Safety, Tolerability, Ascending Dose and Dose Frequency Study of rhHNS Via an IDDD in MPS IIIA Patients

Study Overview
=================
Brief Summary
-----------------
Sanfilippo syndrome, or Mucopolysaccharidosis (MPS) III, is a rare lysosomal storage disease (LSD) caused by loss in activity of 1 of 4 enzymes necessary for degradation of the glycosaminoglycan (GAG) heparan sulfate (HS) in lysosomes. MPS IIIA results from deficiency of the enzyme heparan N-sulfatase (sulfamidase). MPS IIIA symptoms arise on average at 7 months of age, with the average age of diagnosis at 4.5 years for the majority of patients. The central nervous system (CNS) is the most severely affected organ system in patients with MPS IIIA, evidenced by deficits in language development, motor skills, and intellectual development. In addition, there are abnormal behaviors including but not limited to aggression and excess motor activity/hyperactivity that contribute to disturbances in sleep.Overall, individuals with MPS IIIA have a marked developmental delay and significantly reduced lifespan of 15 years of age on average. The purpose of this study is to determine the safety and tolerability of rhHNS via ascending doses administered via an a surgically implanted intrathecal drug delivery device (IDDD) intrathecal (IT) route once monthly (or every two weeks) for 6 months in patients with MPS IIIA.

Detailed Description
-----------------
No effective, disease-modifying therapies are currently approved as treatments for this devastating and disabling disease. Shire Human Genetic Therapies (Shire HGT) is developing a sulfamidase enzyme replacement therapy (ERT)rhHNS for patients with MPS IIIA. recombinant human heparan-N-sulfatase (rhHNS) is being administered into the cerebrospinal fluid (CSF) via an surgically implanted intrathecal drug delivery device (IDDD), because when administered intravenously (IV) it does not cross the blood brain barrier (BBB). This study is a multicenter, multiple-dose, dose escalation study designed to evaluate the safety, tolerability, and clinical activity of up to 3 dose levels (10mg,45mg and 90mg monthly for 6 months) of rhHNS administered via an IDDD in patients with Sanfilippo syndrome Type A ages greater than or equal to 3 years of age. Patients who have completed all study requirements in this study will be invited to participate in an open-label extension study that will be designed to evaluate long term safety and clinical outcomes of intrathecal administration of rhHNS.

Official Title
-----------------
A Phase I/II Safety, Tolerability, Ascending Dose and Dose Frequency Study of Recombinant Human Heparan N-Sulfatase (rhHNS) Intrathecal Administration Via an Intrathecal Drug Delivery Device in Patients With Sanfilippo Syndrome Type A (MPS IIIA)

Conditions
-----------------
Mucopolysaccharidosis (MPS)

Intervention / Treatment
-----------------
* Biological: Recombinant human heparan N-sulfatase (rhHNS)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Each patient had to meet the following criteria to be eligible for the study: a.) Patients had a documented deficiency in sulfamidase enzyme activity of ≤10% of the lower limit of the normal range as measured in fibroblasts or leukocytes. AND either b or c b.) Patients had a normal enzyme activity level of at least 1 other sulfatase (to rule out multiple sulfatase deficiency) as measured in fibroblasts or leukocytes. c.) Patients had 2 documented mutations. The patient was ≥3 years of age and had a developmental age ≥1 year. Patients must have been medically stable, in the opinion of the Investigator, to accommodate the protocol requirements, including travel, assessments, and IDDD surgery, without placing an undue burden on the patient/patient's family. The patient's parent(s) or legal guardian must have voluntarily signed an Institutional Review Board/Independent Ethics Committee-approved informed consent form after all relevant aspects of the study have been explained and discussed with the patient, the patient's parent(s), or legal guardian. The patients, patient's parents or legal guardian's consent and patient's assent as appropriate, must have been obtained. Exclusion Criteria Patients who met any of the following criteria were excluded from the study: The patient had significant non-MPS IIIA related CNS impairment or behavioral disturbances that would confound the scientific integrity or interpretation of study assessments, as determined by the investigator. The patient had MPS IIIA behavioral-related issues, as determined by the investigator, that would have precluded performance of study neurocognitive and developmental testing procedures The patient was pregnant, breast feeding, or was a female patient of childbearing potential who would not or could not comply with the use of an acceptable method of birth control such as condoms, barrier method, oral contraception, etc. The patient was blind and/or deaf. The patient had any known or suspected hypersensitivity to anesthesia or was thought to have an unacceptably high risk for anesthesia due to airway compromise or other conditions. The patient or the patient's family had a history of neuroleptic malignant syndrome, malignant hyperthermia, or other anesthesia-related concerns. The investigator may have chosen to exclude patients who have had complications resulting from prior lumbar punctures. The patient had a CNS shunt. The patient had skeletomuscular/spinal abnormalities or other contraindications for the surgical implantation of the IDDD. The patient had a history of poorly controlled seizure disorder. The patient was currently receiving psychotropic or other medications, which in the investigator's opinion, would have been likely to substantially confound test results and the dose and regimen of which cannot be kept constant throughout the study. The patient could not sustain absence from aspirin, non-steroidal medications, or medications that affected blood clotting within 1 week prior to a relevant study related procedure (eg, device implantation if applicable), or had ingested such medications within 1 week before any procedures in which any change in clotting activity would have been deleterious. The patient had received treatment with any investigational drug or a device intended as a treatment for MPS IIIA within the 30 days prior to, or during the study, or was enrolled in another study that involved an investigational drug or device (screening through safety follow-up contact). The patient received a hematopoietic stem cell or bone marrow transplant. The patient's parent(s), or patient's legal guardian(s) was/were unable to provide consent or the patient could not provide assent, as appropriate, due to, but not limited to, the inability to understand the nature, scope, and possible consequences of the study, or did not agree to comply with the protocol defined schedule of assessments.

Ages Eligible for Study
-----------------
Minimum Age: 3 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 10 mg rhHNS<br>10 mg monthly via an IDDD (every 28 [±7 days]) for a total of 6 months | Biological: Recombinant human heparan N-sulfatase (rhHNS)<br> <br> |
| Experimental: 45 mg rhHNS<br>45 mg monthly via an IDDD (every 28 [±7 days]) for a total of 6 months | Biological: Recombinant human heparan N-sulfatase (rhHNS)<br> <br> |
| Experimental: 90 mg rhHNS<br>Given IDDD as a 45 mg dose every 14 [±2 days] for a monthly total of 90 mg for 6 months | Biological: Recombinant human heparan N-sulfatase (rhHNS)<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Treatment Emergent Serious Adverse Events (SAE) | An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered as a pharmaceutical product that did not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs (TEAEs) were defined as all adverse events (AEs) from the time of the surgery for IDDD implantation to the last follow up contact, 30 (±7) days after the end of study (EOS) procedures. | Baseline to week 30 (follow-up) | 
| Number of Treatment Emergent Adverse Events (TEAE) | An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered as a pharmaceutical product that did not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs (TEAEs) were defined as all adverse events (AEs) from the time of the surgery for IDDD implantation to the last follow up contact, 30 (±7) days after the end of study (EOS) procedures. | Baseline to week 30 (follow-up) | 
| Summary of Anti-rhHNS Antibody Status in Cerebrospinal Fluid (CSF) by Recombinant Human Heparan N-Sulfatase (rhHNS) Dose Group | Participants with positive, negative and missing status were reported. | Baseline, Week 26 | 
| Summary of Anti-rhHNS Antibody Status in Serum by Recombinant Human Heparan N-Sulfatase (rhHNS) Dose Group | Participants with positive, negative and missing status were reported. | Baseline, Week 26 | 
| Number of Participants With Intrathecal Drug Device (IDDD) Failures at Week 26 | Participants with IDDD failures were reported. | Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Developmental Quotient (DQ) Using Bayley Scales of Infant Development Third Edition (BSID III) and Kaufman Assessment Battery for Children Second Edition (KABC II) at Week 22 | BSID-III was used to assess the motor (fine and gross), language (receptive and expressive), and cognitive development of infants and toddlers. This measure consists of a series of developmental play tasks. Raw scores of successfully completed items are converted to scale scores and to composite scores. The mean composite score is 100 and the standard deviation (SD) is 15.Higher scores are indicative of decreased development. KABC-II was an individually administered measure of the processing and reasoning abilities of children and adolescents between the ages of 3 and 18 years and is an alternative to BSID-III. BSID-III DQ score was based on the Cognitive domain. The DQ score was calculated from the data obtained from either BSID-III/KABC-II mental age equivalent of the child in months divided by the calendar age in months (multiplied by 100 to give percentage points). | Baseline, Week 22 | 
| Change From Baseline in Four Point Scoring System/Total Disability Score (FPSS/TDS) at Week 22 and Week 26 (EOS) | FPSS is a sanfilippo-specific disability assessment which assesses motor function, expressive/speech language, and cognitive function on a 0 to 3 point scale. A score of 3 points is assigned for normal function, 2 points for beginning of regression, 1 point for severe level of regression, and 0 points for lost skills. The total disability score (TDS) is the average (0-3) of the motor skills (MS), speech abilities (SA), and cognitive function (CF) scores. Lower scores indicate developmental regression. | Baseline, Week 22, Week 26 | 
| Change From Baseline in Sanfilippo Behavioral Rating Scale (SBRS) at Week 22 and Week 26 (EOS) | SBRS a parent-scored behavioral inventory measuring: comprehensive language skills, expressive language skills, tantrums, mood and emotions, and other behaviors not otherwise classified. Subscale items are scored 0=Never, 1=Occasionally(5-10%), 2=Sometimes (25%), 3=About half the time, 4=Often(75%), 5=Almost always (90%), 6=Always. Summary scores are the sum of responses within a given domain. Higher values = undesirable behavior. Total score range listed below with the abbreviations. Current Communication (CC)(0-42), Past Communication (PC)(0-42), Orality (0-36), Body Movements (BM)(0-30), Interaction With Objects (IWO)(0-24), Activity And Routines (AAR)(0-36), Emotional Function (EF)(0-18), Safety-consciousness (SC)(0-18), Fearfulness (0-36), Social Interaction (SI)(0-36), Eye Contact (EC)(0-18), Emotional Engagement (EE)(0-18), Comfort Seeking (CS)(0-30), Attention (0-18), Self-control/Compliance (SCC)(0-18), Mood, Anger/Aggression (MAA)(0-42), Self-gratification (SG)(0-24). | Baseline, Week 22, Week 26/EOS | 
| Change From Baseline in Developmental Quotient (DQ) Using Vineland Adaptive Behavioral Scales Second Edition (VABS-II) at Week 22 | VABS-II measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. It is an instrument that supports the diagnosis of intellectual and developmental disabilities in participants. This test measures 5 key domains: communication, daily living skills, socialization, motor skills, and the adaptive behavior composite (a composite of the other four domains). Scoring is 'Usually' = 2, 'Sometimes'/Partially' = 1 or 'Never' = 0. The raw scores will be converted to domain standard scores (mean 100, SD 15). Higher scores indicate undesirable behavior. The Overall DQ score was calculated from the mean age-equivalent score obtained by averaging out the age equivalent scores for all the sub-domains except for Gross and Fine motor skills. | Baseline, Week 22 | 
| Change From Baseline in Movement Assessment Battery for Children Second Edition (MABC-2) at Week 26 (EOS) | Movement Assessment Battery for Children, Second Edition (MABC-II) was to be used to identify, describe and guide the treatment of motor impairment in children from 3.0 to 16:11 years of age. As per statistical analysis plan, the outcome was to be assessed only if greater than (>) 50 percent (%) of participants were available for the evaluation. | Baseline, Week 26/EOS | 
| Change From Baseline in Quality of Life (QoL) Using Child Health Questionnaire™ Parent Form 50 (CHQ-PF50) Questions at Week 22 and Week 26 (EOS) | CHQ-PF50 which was designed to measure the physical and psychosocial well-being of children 5 years to 18 years of age, consists of 13 health concepts including 11 multi-item and 2 single item scales: Physical Function (PF), Role/Social-Emotional/Behavioral (REB), Role/Social-Physical (RP), bodily pain (BP), General Behavior (BE), Mental Health (MH), Self Esteem (SE), General Health Perceptions (GH), Change in Health (CH), Parental Impact-Emotional (PE), Parental Impact-Time (PT), Family Activities (FA), and Family Cohesion (FC). Transformed scores for all subscales range from 0 to 100, with a higher score indicating better health. Physical and Psychosocial Summary measures (SM) were scored with the use of norm-based methods that standardize the scores to a mean (± Standard Deviation) of 50 ± 10 on the basis of an assessment of the general United States population. Higher values represent better health. | Baseline, Week 22, Week 26/EOS | 
| Change From Baseline in Quality of Life (QoL) Using Infant Toddler Quality of Life Questionnaire™ (ITQOL) at Week 22 and Week 26 (EOS) | ITQOL is a generic, validated health status measure for children aged 2 months up to 5 years, including items and scales to measure aspects of physical functioning, development, pain, mood, behavior, general health and impact on parents. The ITQOL consists of 97 items that are scored, summed, and transformed on a scale from 0 (worst health) to 100 (best health). The score range for all individual subscales is 0 (worst health) to 100 (best health). Abbreviation: Overall Health (OH), Physical Abilities (PA), Growth And Development (GAD), Bodily Pain (BP), Temperament And Moods (TAM), General Behavior (GEB), Global Behavior (GLB), Getting Along (GA), General Health Perceptions (GHP), PI-Emotion (PIE), PI-Time (PIT), Family Cohesion (FC). | Baseline, Week 22, Week 26/EOS | 
| Change From Baseline in Quality of Life (QoL) Using Child Health Questionnaire™ Child Form 87 (CHQ-CF87) at Week 26 (EOS) | CHQ-CF87 form was designed to be a self-report for participants 10 years and older. It consists of 87 questions and contains the same scales as the PF-50, (with the omission of the parental impact scales and there are no psychosocial and physical summary scores derived). As per statistical analysis plan, the outcome was to be assessed only if greater than (>) 50 percent (%) of participants were available for the evaluation. | Baseline, Week 26/EOS | 
| Change From Baseline in Quality of Life (QoL) Using Children's Sleep Habits Rating Scale at Week 22 and Week 26 (EOS) | Children's sleep habits rating scale consisting of 35 item parent questionnaire sleep screening tool. Items are scored on a 3-point scale from 1 (rarely) to 3 (usually) with a Total Sleep Disturbance score (TSDS) ranging from 35-105. Eight subscale scores are totaled to create the TSDS. The subscales are: Bedtime Resistance (BR)(6 items, score = 6-18), Sleep Duration (SD)(3 items, score = 3-9), Parasomnias (P)(7 items, score = 7-21), Sleep Disordered Breathing (SDB)(3 items, score = 3-9), Night Waking (NW)(3 items, score = 3-9), Daytime Sleepiness (DS)(8 items, score = 8-24), Sleep Anxiety (SA)(4 items, score = 4-12), and Sleep Onset Delay (SOD)(1 item, score = 1-3). The questionnaire was designed for children aged 4 through 12 years. A higher score is indicative of more disturbed sleep. | Baseline, Week 22, Week 26/EOS | 
| Number of Participants With Accumulation of Recombinant Human Heparan N-Sulfatase (rhHNS) in Cerebrospinal Fluid (CSF) at Week 22 | Cerebrospinal fluid samples were collected from participants through an implanted IDDD or via lumbar puncture (LP) immediately prior to each administration of HGT-1410. | Baseline, Week 22 | 
| Change From Baseline in Concentration of Heparan Sulfate and Heparan Sulfate Derivatives in Cerebrospinal Fluid (CSF) at Week 6, 10, 14, 18, 22 and 26(EOS) | Levels of heparan sulfate and its derivatives were evaluated using the proprietary Sensi-Pro (SP) high-performance liquid chromatography (HPLC) based assay. Abbreviation: SP Total Heparan Sulfate (SPTHS), SP Non-Reducing End Assay (SPNREA), | Baseline, Week 6, 10, 14, 18, 22 and 26(EOS) | 
| Change From Baseline in Brain Magnetic Resonance Imaging (MRI) at Week 22 | Brain MRI was measured for grey matter volume (GMV) , white matter volume (WMV) and Intracranial cerebrospinal fluid Volume (ICSFV) (Ventricles + Additional CSF Space). | Baseline, Week 22 | 
| Change From Baseline in Mean Auditory Brainstem Response (ABR) at Week 22 | ABR assessments were to be conducted under anesthesia and measured the electrical response evoked by acoustic stimuli as sound is processed along the auditory pathway. Mean ABR air and bone conduction threshold were assessed. Mean ABR bone conduction threshold was not possible to be reported as there was insufficient data to be analysed. | Baseline, Week 22 | 
| Change From Baseline in Auditory Brainstem Response (ABR) at Week 22: Latencies | ABR assessments were to be conducted under anesthesia and measured the electrical response evoked by acoustic stimuli as sound is processed along the auditory pathway. The Inter-peak Latencies (IPL) were calculated by subtracting the absolute latencies (AL). The Inter-aural Latencies (IAL) were calculated by subtracting the absolute wave V latencies of the right and left ear. IAL, IPL and AL were reported. Abbreviation: Right Ear (RE), Left Ear (LE), Wave (W), Wave V (WV) | Baseline, Week 22 | 
| Change From Baseline in Auditory Brainstem Response (ABR) at Week 22: Amplitudes | ABR assessments were to be conducted under anesthesia and measured the electrical response evoked by acoustic stimuli as sound is processed along the auditory pathway. Data for change from baseline in ABR amplitudes by left ear (LE) and right ear (RE) were reported. | Baseline, Week 22 | 
| Change From Baseline in Auditory Brainstem Response (ABR) at Week 22: Amplitude Ratio | ABR assessments were to be conducted under anesthesia and measured the electrical response evoked by acoustic stimuli as sound is processed along the auditory pathway. Data for change from baseline in ABR amplitudes(A), log-transformed amplitudes (LTA), square-root transformed amplitudes (STA) by left ear (LE) and right ear (RE) wave V/I in ratio was reported. | Baseline, Week 22 | 
| Change From Baseline in Auditory Brainstem Response (ABR) at Week 22: Log Transformed Latencies | ABR assessments were to be conducted under anesthesia and measured the electrical response evoked by acoustic stimuli as sound is processed along the auditory pathway. Data for change from baseline in ABR log-transformed latencies (LTL) by left and right ear were reported. | Baseline, Week 22 | 
| Change From Baseline in Auditory Brainstem Response (ABR) at Week 22: Log Transformed Amplitude | ABR assessments were to be conducted under anesthesia and measured the electrical response evoked by acoustic stimuli as sound is processed along the auditory pathway. Data for change from baseline in ABR log-transformed amplitudes (LTA) by left and right ear were reported. | Baseline, Week 22 | 
| Change From Baseline in Auditory Brainstem Response (ABR) at Week 22: Square-root Transformed Latencies | ABR assessments were to be conducted under anesthesia and measured the electrical response evoked by acoustic stimuli as sound is processed along the auditory pathway. Data for change from baseline in ABR square-root transformed latency (STL) by left and right ear were reported. | Baseline, Week 22 | 
| Change From Baseline in Auditory Brainstem Response (ABR) at Week 22: Square-root Transformed Amplitude | ABR assessments were to be conducted under anesthesia and measured the electrical response evoked by acoustic stimuli as sound is processed along the auditory pathway. Data for change from baseline in ABR square-root transformed amplitude (STA) by left and right ear were reported. | Baseline, Week 22 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Mucopolysaccharidosis (MPS) IIIA, Recombinant Human Heparan N-Sulfatase (rhHNS), Sanfilippo Syndrome Type A (MPS IIIA), Lysosomal Storage Disease (LSD), Intrathecal Drug Delivery Device (IDDD)