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A Study to Evaluate the Efficacy and Safety of BMN 111 in Children With Achondroplasia

Sponsor
BioMarin Pharmaceutical (Industry)
Overall Status
Completed
CT.gov ID
NCT03197766
Collaborator
(none)
121
Enrollment
24
Locations
2
Arms
34.6
Actual Duration (Months)
5
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The intent and design of this Phase 3 study is to assess BMN 111 as a therapeutic option for the treatment of children with Achondroplasia.

Condition or Disease Intervention/Treatment Phase
  • Drug: BMN 111
  • Drug: Placebo
 Phase 3

Detailed Description

This is a Phase 3 randomized, placebo-controlled, double-blind multicenter study with approximately 110 subjects, aged 5 to < 18 years old. Subjects with documented Achondroplasia confirmed by genetic testing will have been enrolled in Study 111-901 for at least a 6-month period immediately before entering into the 111-301 study. Eligible subjects will be randomly assigned to one of two treatment groups: placebo or BMN 111 at 15 μg/kg. The route of administration is subcutaneous injection and the frequency is daily.

Study Design

Study Type:
Interventional
Actual Enrollment :
121 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
Official Title:
A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of BMN 111 in Children With Achondroplasia
Actual Study Start Date :
Dec 12, 2016
Actual Primary Completion Date :
Oct 30, 2019
Actual Study Completion Date :
Oct 30, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Active BMN 111

Daily subcutaneous injection of 15 micrograms per kilogram BMN111

Drug: BMN 111
Subcutaneous injection of 15 μg/kg of BMN 111 daily
Other Names:
  • Vosoritide
  • Modified recombinant human C-type natriuretic peptide

    		•
    Placebo Comparator: Placebo

    Daily subcutaneous injection of placebo

    Drug: Placebo
    Subcutaneous injection of 15 μg/kg of placebo daily

    Outcome Measures

    Primary Outcome Measures

    1. Change From Baseline in Annualized Growth Velocity (AGV) at Week 52 [At Baseline and Week 52]

      AGV at a Post-baseline Visit is defined as [(Height at Post-baseline Visit - Height at Baseline)/(Date of Post-baseline Visit - Date of Baseline Assessment)] x 365.25 AGV at Baseline is defined as [(Height at Baseline - last height measurement in Study 111-901 at least 6 months prior to Baseline)/(Date of Baseline Assessment - Date of last height measurement in Study 111-901 at least 6 months prior to Baseline)] x 365.25

    Secondary Outcome Measures

    1. Change From Baseline in Height Z-score at Week 52 [At baseline and Week 52]

      Z-Scores were derived using age-sex specific reference data (means and SDS) for average stature children per the Centers for Disease Control and Prevention. A height Z score of 0 would indicate that the subject's height is equal to the mean height for the average stature population of the same sex and age. A positive height Z score indicates that the subjects height is above the mean height for the average stature population of the same sex and age, whilst a negative height Z score indicates that the subjects height is below the mean height for the average stature population of the same sex and age. To conclude if the height Z score increases then this means the height deficit has decreased.

    2. Change From Baseline in Upper to Lower Segment Body Ratio at Week 52 [At baseline and Week 52]

      Evaluate change from baseline in mean upper:lower segment body ratio in subjects treated with BMN 111 compared with control subjects in the placebo group at 52 weeks

    3. Summary of Subjects Experiencing Adverse Events (AEs) During Treatment [Up to Week 56]

      AEs with onset or worsening after the initiation of study drug and up to 30 days after study drug discontinuation were included. serious adverse event (SAE)

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    5 Years to 18 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No

    Inclusion Criteria

    • Parent(s) or guardian(s) consent

    • 5 to < 18 years old

    • ACH, documented and confirmed by genetic testing

    • At least a 6-month period of pretreatment growth assessment in Study 111-901 before study entry

    • If sexually active, willing to use a highly effective method of contraception

    • Ambulatory and able to stand without assistance

    Exclusion criteria:

    • Hypochondroplasia or short stature condition other than ACH

    • Have any of the following:

    • Hypothyroidism or hyperthyroidism

    • Insulin-requiring diabetes mellitus

    • Autoimmune inflammatory disease

    • Inflammatory bowel disease

    • Autonomic neuropathy

    • History of any of the following:

    • Renal insufficiency defined as serum creatinine > 2 mg/dL

    • Chronic anemia

    • Baseline systolic blood pressure (BP) < 70 millimeters of mercury (mm Hg) or recurrent symptomatic hypotension (defined as episodes of low BP generally accompanied by symptoms ie, dizziness, fainting) or recurrent symptomatic orthostatic hypotension

    • Cardiac or vascular disease

    • Have a clinically significant finding or arrhythmia on screening electrocardiogram (ECG) that indicates abnormal cardiac function or conduction or Fridericias corrected QTc-F > 450 msec

    • Have an unstable condition likely to require surgical intervention during the study (including progressive cervical medullary compression or severe untreated sleep apnea)

    • Decreased growth velocity (< 1.5 cm/yr) over a period of 6 months or evidence of growth plate closure (proximal tibia, distal femur)

    • Treated with growth hormone, insulin-like growth factor 1 (IGF-1), or anabolic steroids in the previous 6 months or treatment greater than 6 months at any time

    • Greater than 1 month treatment with oral corticosteroids (low-dose ongoing inhaled steroid for asthma, or intranasal steroids, are acceptable) in the previous 12 months

    • Planned or expected to have limb-lengthening surgery during the study period. Subjects with previous limb- lengthening surgery may enroll if surgery occurred at least 18 months prior to the study and healing is complete without sequelae.

    • Planned or expected bone-related surgery (ie. surgery involving disruption of bone cortex, excluding tooth extraction), during the study period. Subjects with previous bone-related surgery may enroll if surgery occurred at least 6 months prior to the study and healing is complete without sequelae.

    • Had a fracture of the long bones or spine within 6 months prior to screening

    • History of severe untreated sleep apnea

    • New initiation of sleep apnea treatment (e.g. CPAP or sleep apnea-mitigating surgery) in the previous 2 months prior to screening

    • History of hip surgery or hip dysplasia atypical for achondroplastic subjects

    • History of clinically significant hip injury in the 30 days prior to screening

    • History of slipped capital femoral epiphysis or avascular necrosis of the femoral head

    • Abnormal findings on baseline clinical hip exam or imaging assessments that are determined to be clinically significant

    • Concurrent disease or condition that would interfere with study participation or safety evaluations, for any reason

    • Condition or circumstance that places the subject at high risk for poor treatment compliance or for not completing the study

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Children's Hospital & Research Center Oakland Oakland California United States 94609
    2 Harbor - UCLA Medical Center Torrance California United States 90509
    3 Alfred I. duPont Hospital for Children Wilmington Delaware United States 19803
    4 Emory University Decatur Georgia United States 30033
    5 Ann and Robert H. Lurie Children's Hospital of Chicago Chicago Illinois United States 60611
    6 Johns Hopkins University Baltimore Maryland United States 21287
    7 University of Missouri Columbia Missouri United States 65201
    8 Cincinnati Children's Hospital Medical Center Cincinnati Ohio United States 45229
    9 Baylor College of Medicine Houston Texas United States 77030
    10 Seattle Children's Hospital Seattle Washington United States 98105
    11 Medical College of Wisconsin, Children's Hospital Milwaukee Wisconsin United States 53226
    12 The Children's Hospital at Westmead Westmead New South Wales Australia 2145
    13 Murdoch Children's Research Institute Parkville Victoria Australia 3052
    14 Otto-von-Guericke Universitaet, Universitaetskinderklinik Magdeburg Germany 39120
    15 Universitätsklinikum Münster Münster Germany 48149
    16 Osaka University Hospital Osaka Japan
    17 Saitama Children's Medical Center Saitama Japan
    18 Tokushima University Hospital Tokushima Japan
    19 Institut Catala de Traumatologica I Medicina de l'Esport Barcelona Spain 08028
    20 Hospital Sant Joan de Deu Barcelona Spain 08950
    21 Hospital Universitario Virgen de la Victoria Málaga Spain 29010
    22 Acibadem University School of Medicine Istanbul Turkey 34752
    23 Guy's and St. Thomas NHS Foundation Trust Evelina Children's Hospital London United Kingdom SE1 9RT
    24 Sheffield Children's NHS Foundation Trust Sheffield United Kingdom S10 2TH

    Sponsors and Collaborators

    • BioMarin Pharmaceutical

    Investigators

    • Study Director: Medical Director, MD, BioMarin Pharmaceutical

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    BioMarin Pharmaceutical
    ClinicalTrials.gov Identifier:
    NCT03197766
    Other Study ID Numbers:
    • 111-301
    • 2015-003836-11
    First Posted:
    Jun 23, 2017
    Last Update Posted:
    Mar 2, 2022
    Last Verified:
    Feb 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by BioMarin Pharmaceutical
    Achondroplasia
    Dwarfism
    Bone Diseases
    Bone Diseases, Developmental
    ACH
    Natriuretic Peptide, C-Type
    Musculoskeletal Diseases
    Natriuretic Agents
    Physiological Effects of Drugs
    Skeletal Dysplasias
    Genetic Diseases, Inborn
    Osteochondrodysplasias
    Additional relevant MeSH terms:
    Achondroplasia
    Natriuretic Peptide, C-Type

    Study Results

    Participant Flow

    Recruitment Details This was a multi-centre study conducted by 24 principal investigators at 24 study centers in 7 countries
    Pre-assignment Detail A total of 121 subjects were enrolled into the study, 119 subjects completed and 2 subjects withdrew from the study.
    Arm/Group Title BMN 111 - 15 μg/kg Placebo
    Arm/Group Description BMN 111: Subcutaneous injection of 15 μg/kg of BMN 111 daily Placebo: Subcutaneous injection of placebo daily
    Period Title: Overall Study
    STARTED 60 61
    COMPLETED 58 61
    NOT COMPLETED 2 0

    Baseline Characteristics

    Arm/Group Title BMN 111 - 15 μg/kg Placebo Total
    Arm/Group Description BMN 111: Subcutaneous injection of 15 μg/kg of BMN 111 daily Placebo: Subcutaneous injection of placebo daily Total of all reporting groups
    Overall Participants 60 61 121
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    8.35
    (2.43)
    9.06
    (2.47)
    8.71
    (2.47)
    Sex: Female, Male (Count of Participants)
    Female
    29
    48.3%
    28
    45.9%
    57
    47.1%
    Male
    31
    51.7%
    33
    54.1%
    64
    52.9%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    1
    1.7%
    6
    9.8%
    7
    5.8%
    Not Hispanic or Latino
    59
    98.3%
    55
    90.2%
    114
    94.2%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Race/Ethnicity, Customized (Count of Participants)
    White
    45
    75%
    41
    67.2%
    86
    71.1%
    Asian-Other
    7
    11.7%
    9
    14.8%
    16
    13.2%
    Asian-Japanese
    3
    5%
    4
    6.6%
    7
    5.8%
    Multiple
    2
    3.3%
    5
    8.2%
    7
    5.8%
    Black or African American
    3
    5%
    2
    3.3%
    5
    4.1%
    Annualized Growth Velocity (AGV) (cm/year) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [cm/year]
    4.26
    (1.53)
    4.06
    (1.20)
    4.16
    (1.37)
    Height Z-Score (Z-score) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Z-score]
    -5.13
    (1.11)
    -5.14
    (1.07)
    -5.13
    (1.09)
    Upper to Lower Body Segment Ratio (Ratio) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Ratio]
    1.98
    (0.20)
    2.01
    (0.21)
    2.00
    (0.20)

    Outcome Measures

    1. Primary Outcome
    Title Change From Baseline in Annualized Growth Velocity (AGV) at Week 52
    Description AGV at a Post-baseline Visit is defined as [(Height at Post-baseline Visit - Height at Baseline)/(Date of Post-baseline Visit - Date of Baseline Assessment)] x 365.25 AGV at Baseline is defined as [(Height at Baseline - last height measurement in Study 111-901 at least 6 months prior to Baseline)/(Date of Baseline Assessment - Date of last height measurement in Study 111-901 at least 6 months prior to Baseline)] x 365.25
    Time Frame At Baseline and Week 52

    Outcome Measure Data

    Analysis Population Description
    Analysis were performed on the Full Analysis Set (FAS) which included all randomized subjects with a signed informed consent
    Arm/Group Title BMN 111 - 15 μg/kg Placebo
    Arm/Group Description BMN 111: Subcutaneous injection of 15 μg/kg of BMN 111 daily Placebo: Subcutaneous injection of placebo daily
    Measure Participants 60 61
    Least Squares Mean (95% Confidence Interval) [cm/year]
    1.71
    0.13
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection BMN 111 - 15 μg/kg, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Confirmatory statistical testing controlling for the Type I error rate was performed on the primary analysis for the primary endpoint.
    Method ANCOVA
    Comments Two subjects in the BMN 111 group discontinued from the study before Week 52. The values for these 2 subjects were imputed for this analysis.
    2. Secondary Outcome
    Title Change From Baseline in Height Z-score at Week 52
    Description Z-Scores were derived using age-sex specific reference data (means and SDS) for average stature children per the Centers for Disease Control and Prevention. A height Z score of 0 would indicate that the subject's height is equal to the mean height for the average stature population of the same sex and age. A positive height Z score indicates that the subjects height is above the mean height for the average stature population of the same sex and age, whilst a negative height Z score indicates that the subjects height is below the mean height for the average stature population of the same sex and age. To conclude if the height Z score increases then this means the height deficit has decreased.
    Time Frame At baseline and Week 52

    Outcome Measure Data

    Analysis Population Description
    Analysis were performed on the Full Analysis Set (FAS) which included all randomized subjects with a signed informed consent.
    Arm/Group Title BMN 111 - 15 μg/kg Placebo
    Arm/Group Description BMN 111: Subcutaneous injection of 15 μg/kg of BMN 111 daily Placebo: Subcutaneous injection of placebo daily
    Measure Participants 60 61
    Least Squares Mean (95% Confidence Interval) [Z-Score]
    0.27
    -0.01
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection BMN 111 - 15 μg/kg, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments Confirmatory statistical testing controlling for the Type I error rate was performed on the primary analyses for the two key secondary endpoints.
    Method ANCOVA
    Comments Missing assessments at Week 52 were imputed
    3. Secondary Outcome
    Title Change From Baseline in Upper to Lower Segment Body Ratio at Week 52
    Description Evaluate change from baseline in mean upper:lower segment body ratio in subjects treated with BMN 111 compared with control subjects in the placebo group at 52 weeks
    Time Frame At baseline and Week 52

    Outcome Measure Data

    Analysis Population Description
    Analysis were performed on the Full Analysis Set (FAS) which included all randomized subjects with a signed informed consent
    Arm/Group Title BMN 111 - 15 μg/kg Placebo
    Arm/Group Description BMN 111: Subcutaneous injection of 15 μg/kg of BMN 111 daily Placebo: Subcutaneous injection of placebo daily
    Measure Participants 60 61
    Least Squares Mean (95% Confidence Interval) [Ratio]
    -0.03
    -0.02
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection BMN 111 - 15 μg/kg, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value = 0.506
    Comments Confirmatory statistical testing controlling for the Type I error rate was performed on the primary analyses for the two key secondary endpoints.
    Method ANCOVA
    Comments Missing assessments at Week 52 were imputed
    4. Secondary Outcome
    Title Summary of Subjects Experiencing Adverse Events (AEs) During Treatment
    Description AEs with onset or worsening after the initiation of study drug and up to 30 days after study drug discontinuation were included. serious adverse event (SAE)
    Time Frame Up to Week 56

    Outcome Measure Data

    Analysis Population Description
    The Safety Population was defined as all subjects in the FAS who received at least one dose of double-blind BMN 111 or placebo in this study.
    Arm/Group Title BMN 111 - 15 μg/kg Placebo
    Arm/Group Description BMN 111: Subcutaneous injection of 15 μg/kg of BMN 111 daily Placebo: Subcutaneous injection of placebo daily
    Measure Participants 60 61
    Subjects with any AE
    59
    98.3%
    60
    98.4%
    Subjects with any SAE
    3
    5%
    4
    6.6%
    Subjects with any treatment-related AE
    53
    88.3%
    51
    83.6%
    Subjects who died
    0
    0%
    0
    0%

    Adverse Events

    Time Frame Up to Week 56
    Adverse Event Reporting Description A treatment-emergent Adverse Event (TEAE) is any Adverse Event with onset or worsening after the initiation of study drug and up to 30 days after study drug discontinuation were included. The Safety Population is defined as all subjects in the FAS who received at least one dose of double-blind BMN 111 or placebo in this study
    Arm/Group Title BMN 111 - 15 μg/kg Placebo
    Arm/Group Description BMN 111: Subcutaneous injection of 15 μg/kg of BMN 111 daily Placebo: Subcutaneous injection of placebo daily
    All Cause Mortality
    BMN 111 - 15 μg/kg Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/60 (0%) 0/61 (0%)
    Serious Adverse Events
    BMN 111 - 15 μg/kg Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/60 (5%) 4/61 (6.6%)
    Infections and infestations
    Influenza 1/60 (1.7%) 0/61 (0%)
    Appendicitis 0/60 (0%) 1/61 (1.6%)
    Injury, poisoning and procedural complications
    Radius fracture 1/60 (1.7%) 0/61 (0%)
    Nervous system disorders
    Intracranial pressure increased 0/60 (0%) 1/61 (1.6%)
    Spinal cord compression 0/60 (0%) 1/61 (1.6%)
    Respiratory, thoracic and mediastinal disorders
    Adenoidal hypertrophy 1/60 (1.7%) 1/61 (1.6%)
    Sleep apnoea syndrome 1/60 (1.7%) 0/61 (0%)
    Dyspnoea 0/60 (0%) 1/61 (1.6%)
    Other (Not Including Serious) Adverse Events
    BMN 111 - 15 μg/kg Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 59/60 (98.3%) 60/61 (98.4%)
    Cardiac disorders
    Defect conduction intraventricular 0/60 (0%) 1/61 (1.6%)
    Congenital, familial and genetic disorders
    Diastematomyelia 0/60 (0%) 1/61 (1.6%)
    Ear and labyrinth disorders
    Ear pain 6/60 (10%) 3/61 (4.9%)
    Otorrhoea 3/60 (5%) 3/61 (4.9%)
    Tympanic membrane perforation 2/60 (3.3%) 1/61 (1.6%)
    Ear discomfort 1/60 (1.7%) 1/61 (1.6%)
    Excessive cerumen production 1/60 (1.7%) 0/61 (0%)
    External ear inflammation 1/60 (1.7%) 0/61 (0%)
    Middle ear effusion 1/60 (1.7%) 0/61 (0%)
    Hypoacusis 0/60 (0%) 1/61 (1.6%)
    Vertigo 0/60 (0%) 1/61 (1.6%)
    Eye disorders
    Ocular hyperaemia 1/60 (1.7%) 0/61 (0%)
    Eye pruritus 0/60 (0%) 1/61 (1.6%)
    Gastrointestinal disorders
    Vomiting 16/60 (26.7%) 12/61 (19.7%)
    Diarrhoea 6/60 (10%) 2/61 (3.3%)
    Abdominal pain 3/60 (5%) 3/61 (4.9%)
    Nausea 3/60 (5%) 4/61 (6.6%)
    Abdominal pain upper 2/60 (3.3%) 1/61 (1.6%)
    Constipation 1/60 (1.7%) 2/61 (3.3%)
    Gingival pain 1/60 (1.7%) 0/61 (0%)
    Lip swelling 1/60 (1.7%) 0/61 (0%)
    Malpositioned teeth 1/60 (1.7%) 0/61 (0%)
    Abdominal discomfort 0/60 (0%) 1/61 (1.6%)
    Abdominal distension 0/60 (0%) 1/61 (1.6%)
    Abdominal pain lower 0/60 (0%) 2/61 (3.3%)
    Anal pruritus 0/60 (0%) 1/61 (1.6%)
    Dental caries 0/60 (0%) 1/61 (1.6%)
    Food poisoning 0/60 (0%) 1/61 (1.6%)
    Gastrointestinal inflammation 0/60 (0%) 1/61 (1.6%)
    Odynophagia 0/60 (0%) 2/61 (3.3%)
    Oral pain 0/60 (0%) 1/61 (1.6%)
    Tooth loss 0/60 (0%) 2/61 (3.3%)
    General disorders
    Injection site reaction 44/60 (73.3%) 29/61 (47.5%)
    Injection site erythema 41/60 (68.3%) 40/61 (65.6%)
    Injection site swelling 23/60 (38.3%) 6/61 (9.8%)
    Pyrexia 10/60 (16.7%) 13/61 (21.3%)
    Injection site urticaria 8/60 (13.3%) 2/61 (3.3%)
    Injection site bruising 5/60 (8.3%) 8/61 (13.1%)
    Fatigue 4/60 (6.7%) 0/61 (0%)
    Injection site mass 4/60 (6.7%) 1/61 (1.6%)
    Injection site rash 3/60 (5%) 0/61 (0%)
    Injection site haemorrhage 2/60 (3.3%) 7/61 (11.5%)
    Injection site induration 2/60 (3.3%) 0/61 (0%)
    Injection site inflammation 2/60 (3.3%) 1/61 (1.6%)
    Injection site pain 2/60 (3.3%) 5/61 (8.2%)
    Injection site vesicles 2/60 (3.3%) 3/61 (4.9%)
    Gait disturbance 1/60 (1.7%) 0/61 (0%)
    Influenza like illness 1/60 (1.7%) 0/61 (0%)
    Injection site discolouration 1/60 (1.7%) 2/61 (3.3%)
    Injection site pruritus 1/60 (1.7%) 4/61 (6.6%)
    Malaise 1/60 (1.7%) 2/61 (3.3%)
    Pain 1/60 (1.7%) 0/61 (0%)
    Feeling hot 0/60 (0%) 1/61 (1.6%)
    Injection site haematoma 0/60 (0%) 1/61 (1.6%)
    Medical device pain 0/60 (0%) 1/61 (1.6%)
    Peripheral swelling 0/60 (0%) 1/61 (1.6%)
    Secretion discharge 0/60 (0%) 1/61 (1.6%)
    Vaccination site reaction 0/60 (0%) 1/61 (1.6%)
    Immune system disorders
    Seasonal allergy 4/60 (6.7%) 1/61 (1.6%)
    Hypersensitivity 0/60 (0%) 1/61 (1.6%)
    Infections and infestations
    Nasopharyngitis 16/60 (26.7%) 18/61 (29.5%)
    Upper respiratory tract infection 8/60 (13.3%) 10/61 (16.4%)
    Ear infection 6/60 (10%) 6/61 (9.8%)
    Influenza 5/60 (8.3%) 3/61 (4.9%)
    Otitis media 6/60 (10%) 6/61 (9.8%)
    Viral infection 5/60 (8.3%) 3/61 (4.9%)
    Gastroenteritis 4/60 (6.7%) 3/61 (4.9%)
    Gastroenteritis viral 4/60 (6.7%) 1/61 (1.6%)
    Tonsillitis 3/60 (5%) 1/61 (1.6%)
    Bronchitis 2/60 (3.3%) 1/61 (1.6%)
    Enterobiasis 2/60 (3.3%) 0/61 (0%)
    Otitis externa 2/60 (3.3%) 1/61 (1.6%)
    Cellulitis 1/60 (1.7%) 0/61 (0%)
    Croup infectious 1/60 (1.7%) 0/61 (0%)
    Hand-foot-and-mouth disease 1/60 (1.7%) 1/61 (1.6%)
    Impetigo 1/60 (1.7%) 1/61 (1.6%)
    Localised infection 1/60 (1.7%) 0/61 (0%)
    Lower respiratory tract infection 1/60 (1.7%) 1/61 (1.6%)
    Otitis media acute 1/60 (1.7%) 1/61 (1.6%)
    Pharyngitis 1/60 (1.7%) 4/61 (6.6%)
    Scarlet fever 1/60 (1.7%) 0/61 (0%)
    Sinusitis 1/60 (1.7%) 2/61 (3.3%)
    Streptococcal infection 1/60 (1.7%) 0/61 (0%)
    Tooth abscess 1/60 (1.7%) 0/61 (0%)
    Varicella 1/60 (1.7%) 0/61 (0%)
    Viral pharyngitis 1/60 (1.7%) 0/61 (0%)
    Viral upper respiratory tract infection 1/60 (1.7%) 0/61 (0%)
    Acute sinusitis 0/60 (0%) 1/61 (1.6%)
    Conjunctivitis 0/60 (0%) 2/61 (3.3%)
    Fungal skin infection 0/60 (0%) 1/61 (1.6%)
    Infectious mononucleosis 0/60 (0%) 1/61 (1.6%)
    Lice infestation 0/60 (0%) 2/61 (3.3%)
    Molluscum contagiosum 0/60 (0%) 1/61 (1.6%)
    Pharyngitis streptococcal 0/60 (0%) 1/61 (1.6%)
    Rhinitis 0/60 (0%) 1/61 (1.6%)
    Tracheitis 0/60 (0%) 1/61 (1.6%)
    Injury, poisoning and procedural complications
    Fall 4/60 (6.7%) 4/61 (6.6%)
    Arthropod bite 3/60 (5%) 2/61 (3.3%)
    Bone contusion 2/60 (3.3%) 0/61 (0%)
    Ligament sprain 2/60 (3.3%) 1/61 (1.6%)
    Procedural anxiety 2/60 (3.3%) 0/61 (0%)
    Arthropod sting 1/60 (1.7%) 0/61 (0%)
    Back injury 1/60 (1.7%) 0/61 (0%)
    Contusion 1/60 (1.7%) 3/61 (4.9%)
    Procedural dizziness 1/60 (1.7%) 0/61 (0%)
    Scratch 1/60 (1.7%) 1/61 (1.6%)
    Skin abrasion 1/60 (1.7%) 0/61 (0%)
    Thermal burn 1/60 (1.7%) 0/61 (0%)
    Eye injury 0/60 (0%) 1/61 (1.6%)
    Face injury 0/60 (0%) 1/61 (1.6%)
    Head injury 0/60 (0%) 2/61 (3.3%)
    Joint dislocation 0/60 (0%) 1/61 (1.6%)
    Joint injury 0/60 (0%) 2/61 (3.3%)
    Muscle strain 0/60 (0%) 1/61 (1.6%)
    Post-traumatic pain 0/60 (0%) 1/61 (1.6%)
    Procedural pain 0/60 (0%) 1/61 (1.6%)
    Investigations
    Blood pressure decreased 7/60 (11.7%) 3/61 (4.9%)
    Body temperature increased 2/60 (3.3%) 0/61 (0%)
    Metabolism and nutrition disorders
    Vitamin D deficiency 3/60 (5%) 7/61 (11.5%)
    Hyponatraemia 0/60 (0%) 1/61 (1.6%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 9/60 (15%) 4/61 (6.6%)
    Pain in extremity 5/60 (8.3%) 4/61 (6.6%)
    Neck pain 2/60 (3.3%) 2/61 (3.3%)
    Arthropathy 1/60 (1.7%) 0/61 (0%)
    Back pain 1/60 (1.7%) 3/61 (4.9%)
    Coccydynia 0/60 (0%) 1/61 (1.6%)
    Knee deformity 0/60 (0%) 1/61 (1.6%)
    Musculoskeletal stiffness 0/60 (0%) 1/61 (1.6%)
    Nervous system disorders
    Headache 14/60 (23.3%) 16/61 (26.2%)
    Dizziness 4/60 (6.7%) 1/61 (1.6%)
    Paraesthesia 2/60 (3.3%) 1/61 (1.6%)
    Presyncope 2/60 (3.3%) 0/61 (0%)
    Disturbance in attention 1/60 (1.7%) 0/61 (0%)
    Hyperreflexia 1/60 (1.7%) 0/61 (0%)
    Lethargy 1/60 (1.7%) 0/61 (0%)
    Migraine 1/60 (1.7%) 0/61 (0%)
    Extensor plantar response 0/60 (0%) 1/61 (1.6%)
    Hypoaesthesia 0/60 (0%) 2/61 (3.3%)
    Poor quality sleep 0/60 (0%) 1/61 (1.6%)
    Sinus headache 0/60 (0%) 1/61 (1.6%)
    Tremor 0/60 (0%) 1/61 (1.6%)
    Product Issues
    Device expulsion 1/60 (1.7%) 0/61 (0%)
    Psychiatric disorders
    Enuresis 1/60 (1.7%) 0/61 (0%)
    Attention deficit/hyperactivity disorder 0/60 (0%) 1/61 (1.6%)
    Depression 0/60 (0%) 1/61 (1.6%)
    Trichotillomania 0/60 (0%) 1/61 (1.6%)
    Renal and urinary disorders
    Haematuria 0/60 (0%) 1/61 (1.6%)
    Nephrolithiasis 0/60 (0%) 1/61 (1.6%)
    Pollakiuria 0/60 (0%) 1/61 (1.6%)
    Reproductive system and breast disorders
    Vulvovaginal pain 1/60 (1.7%) 0/61 (0%)
    Pruritus genital 0/60 (0%) 1/61 (1.6%)
    Respiratory, thoracic and mediastinal disorders
    Cough 7/60 (11.7%) 8/61 (13.1%)
    Oropharyngeal pain 6/60 (10%) 4/61 (6.6%)
    Nasal congestion 3/60 (5%) 4/61 (6.6%)
    Rhinorrhoea 2/60 (3.3%) 1/61 (1.6%)
    Nasal obstruction 1/60 (1.7%) 0/61 (0%)
    Pulmonary congestion 1/60 (1.7%) 0/61 (0%)
    Sleep apnoea syndrome 1/60 (1.7%) 1/61 (1.6%)
    Epistaxis 0/60 (0%) 1/61 (1.6%)
    Rhinitis allergic 0/60 (0%) 1/61 (1.6%)
    Sinus disorder 0/60 (0%) 1/61 (1.6%)
    Upper-airway cough syndrome 0/60 (0%) 1/61 (1.6%)
    Skin and subcutaneous tissue disorders
    Dry skin 3/60 (5%) 0/61 (0%)
    Acanthosis nigricans 1/60 (1.7%) 1/61 (1.6%)
    Acne 1/60 (1.7%) 1/61 (1.6%)
    Dermatitis allergic 1/60 (1.7%) 0/61 (0%)
    Drug eruption 1/60 (1.7%) 0/61 (0%)
    Hyperhidrosis 1/60 (1.7%) 0/61 (0%)
    Pruritus 1/60 (1.7%) 0/61 (0%)
    Rash 1/60 (1.7%) 1/61 (1.6%)
    Rash pruritic 1/60 (1.7%) 0/61 (0%)
    Blister 0/60 (0%) 2/61 (3.3%)
    Dermatitis atopic 0/60 (0%) 1/61 (1.6%)
    Dermatitis contact 0/60 (0%) 1/61 (1.6%)
    Erythema 0/60 (0%) 1/61 (1.6%)
    Vascular disorders
    Hypotension 1/60 (1.7%) 0/61 (0%)
    Pallor 1/60 (1.7%) 0/61 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Results Point of Contact

    Name/Title Alice Huntsman Labed
    Organization BioMarin Pharmaceutical Inc.
    Phone +44 207 4203392
    Email alice.huntsmanlabed@bmrn.com
    Responsible Party:
    BioMarin Pharmaceutical
    ClinicalTrials.gov Identifier:
    NCT03197766
    Other Study ID Numbers:
    • 111-301
    • 2015-003836-11
    First Posted:
    Jun 23, 2017
    Last Update Posted:
    Mar 2, 2022
    Last Verified:
    Feb 1, 2022