| 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 objectives of the study are to:
- Evaluate the safety and tolerability of BMN 111 in children age 0 to < 60 months with ACH
- Evaluate the effect of BMN 111 on change from baseline in length/ height Z-score |
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| E.2.2 | Secondary objectives of the trial |
- Evaluate the effect of BMN 111 on change from baseline in AGV throughout the 52 weeks of the study
- Evaluate the effect of BMN 111 on bone morphology/quality by x-ray and dual x-ray absorptiometry (DXA)
- Evaluate the PK of BMN 111 in children age 0 to < 60 months with ACH
- Evaluate hip function
- Evaluate for hip, thigh, or knee pain, or change in gait from medical history
- Evaluate the effect of BMN 111 on health related quality of life (HRQol), developmental status, and functional using age-specific QoL and functional independence questionnaires (Bayley-Scales of Infant and Toddler Development, Third eddition [Bayley III], Activity of Daily Living and Functional Independence Meaure (Wee-FIM), Infant Toddler Quality of Life Questionnaire (ITQOL), Child Behavior Checklist [CBCL]
- Evaluate immunogenicity of BMN 111 and assess impact on safety, PK, and efficacy measures
- Evaluate the effect of BMN 111 on bone metabolism and BMN 111 pharmacodynamic biomarkers |
Evaluate the effect of BMN 111 on growth parameters and body
proportions, including change from baseline in upper:lower segment
body ratio
Evaluate the effect of BMN 111 on sleep apnea
Evaluate the effect of BMN 111 on skull and brain morphology, including
foramen magnum, ventricular and brain parenchymal dimensions
Describe the incidence of surgical interventions, including cervical
decompression, adenotonsillectomy,and tympanostomy |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Diagnosis of ACH, confirmed by genetic testing. If subjects had previous genetic testing, subjects must have a lab report from a certified laboratory with the study specific mutation documented.
2. Age 0 to < 60 months, at study entry (Day 1)
3. Cohort 1 and 2 subjects must have at least a 6-month period of pre-treatment growth assessment in Study 111-901 immediately before screening and have one documented measurement of height/body length a minimum of 6 months (+/- 10 days) prior to the screening visit for 111-206. Cohort 3 subjects must have a minimum of 3 months of observation prior to treatment. This observational period can be obtained either (1) via prior enrolment in Study 111-901 or (2) via enrolment in this Study 111-206 for a minimum of 3 months of non-treatment observation prior to commencement of treatment.
4. Parent(s) or guardian(s) (and the subjects themselves, if required by local regulations or ethics committee) are willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to performance of any research-related procedure
5. Willing and able to perform all study procedures as physically possible
6. Parent(s) or caregiver(s) are willing to administer daily injections to the subjects and complete the required training.
Inclusion Criteria for Cohort 3 Observation Period
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. Also, willing and able to provide written assent (if applicable) after the nature of the study has been explained and prior to performance of any research-related procedure.
2.Birth to ≤ 3 months of age at study entry.
3.Have ACH, documented by genetic testing
4.Are willing and able to perform all study procedures as physically possible
After completing observation period subjects must fulfil the general eligibility criteria prior to receiving treatment with study drug. |
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| E.4 | Principal exclusion criteria |
1. Have hypochondroplasia or short-stature condition other than achondroplasia (e.g., trisomy 21, pseudoachondroplasia, etc.)
2. Subject weighs < 5.0 kg (Cohort 1 and 2) or < 4.0 kg (Cohort 3; treatment phase)
3. Have any of the following:
- Hypothyroidism or hyperthyroidism
- Insulin-requiring diabetes mellitus
- Autoimmune inflammatory disease (including celiac disease, systemic lupus erythematosus, juvenile dermatomyositis, scleroderma, etc.)
- Inflammatory bowel disease
- Autonomic neuropathy
4. Have a history of any of the following:
- Renal insufficiency defined as serum creatinine > 2 mg/dL
- Chronic anemia or Hgb < 10.0 g/dL (based on screening clinical laboratory testing)
- Baseline systolic blood pressure (BP) below age and gender specified normal range or recurrent symptomatic hypotension (defined as episodes of low BP generally accompanied by symptoms e.g., dizziness, fainting) or recurrent symptomatic orthostatic hypotension
- Cardiac or vascular disease, including the following
o Cardiac dysfunction (abnormal echocardiogram determined to be
clinically significant by PI and medical monitor) at Screening Visit
o Hypertrophic cardiomyopathy
o Pulmonary hypertension
o Congenital heart disease with ongoing cardiac dysfunction
o Cerebrovascular disease
o Aortic insufficiency or other clinically significant valvular dysfunction
o 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. Have evidence of cervicomedullary compression (CMC) likely to require surgical intervention within 60 days of Screening as determined by the Investigator and informed on the following assessments:
- Physical exam (e.g., neurologic findings of clonus, opisthotonus, exaggerated reflexes, dilated facial veins)
- Polysomnography (e.g., severe central sleep apnea)
- MRI indicating presence of severe CMC or spinal cord damage
7. Have an unstable medical condition likely to require surgical intervention in the next 6 months, or planned spine or long-bone surgery (i.e., surgery involving significant disruption of bone cortex) during the study period
8. Have documented uncorrected Vitamin D deficiency: 25(OH)D ≤ 15 ng/mL (37.5 nmol/L)
9. Require any other investigational product prior to completion of the study period
10. Have received another investigational product or investigational medical device within 30 days prior to the Screening visit
11. Have used any other investigational product or investigational medical device for the treatment of achondroplasia or short stature at any time
12. 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
13. Have been treated with growth hormone, insulin-like growth factor 1 (IGF-1), or anabolic steroids in the 6 months prior to screening, or long-term treatment (> 3 months) at any time
14. Have had regular long-term treatment (> 1 month) with oral corticosteroids (low-dose ongoing inhaled steroid for asthma, or intranasal steroids, are acceptable) in the 12 months prior to screening.
15. Have ever had CMC surgery (Cohorts 2 and 3 only), spine or long-bone surgery (i.e., surgery involving disruption of bone cortex) or have ever had bone-related surgery with chronic complications.
NOTE: Subjects with prior cervicomedullary decompression may be allowed into Cohort 1 only after discussion and agreement with the Medical Monitor.
16. Have ever had limb-lengthening surgery or plan to have limb-lengthening surgery during the study period.
17. Have had a fracture of the long bones or spine within 6 months prior to screening.
18. Have aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or total bilirubin greater than upper limit of normal (ULN) at screening (except for subjects with a known history of Gilberts or newborns entering screening in Cohort 3).
19. Have evidence of severe untreated sleep apnea; or have newly initiated sleep apnea treatment (eg, continuous positive airway pressure [CPAP] or sleep apnea-mitigating surgery) in the 2 months prior to screening.
20. Have current malignancy, history of malignancy, or currently under work-up for suspected malignancy.
21. Have known hypersensitivity to BMN 111 or its excipients
22. Have a history of hip surgery or severe hip dysplasia.
23. Have a history of clinically significant hip injury in the 30 days prior to screening.
24. Have a history of slipped capital femoral epiphysis or avascular necrosis of the femoral head
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25. Have abnormal findings on baseline clinical hip exam or imaging assessments that are determined to be clinically significant as determined by the Investigator.
26. 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. 27. Have any concurrent disease or condition that, in the view of the Investigator, would interfere with study participation or safety evaluations, for any reason
Exclusion Criteria for Cohort 3 Observation Period
Individuals who meet any of the following exclusion criteria are not eligible to participate in the study:
1.Have hypochondroplasia or short stature condition other than ACH (e.g., trisomy 21, pseudoachondroplasia)
2.Have any of the following disorders:
•Hypothyroidism
•Insulin-requiring diabetes mellitus
•Autoimmune inflammatory disease (including celiac disease, lupus (SLE), juvenile dermatomyositis, scleroderma, and others)
•Inflammatory bowel disease
•Autonomic neuropathy
3.Have an unstable clinical condition likely to lead to intervention during the course of the study, including progressive cervical medullary compression
4.Have a history of any of the following:
•Renal insufficiency
•Anemia
5.Have a history of cardiac or vascular disease, including the following:
•Cardiac dysfunction
•Hypertrophic cardiomyopathy
•Congenital heart disease
•Cerebrovascular disease, aortic insufficiency
•Clinically significant atrial or ventricular arrhythmias
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.Have had regular long-term treatment (> 1 month) with oral corticosteroids (low dose ongoing inhaled steroid for asthma is acceptable) in the previous 3 months
8.Concomitant medication that prolongs the QT/QTc interval within 14 days or 5 half lives, whichever is longer, before the Screening visit
9.Have used any other investigational product or investigational medical device for the treatment of ACH or short stature
10.Planned or expected bone-related surgery (ie. surgery involving disruption of bone cortex), during the study period.
11.Planned or expected to have limb-lengthening surgery during the study period.
12.Have any condition that, in the view of the Investigator, places the subject at high risk of poor compliance with the visit schedule or of not completing the study.
13.Concurrent disease or condition that, in the view of the Investigator, would interfere with study participation
After completing observation period subjects must fulfill the general eligibility criteria prior to recieving treatment with study drug. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- To assess the safety and tolerability of daily SC BMN 111 administered
in children age 0 to < 60 months with ACH
- To evaluate the effect of BMN 111 on length/height Z-score. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
-Duration of trial
-Anthropometric Measurement: Screening/ Baseline, Day 1, Week 6, Week 13, Week 26, Week 39, Week 52
-Imaging assessments (X-rays of the spine and entire lower extremities,
DXA of total body less head and spine)
-CBCL |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints include:
1) Change from baseline in AGV (annualized to cm/yr),
2) Change from baseline in bone morphology/quality,
3) PK sampling,
4) hip function,
5) hip, thigh, or knee pain, or change in gait from medical history,
6) developmental/functional/QOL status
7) Evaluate immunogenicity of BMN 111
8) Biomarker samples to evaluate the effect of BMN 111 on bone metabolism and BMN 111 pharmacodynamic biomarkers. Growth
parameters and body proportions, sleep apnea, skull and brain
morphology, and clinical outcome assessments (developmental/functional/HRQoL status). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Anthropometric Measurement: Screening/ Baseline, Day 1, Week 6, Week 13, Week 26, Week 39, Week 52
2) DXA and AP and lateral X-rays: Screening/ Baseline, Week 52
3) Day 1, Week 13, Week 26, Week 39, Week 52
4) Screening/ Baseline, Week 26, Week 52
5) Screening/ Baseline, Day 1, Day 2, Day 3, Day 8, Week 3, Week 6, Week 13, Week 20, Week 26, Week 39, Week 52, Week 56
6) Screening/ Baseline, Week 26, Week 52
7) Day 1, Week 13, Week 26, Week 52
8)
- Blood and urine biomarkers: Screening/ Baseline, Day 1, Day 2, Day 3, Day 8, Week 3, Week 6, Week 13, Week 20, Week 26, Week 39, Week 52
- Biomarker samples (optional): Week 6 and Week 52
|
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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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| 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 | Yes |
| E.8.2.3 | Other | No |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| 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 |
| Australia |
| Japan |
| United Kingdom |
| United States |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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