| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Bones and nerves physological processes [G11] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000452 |
| E.1.2 | Term | Achondroplasia |
| E.1.2 | System Organ Class | 100000004850 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the study is to evaluate the safety of BMN 111 in children who are at risk of requiring cervicomedullary decompression surgery. |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objective of the study is to evaluate the efficacy of BMN 111 in children who are at risk of requiring cervicomedullary decompression surgery. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Individuals eligible to participate in this study must meet all of the following criteria:
1. Parent(s) or guardian(s) willing and able to provide signed informed consent after the nature of the study has been explained and prior to performance of any research related procedure.
2. Have ACH, documented by genetic testing.
3. Are willing and able to perform all study procedures as physically possible.
4. Age from 0 months to ≤12 months, at study entry (Day 1).
5. Parent(s) or caregiver(s) are willing to administer daily injections to the subject and complete the required training.
6. Have evidence of cervicomedullary compression (CMC) that “may” require surgical intervention defined as:
o Baseline MRI assessment from central blinded evaluation showing at least one of the following findings:
-Narrowing of the foramen magnum with loss of cerebrospinal fluid space surrounding the cord.
-Narrowing of the foramen magnum with flattening of the cervical cord without T2 signal change.
o Supported by (but not required for eligibility) the following clinical findings:
Baseline physical examination
-Gross or fine motor developmental milestone delay compared to expected for ACH (eg, lifting head when lying on stomach).
• Abnormal reflex (eg, brisk reflex / abnormal clonus for age).
• Weakness (eg, opisthotonus).
-Baseline sleep study
• Sleep apnea with a primary central component (eg, not secondary to obstructive sleep apnea).
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| E.4 | Principal exclusion criteria |
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study:
1. Have hypochondroplasia or short-stature condition other than achondroplasia (eg, trisomy 21, pseudoachondroplasia, etc).
2. Have CMC that either does not require surgical intervention (for example foramen magnum narrowing with preservation of the cerebrospinal fluid space) or does require immediate surgical intervention (for example narrowing of the foramen magnum with cervical cord signal change).
3. Have any of the following:
o Untreated congenital hypothyroidism or maternal history of hyperthyroidism.
o Insulin-requiring neonatal diabetes mellitus.
o Autoimmune inflammatory disease.
o Inflammatory bowel disease.
o Autonomic neuropathy.
4. Have a history of any of the following:
o Renal insufficiency.
o Chronic anemia.
o Baseline systolic blood pressure below age and gender specified normal range or recurrent symptomatic hypotension (defined as episodes of low blood pressure generally accompanied by symptoms eg, pallor, cyanosis, irritability, poor feeding).
o Cardiac or vascular disease, including the following:
Cardiac dysfunction (abnormal echocardiogram determined to be clinically significant by Investigator and Medical Monitor) at Screening.
Hypertrophic cardiomyopathy.
Pulmonary hypertension.
Clinically significant structural heart disease or valvular insufficiency (associated with symptoms or requiring intervention).
Clinically significant cerebrovascular disease.
Clinically significant atrial or ventricular arrhythmias.
5. Have a clinically significant finding or arrhythmia that indicates abnormal cardiac function or conduction or QTc-F ≥ 450 msec on screening ECG.
6. Current treatment with antihypertensive medications, ACE inhibitors, angiotensin II receptor blockers, diuretics, beta-blockers, calcium-channel blockers, cardiac glycosides, systemic anticholinergic agents, any medication that may impair or enhance compensatory tachycardia, drugs known to alter renal function that is expected to continue for the duration of the study.
7. Require any other investigational product prior to completion of the study period.
8. Have received another investigational product or investigational medical device within 30 days prior to Screening.
9. Have used any other investigational product or investigational medical device for the treatment of achondroplasia or short stature at any time.
10. Require current chronic therapy with antihypertensive medication or any medication that, in the Investigator’s judgment, may compromise the safety or ability of the subject to participate in this clinical study.
11. Have been treated with growth hormone, insulin-like growth factor 1, or anabolic steroids in the 6 months prior to Screening, or long-term treatment (> 3 months) at any time.
12. Have had regular long-term treatment ( > 1 month) with oral corticosteroids (low-dose ongoing inhaled steroid for asthma, or intranasal steroids, are acceptable) prior to Screening
13. Have ever had prior cervicomedullary decompression surgery.
14. Have had a fracture of the long bones or spine within 6 months prior to Screening.
15. Have aspartate aminotransferase, alanine aminotransferase, or total bilirubin > 2 × the upper limit of normal at Screening (except for subjects with a known history of Gilbert’s syndrome or transient indirect hyperbilirubinemia).
16. Have current malignancy, history of malignancy, or currently under work-up for suspected malignancy.
17. Have known hypersensitivity to BMN 111 or its excipients.
18. Have a history of hip surgery or clinically significant hip abnormality in the 30 days prior to Screening.
19. Have a condition or circumstance that, in the view of the Investigator, places the subject at high risk for poor treatment compliance or for not completing the study.
20. Have any concurrent disease or condition that, in the view of the Investigator, would interfere with study participation or safety evaluations, for any reason
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Safety will be evaluated by the incidence of AEs, SAEs, laboratory test results (chemistry and hematology), vital signs (heart rate, blood pressure, respiratory rate, and temperature), physical examination, electrocardiogram, echocardiography, and concomitant medications. Clinical laboratory tests will be limited to the minimum necessary for evaluation of safety in order to minimize the required blood draw volume in this young pediatric population. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
AE, SAE recording: All visits
Concomitant meds: All visits
Clin lab assessments: Screen, Day 1, Weeks 6, 13, 26, 39, 52, 65, 78, 91, 104, every 26 weeks up to Week 260, Safety Follow up
Vital Signs: Screening, Day 1, Day 2 and 3 for subjects randomized to BMN 111+ SoC only, Weeks 6, 13, 26, 39, 52, 65, 78, 91, 104, week 104 Day 2 and 3 for subjects crossing-over to BMN 111 + SoC only, every 26 weeks up to Week 260, Safety FU
Phys exam: Screen, Day 1, Weeks 6, 13, 26, 39, 52, 65, 78, 91, 104, every 26 weeks up to Week 260 Safety Follow up
ECG: Screen, Day 1, Day 2 and 3 for subjects randomized to BMN 111 + SoC only, Weeks 6, 13, 26, 39, 52, 65, 78, 91, 104, week 104 Day 2 and 3 for subjects crossing-over to BMN 111 + SoC only, every 26 weeks up to Week 260, Safety Follow up
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| E.5.2 | Secondary end point(s) |
Efficacy will be assessed by careful neurological clinical examination, MRI including the brain stem, foramen magnum, and spine, and age-specific developmental milestone acquisition (Bayley-III score). A board-certified, fellowship-trained (or equivalent) pediatric anesthesiologist will administer anesthesia during MRI measurements. Independent expert review of all MRI assessments will be performed to standardize eligibility assessment and interpretation of changes during study). Specific criteria for evaluation of signs and symptoms of foramen magnum stenosis leading to CMC include:
• Incidence of surgical interventions for CMC including cervicomedullary decompression.
• The effect of BMN 111 on the foramen magnum and neuroanatomy at the cervicomedullary junction.
• The effect of BMN 111 on the anatomy of the spine including the thoracolumbar spine.
• The effect of BMN 111 on neurological signs and symptoms of CMC.
• The effect of BMN 111 on age-specific developmental milestones using the Bayley-III score.
In addition, the effect of BMN 111 on sleep apnea will be evaluated and anthropometric measurements will be performed
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Anthropometric measurements: Day 1, Weeks 13, 26, 39, 52, 65, 78, 91, 104, every 26 weeks up to Week 260
MRI measurements: Screening, Weeks 26, 52, 78, 104, every 52 weeks up to Week 260
Bayley-III: Screening, Weeks 26, 52, 78, 104, every 52 weeks up to Week 260
Neurological examination: Screening, Day 1, Weeks 6, 13, 26, 39, 52, 65, 78, 91,
104, every 52 weeks up to Week 260, Safety Follow up
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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