E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 | 19.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000452 |
E.1.2 | Term | Achondroplasia |
E.1.2 | System Organ Class | 100000004850 |
|
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 initial 6-month phase is:
To evaluate the safety and tolerability of daily SC injections of BMN 111 administered for 6 months
The primary objective of the study extension is:
To evaluate the safety and tolerability of daily SC injections of BMN 111 administered for up to 24 months |
|
E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
- To evaluate change from baseline in annualized growth velocity following daily SC injections of BMN 111 administered for 6 months, and up to 24 months
- To evaluate changes from baseline in growth parameters following daily SC injections of BMN 111 administered for 6 months, and up to 24 months
- To evaluate changes from baseline in body proportions (upper arm to forearm length, upper leg to lower leg length, and upper to lower body segment ratios) following daily SC injections of BMN 111 administered for 6 months, and up to 24 months
- To evaluate dose-exposure and PK profiles of BMN 111 in children with ACH following daily SC injections of BMN 111 at each dose level and over multiple days |
|
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.
2. 5 to 14 years old, inclusive 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 assessment in Study 111-901 immediately before study entry, and has one documented standing height at least 6 months (+/- 10 days) prior to the screening visit for 111-202
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. Parents or caregivers are willing to administer daily injections to the subjects
Additional Inclusion Criteria Option, Open-Label Extension Phase:
1. Appropriate written informed consent (and assent, if applicable) |
|
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, or Recent acute illness associated with volume depletion (e.g., nausea, vomiting, diarrhea) that has not completely resolved prior to the first dose of the study drug
3. Have an unstable condition likely to require surgical intervention during the study (including progressive cervical medullary compression)
4. Growth plates have fused
5. Have a history of any of the following: Renal insufficiency (defined as serum creatinine >2 mg/dl), Anemia, Baseline systolic blood pressure (BP) <75 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, or Cardiac or vascular disease, including the following: Cardiac dysfunction (abnormal ECHO including abnormal LV mass) at Screening Visit, Hypertrophic cardiomyopathy, Pulmonary hypertension, Congenital heart disease with ongoing cardiac dysfunction, Cerebrovascular disease, Aortic insufficiency, or Clinically significant atrial or ventricular arrhythmias
6. Have the following confirmed ECG findings: Right or left atrial enlargement or ventricular hypertrophy, PR interval >200msec, QRS interval >110msec, Corrected QTc-F >450msec, or Second- or third-degree atrioventricular block
7. Documented Vitamin D deficiency (i.e., concentration of 25-hydroxyvitamin D in the blood serum occurs at 12ng/mL or less)
8. Require any investigational agent prior to completion of study period
9. Have received another investigational product or investigational medical device within 30 days before Screening visit
10. Have used any other investigational product or investigational medical device for the treatment of ACH or short stature at any time
11. Current chronic therapy 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, diuretics, or other drugs known to alter renal or tubular function
12. Have been treated with growth hormone, IGF-1, or anabolic steroids in the previous 6 mos or long-term treatment (> 3 mo) at any time
13. Have had regular long-term treatment (> 1 mo) with oral corticosteroids (low-dose ongoing inhaled steroid for asthma, or intranasal steroids, are acceptable)
14. Concomitant medication that prolongs the QT/QTc-F interval within 14 days or 5 half lives, whichever is longer, before Screening visit
15. Pregnant or breastfeeding at Screening Visit or planning to become pregnant (self or partner) at any time during the study
16. Have had limb-lengthening or bone-related surgery or expected to have limb-lengthening or bone-related surgery during the study period. Subjects with previous limb-lengthening or bone-related surgery may enroll if surgery occurred at least 18 mo prior to the study and
healing is complete without sequelae
17. Have had a fracture of the long bones or spine within 6 mos prior to screening (except for fracture of digits or toes)
18. Have AST or ALT at least 3x ULN or total bilirubin at least 2x ULN (except for subjects with known history of Gilbert's disease)
19. Evidence of severe sleep apnea requiring surgery or new initiation of CPAP (based on the screening sleep study)
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. Has 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
23. Concurrent disease or condition that, in the view of the Investigator, would interfere with study participation or safety evaluations, or would predispose the subject to hypotension (such as recent gastroenteritis or dehydration for any reason)
24. Have abnormal findings on baseline clinical hip exam or imaging assessments that are determined to be clinically significant as determined by the PI
25. Have a history of hip surgery or severe hip dysplasia
26. Have a history of clinically significant hip injury in the 30 days prior to screening
27. History of slipped capital femoral epiphysis or avascular necrosis of the femoral head
28. Are unable to lie flat when in prone position (needed for hip monitoring exam)
Add'l Exclusion Criteria for Optional, Open-label Extension Phase:
-Use of restricted therapies during the initial 6 mo of the study
-Permanently discontinued BMN 111 during the initial 6 mo of the study
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Safety will be evaluated by the incidence of AEs, serious adverse events (SAEs), laboratory test results (urinalysis, chemistry, hematology), changes in vital signs, physical examination, ECG and ECHO results, imaging, clinical hip assessment, and anti-BMN 111 immunogenicity assessments. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
AEs,SAEs,vital signs,phys exam-
Screening,D1,2,3,4,10,15,22,29,43,85,127,183,208,Early
Term,M8,10,12,15,18,21,24,25,Dose Escalation,Early Term
ECG-Screening,D10,29,85,183,208,Early
Term,M8,10,12,15,18,21,24,Dose Esc,Early Term
ECHO-Screening,D183,M12,18,24,Early Term
Anti-BMN 111 immuno-D1,10,29,85,183,208,Early
Term,M8,10,12,15,18,21,24,25,Dose Esc,Early Term
Lab tests-Screening,D1,4,10,15,29,43,85,127,183,208,Early
Term,M8,10,12,15,18,21,24,25,Dose Esc,Early Term
Hip Monitoring-Screening,D183,Early Term, M12,18,24,Early Term
Imaging:
X-ray (PA of hand and wrist)-Screening,D183,Early
Term,M12,18,24,Early Term; AP lower extremity radiograph-
Screening,D183,Early Term,M12,24,Early Term |
|
E.5.2 | Secondary end point(s) |
Efficacy will be assessed by change from baseline in height growth velocity (annualized to cm/yr), growth parameters, and in body proportions. These will be assessed by anthropometric measurements and measurement ratios. Anthropometric measurements may include but are not limited to standing height, sitting height, weight, head circumference, upper and lower arm and leg, hand and foot. Upper arm to forearm length ratio, upper leg to lower leg length ratio, and upper to lower body segment ratio will be calculated. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
6-month initial phase:
Screening, Days 43, 85, 127, 183, and Early Term
Extension phase:
Months 8, 10, 12, 15, 18, 21, 24, 25, and Early Term |
|
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 | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
|
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 | No |
E.8.1.1 | Randomised | No |
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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
sequential cohort dose-escalation |
|
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 | No |
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
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 |
France |
United Kingdom |
United States |
|
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 | |
E.8.9.1 | In the Member State concerned months | 25 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 25 |