigational central nervous system (CNS)-penetrant enzyme replacement therapy (ERT), designed to treat both the peripheral and CNS manifestations of Mucopolysaccharidosis type II (MPS II; Hunter syndrome).

The study has two staggered cohorts: the first will enroll subjects with neuronopathic MPS II aged 5 to 10 years; and the second will enroll subjects with MPS II, either neuronopathic or non-neuronopathic, aged 2 to 18 years.

Subjects, whose physicians feel they are deriving benefit, will have the opportunity to be reconsented into a safety extension for continued evaluation, if implemented.


Condition or disease Intervention/treatment Phase
Mucopolysaccharidosis II Drug: DNL310 Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 16 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2, Multicenter, Open-Label Study to Determine the Safety, Pharmacokinetics, and Pharmacodynamics of DNL310 in Pediatric Subjects With Hunter Syndrome
Actual Study Start Date : July 16, 2020
Estimated Primary Completion Date : January 2023
Estimated Study Completion Date : January 2023


Arm Intervention/treatment
Experimental: Cohort A
Dose escalation followed by continuous dosing in subjects with neuronopathic MPS II
Drug: DNL310
Intravenous weekly administration

Experimental: Cohort B
Dose escalation followed by continuous dosing in subjects with non-neuronopathic MPS II, neuronopathic MPS II, or unknown phenotype
Drug: DNL310
Intravenous weekly administration




Primary Outcome Measures :
  1. Incidence and severity of adverse events (AEs) including infusion-related reactions (IRRs) [ Time Frame: 24 weeks ]
  2. Urine total glycosaminoglycan (GAG) concentrations [ Time Frame: 24 weeks ]

Secondary Outcome Measures :
  1. Change from baseline in cerebrospinal fluid (CSF) of heparan sulfate [ Time Frame: 24 weeks ]
  2. PK parameter: Maximum observed concentration (Cmax) of DNL310 in serum [ Time Frame: 24 weeks ]
  3. PK parameter: Trough concentration (Cmin) of DNL310 in serum [ Time Frame: 24 weeks ]
  4. PK parameter: Time to maximum observed concentration (Tmax) of DNL310 in serum [ Time Frame: 24 weeks ]
  5. PK parameter: Area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUC[0-last]) of DNL310 in serum [ Time Frame: 24 weeks ]
  6. PK parameter: Area under the concentration-time curve over a dosing interval (AUC[0-τ]) of DNL310 in serum [ Time Frame: 24 weeks ]
  7. PK parameter: Apparent terminal elimination rate constant (λz) of DNL310 in serum [ Time Frame: 24 weeks ]
  8. PK parameter: Apparent terminal elimination t½ of DNL310 in serum [ Time Frame: 24 weeks ]
  9. PK parameter: Accumulation ratio of DNL310 in serum [ Time Frame: 24 weeks ]
  10. Characterization of immunogenicity of DNL310 in serum, as measured by the incidence of anti-drug antibodies (ADAs) relative to baseline [ Time Frame: 24 weeks ]
  11. Change from baseline in urine concentration of heparan sulfate (HS) [ Time Frame: 24 weeks ]

Other Outcome Measures:
  1. Change from baseline in CSF of dermatan sulfate (DS) [ Time Frame: 24 weeks ]
  2. Change from baseline in urine concentration of DS [ Time Frame: 24 weeks ]
  3. Change from baseline in serum concentrations of HS and DS [ Time Frame: 24 weeks ]
  4. Change from baseline in levels of CSF biomarkers of lysosomal function [ Time Frame: 24 weeks ]
  5. Liver and spleen volumes as assessed by ultrasound [ Time Frame: 24 weeks ]
  6. Change from baseline in Clinical Global Impression-Severity (CGI-S) score [ Time Frame: 24 weeks ]
  7. Clinical Global Impression-Improvement (CGI-I) score [ Time Frame: 24 weeks ]
  8. Change from baseline in Parent/Caregiver Global Impression-Severity (PGI-S) score [ Time Frame: 24 weeks ]
  9. Parent/Caregiver Global Impression-Improvement (PGI-I) score [ Time Frame: 24 weeks ]
  10. Change from baseline in Activities of Daily Living for Hunter Syndrome (ADL-HS) score [ Time Frame: 24 weeks ]
  11. Change from baseline in stool consistency, per the Bristol Stool Scale [ Time Frame: 24 weeks ]
  12. Change from baseline in Six-Minute Walk Test (6MWT) for subjects ≥6 years old who are able to follow instructions at baseline [ Time Frame: 24 weeks ]
  13. Change from baseline in the toileting abilities percentage (TAP), as measured by the Toileting Abilities Survey (TAS) [ Time Frame: 24 weeks ]
  14. Change from baseline in auditory brainstem response (ABR) parameters [ Time Frame: 24 weeks ]
  15. Change from baseline in the cognitive-domain and the language- and motor-domain score and scores on either the Bayley Scales of Infant and Toddler Development (BSID-III) or the nonverbal index of the Kaufman Assessment Battery for Children (KABC-II) [ Time Frame: 24 weeks ]
  16. Change from baseline in the composite age-equivalent score and standard scores on the VABS-II [ Time Frame: 24 weeks ]
  17. Change from baseline in Infant and Toddler Quality of Life Questionnaire (ITQOL) for subjects <5 years of age [ Time Frame: 24 weeks ]
  18. Change from baseline in Childhood Health Questionnaire Parent Form (CHQ-PF28) for subjects ≥5 years of age [ Time Frame: 24 weeks ]
  19. Change from baseline in Pediatric Quality of Life Inventory Family Impact Module (PedsQL-FIM) [ Time Frame: 24 weeks ]


Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • Confirmed diagnosis of MPS II
  • Cohort A: Subjects aged 5 to 10 years with neuronopathic MPS II
  • Cohort B: Subjects aged 2 to 18 years with non-neuronopathic MPS II, neuronopathic MPS II, or unknown phenotype
  • For subjects receiving intravenous iduronate 2-sulfatase (IDS) ERT, tolerated a minimum of 4 months of therapy during the period immediately prior to screening.

Key Exclusion Criteria:

  • Unstable or poorly controlled medical condition(s) or significant medical or psychological comorbidity or comorbidities that, in the opinion of the investigator, would interfere with safe participation in the trial or interpretation of study assessments
  • Use of any CNS-targeted MPS II ERT within 3 months before study start for subjects aged ≥5 years, and within 6 months before study start for subjects aged <5 years.
  • Use of IDS gene therapy or stem cell therapy at any time
  • Clinically significant thrombocytopenia, other clinically significant coagulation abnormality, or significant active bleeding, or required treatment with an anticoagulant or more than two antiplatelet agents
  • Contraindication for lumbar punctures
  • Have a clinically significant history of stroke, status epilepticus, head trauma with loss of consciousness, or any CNS disease that is not MPS II-related within 1 year of screening
  • Have had a ventriculoperitoneal (VP) shunt placed, or any other brain surgery, or have a clinically significant VP shunt malfunction within 30 days of screening
  • Have any clinically significant CNS trauma or disorder that, in the opinion of the investigator, may interfere with assessment of study endpoints or make participation in the study unsafe

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): NCT04251026


Contacts
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Contact: Clinical Trials at Denali Therapeutics Email: clinical-trials@dnli.com

Locations
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United States, California
UCSF Benioff Children's Hospital Recruiting
Oakland, California, United States, 94609
Contact: Huong Phan    510-428-3885 ext 5917    huong.phan@ucsf.edu   
Contact: Paul Harmatz, MD       paul.harmatz@ucsf.edu   
United States, Pennsylvania
UPMC | Children's Hospital of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Maria Escolar, MD    412-692-6340    maria.escolar@chp.edu   
Contact: Alyssa Aburachis       alyssa.aburachis@chp.edu   
Sponsors and Collaborators
Denali Therapeutics Inc.
Investigators
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Study Director: Heather Cahan, MD Denali Therapeutics
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Responsible Party: Denali Therapeutics Inc.
ClinicalTrials.gov Identifier: NCT04251026    
Other Study ID Numbers: DNLI-E-0002
2019-004909-27 ( EudraCT Number )
First Posted: January 31, 2020    Key Record Dates
Last Update Posted: September 3, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Denali Therapeutics Inc.:
MPS II
Hunter Syndrome
nMPS II
Additional relevant MeSH terms:
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Mucopolysaccharidosis II
Mucopolysaccharidoses
Carbohydrate Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lysosomal Storage Diseases
Mucinoses
Connective Tissue Diseases
Metabolic Diseases
Mental Retardation, X-Linked
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Genetic Diseases, X-Linked
Heredodegenerative Disorders, Nervous System