| 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 |
| Evaluate change from baseline in annualized growth velocity at 52 weeks in subjectstreated with BMN 111 compared with control subjects in the placebo group |
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| E.2.2 | Secondary objectives of the trial |
•Evaluate change from baseline in height Z-score in subjects treated with BMN 111 compared with control subjects in the placebo group at 52 weeks
•Evaluate change from baseline in upper:lower segment body ratio in subjects treated with BMN 111 compared with control subjects in the placebo group at 52 weeks
•Evaluate safety and tolerability of BMN 111 in children with ACH
•Evaluate the pharmacokinetics of BMN 111
•Evaluate change from baseline in bone metabolism biomarkers |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Parent(s) or guardian(s) 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. Also, subjects under the age of 18 are willing and able to provide written assent (if required by local regulations or the IRB/EC) after the nature of the study has been explained and prior to performance of any research-related procedure. Subjects who reach the age of 18 years while the study is ongoing will be asked to provide their own written consent.
2. 5 to < 18 years old at study entry
3. Have ACH, documented by clinical grounds and confirmed by genetic testing
4. Have at least a 6-month period of pretreatment growth assessments, including standing height, and are currently active participants in 111-901.
5. Females ≥ 10 years old or who have begun menses must have a negative pregnancy test at the Screening Visit and be willing to have additional pregnancy tests during the study
6. If sexually active, willing to use a highly effective method of contraception while participating in the study
7. Are ambulatory and able to stand without assistance
8. Are willing and able to perform all study procedures as physically possible
9. Caregivers are willing to administer daily injections to the subjects and complete the required training |
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| E.4 | Principal exclusion criteria |
1. Have hypochondroplasia or short stature condition other than ACH (e.g., trisomy 21, pseudoachondroplasia)
2. Have any of the following: Hypothyroidism or hyperthyroidism; Insulin-requiring diabetes mellitus; Autoimmune
inflammatory disease (including celiac disease, lupus (SLE), juvenile dermatomyositis, scleroderma, and others); Inflammatory bowel disease; Autonomic neuropathy
3. Have a 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 i.e., dizziness, fainting) or recurrent symptomatic orthostatic hypotension; Cardiac or vascular disease (including Cardiac dysfunction (abnormal echocardiogram) at Screening Visit; Hypertrophic cardiomyopathy; Pulmonary hypertension; Congenital heart disease; Cerebrovascular disease; Aortic insufficiency or other clin significant valvular dysfunction; Clinically significant atrial or ventricular arrhythmias)
4. Have a clinically significant finding or arrhythmia on screening electrocardiogram (ECG) that indicates abnormal cardiac function or conduction or QTc-F > 450 msec
5. Have an unstable condition likely to require surgical intervention during the study (including progressive cervical medullary compression or severe untreated sleep apnea)
6. Evidence of decreased growth velocity (AGV<1.5 cm/y) as assessed over a period of at least 6 mths or of growth plate closure (proximal tibia, distal femur) through bilateral lower extremity X-rays including both AP and lateral views
7. Documented Vitamin D deficiency (concentration of blood 25-hydroxy-vitamin D <12 ng/mL or <30 nmol/L)
8. Require any investigational agent prior to completion of study period9. Have received another investigational product or investigational medical device within 6 mths before the Screening Visit
10. Have used any investigational product or investigational medical device for the treatment of ACH or short stature at any time, including BMN 111
11. Current therapy with antihypertensive medications, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, diuretics, beta-blockers, calcium-channel blockers, cardiac glycosides, systemic anticholinergic agents, GnRH agonists, any medication that may impair or enhance compensatory tachycardia, diuretics, or other drugs known to alter renal or tubular function
12. Have been 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
13. Have had > 1 month treatment with oral corticosteroids (low-dose ongoing inhaled steroid for asthma, or intranasal steroids, are acceptable) in the previous 12 months
14. 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 screening and healing is complete without sequelae.
15. 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 screening and healing is complete without sequelae.
16. Have had a fracture of the long bones or spine within 6 mth prior to screening
17. Pregnant or breastfeeding at the Screening Visit or planning to become pregnant (self or partner) at any time during the study
18. Have aspartate aminotransferase (AST) or alanine aminotransferase (ALT) at least 3x upper limit of normal (ULN) or total bilirubin at least 2x ULN (except for subjects with known history of Gilbert’s disease)
19. History of severe untreated sleep apnea
20. Have had new initiation of sleep apnea treatment (e.g. CPAP or sleep apnea-mitigating surgery) in the previous 2 mths prior to screening
21. Have current malignancy, history of malignancy, or currently under work-up for suspected malignancy
22. Have known hypersensitivity to BMN 111 or its excipients
23. Have a history of hip surgery or hip dysplasia atypical for achondroplasia subjects
24. Have a clinically significant hip injury in the 30 days prior to screening
25. History of slipped capital femoral epiphysis or avascular necrosis of the femoral head
26. Are unable to lie flat when in prone position
27. Have abnormal findings on baseline clinical hip exam or imaging assessments that are determined to be clinically significant as determined by the investigator
28. Concurrent disease or condition that, in the view of the investigator, would interfere with study participation or safety evaluations, for any reason
29. 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 |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the change from baseline in annualized growth velocity (AGV) at Week 52 (12- month). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Anthropometric measurements: Screen, Day 1, Week 13, Week 26, Week 39, Week 52 |
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| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints include the change from baseline in height Z-score and the change from baseline in upper:lower body segment ratio.
Safety will be evaluated by assessment of AEs, SAEs, laboratory test results (urinalysis, chemistry, hematology), changes in vital signs, physical examination, ECG, X-rays/DXA, clinical hip assessment, and anti-BMN 111 immunogenicity assessments.
PK sampling will be carried out over the 12-month study period in subjects randomized to BMN 111 or placebo. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Anthropometric measurements: Screen, Day 1, Week 13, Week 26, Week 39, Week 52
Clinical labs (urinalysis, chemistry, hematology): Screen, Day 1, Day 10, Week 6, Week 13, Week 26, Week 39, Week 52, Week 54
Vital signs and AEs: Screen, Day 1, Day 2, Day 3, Day 10, Week 6, Week 26, Week 39, Week 52, Week 54 (follow-up)
Physical exam: Screen, Day 1, Day 10, Week 6, Week 13, Week 26, Week 39, Week 52, Week 54 (follow-up)
ECG: Screen, Day 1, Day 10, Week 13, Week 26, Week 39, Week 52, Week 54 (follow-up)
X-Ray/DXA: Screen, Week 26, Week 52
Clinical hip assessment: Screen, Week 26, Week 52
Anti-BMN 111 immunogenicity: Day 1, Week 13, Week 26, Week 39, Week 52, Week 54 (follow-up)
PK: Day 1 (full), Week 13 (partial), Week 26 (full), Week 39 (partial), Week 52 (full) |
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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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| 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 |
| Germany |
| Japan |
| Spain |
| Turkey |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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