Achondroplasia
Conditions
Keywords
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
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.
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.
Interventions
DRUGBMN 111
Subcutaneous injection of 15 μg/kg of BMN 111 daily
DRUGPlacebo
Subcutaneous injection of 15 μg/kg of placebo daily
Sponsors
BioMarin Pharmaceutical
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
5 Years to 18 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 |
| 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) |
Countries
Australia, Germany, Japan, Spain, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
This was a multi-centre study conducted by 24 principal investigators at 24 study centers in 7 countries
Pre-assignment details
A total of 121 subjects were enrolled into the study, 119 subjects completed and 2 subjects withdrew from the study.
Participants by arm
| Arm | Count |
|---|---|
| BMN 111 - 15 μg/kg BMN 111: Subcutaneous injection of 15 μg/kg of BMN 111 daily | 60 |
| Placebo Placebo: Subcutaneous injection of placebo daily | 61 |
| Total | 121 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | BMN 111 - 15 μg/kg |
|---|---|---|---|
| Age, Continuous | 9.06 years STANDARD_DEVIATION 2.47 | 8.71 years STANDARD_DEVIATION 2.47 | 8.35 years STANDARD_DEVIATION 2.43 |
| Annualized Growth Velocity (AGV) | 4.06 cm/year STANDARD_DEVIATION 1.2 | 4.16 cm/year STANDARD_DEVIATION 1.37 | 4.26 cm/year STANDARD_DEVIATION 1.53 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 7 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 55 Participants | 114 Participants | 59 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height Z-Score | -5.14 Z-score STANDARD_DEVIATION 1.07 | -5.13 Z-score STANDARD_DEVIATION 1.09 | -5.13 Z-score STANDARD_DEVIATION 1.11 |
| Race/Ethnicity, Customized Race Asian-Japanese | 4 Participants | 7 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Asian-Other | 9 Participants | 16 Participants | 7 Participants |
| Race/Ethnicity, Customized Race Black or African American | 2 Participants | 5 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Multiple | 5 Participants | 7 Participants | 2 Participants |
| Race/Ethnicity, Customized Race White | 41 Participants | 86 Participants | 45 Participants |
| Sex: Female, Male Female | 28 Participants | 57 Participants | 29 Participants |
| Sex: Female, Male Male | 33 Participants | 64 Participants | 31 Participants |
| Upper to Lower Body Segment Ratio | 2.01 Ratio STANDARD_DEVIATION 0.21 | 2.00 Ratio STANDARD_DEVIATION 0.2 | 1.98 Ratio STANDARD_DEVIATION 0.2 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 60 | 0 / 61 |
| other Total, other adverse events | 59 / 60 | 60 / 61 |
| serious Total, serious adverse events | 3 / 60 | 4 / 61 |
Outcome results
Primary
Change From Baseline in Annualized Growth Velocity (AGV) at 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
Time frame: At Baseline and Week 52
Population: Analysis were performed on the Full Analysis Set (FAS) which included all randomized subjects with a signed informed consent
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BMN 111 - 15 μg/kg | Change From Baseline in Annualized Growth Velocity (AGV) at Week 52 | 1.71 cm/year |
| Placebo | Change From Baseline in Annualized Growth Velocity (AGV) at Week 52 | 0.13 cm/year |
p-value: <0.0001ANCOVA
Secondary
Change From Baseline in Height Z-score at 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.
Time frame: At baseline and Week 52
Population: Analysis were performed on the Full Analysis Set (FAS) which included all randomized subjects with a signed informed consent.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BMN 111 - 15 μg/kg | Change From Baseline in Height Z-score at Week 52 | 0.27 Z-Score |
| Placebo | Change From Baseline in Height Z-score at Week 52 | -0.01 Z-Score |
p-value: <0.0001ANCOVA
Secondary
Change From Baseline in Upper to Lower Segment Body Ratio at 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
Time frame: At baseline and Week 52
Population: Analysis were performed on the Full Analysis Set (FAS) which included all randomized subjects with a signed informed consent
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BMN 111 - 15 μg/kg | Change From Baseline in Upper to Lower Segment Body Ratio at Week 52 | -0.03 Ratio |
| Placebo | Change From Baseline in Upper to Lower Segment Body Ratio at Week 52 | -0.02 Ratio |
p-value: =0.506ANCOVA
Secondary
Summary of Subjects Experiencing Adverse Events (AEs) During Treatment
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BMN 111 - 15 μg/kg | Summary of Subjects Experiencing Adverse Events (AEs) During Treatment | Subjects with any AE | 59 participants |
| BMN 111 - 15 μg/kg | Summary of Subjects Experiencing Adverse Events (AEs) During Treatment | Subjects with any SAE | 3 participants |
| BMN 111 - 15 μg/kg | Summary of Subjects Experiencing Adverse Events (AEs) During Treatment | Subjects with any treatment-related AE | 53 participants |
| BMN 111 - 15 μg/kg | Summary of Subjects Experiencing Adverse Events (AEs) During Treatment | Subjects who died | 0 participants |
| Placebo | Summary of Subjects Experiencing Adverse Events (AEs) During Treatment | Subjects who died | 0 participants |
| Placebo | Summary of Subjects Experiencing Adverse Events (AEs) During Treatment | Subjects with any AE | 60 participants |
| Placebo | Summary of Subjects Experiencing Adverse Events (AEs) During Treatment | Subjects with any treatment-related AE | 51 participants |
| Placebo | Summary of Subjects Experiencing Adverse Events (AEs) During Treatment | Subjects with any SAE | 4 participants |