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 this extension study is to: - Evaluate the long-term safety, tolerability, and efficacy for growth in children with ACH treated with BMN 111 |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are to: •Evaluate the pharmacokinetics of BMN 111 •Evaluate immunogenicity of BMN 111 and assess impact on safety, PK, and efficacy measures •Evaluate body proportion ratios of the extremities •Evaluate effect of BMN 111 on bone morphology/quality by X-ray and DXA •Evaluate changes in health-related quality of life as measured the Quality of Life in Short Stature Youth (QoLISSY) and the PedsQL questionnaires •Evaluate changes in functional independence as measured by the Wee FIM clinician-reported outcome •Evaluate change from baseline in bone metabolism biomarkers
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Must have completed Study 111-301 2. 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 majority are willing and able to provide written assent (if required by local regulations or the IRB/IEC) after the nature of the study has been explained and prior to performance of any research-related procedure. Subjects who reach the age of majority in their country while the study is ongoing will be asked to provide their own written consent again upon reaching the legal age of majority. 3. Females ≥ 10 years old or who have begun menses must have a negative pregnancy test at the Baseline Visit and be willing to have additional pregnancy tests during the study 4. If sexually active, are willing to use contraception as specified in section 9.3.3 of the protocol, 5. Are willing and able to perform all study procedures |
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E.4 | Principal exclusion criteria |
1. Permanently discontinued BMN 111 or placebo prior to completion of Study 111-301 2. Have a clinically significant finding or arrhythmia on Baseline electrocardiogram (ECG) that indicates abnormal cardiac function or conduction or QTc-F > 450 msec 3. Evidence of decreased growth velocity (AGV < 1.5 cm/year) as assessed over a period of at least 6 months or of growth plate closure (proximal tibia, distal femur) through bilateral lower extremity X-rays 4.Require any investigational agent prior to completion of study period 5.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 (Table 9.3.2.1) 6.Planned or expected to have limb-lengthening surgery during the study period 7.Pregnant or breastfeeding at the Baseline Visit or planning to become pregnant (self or partner) at any time during the study 8.Concurrent disease or condition that, in the view of the investigator, would interfere with study participation or safety evaluations, for any reason 9.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).
Safety will be evaluated by the incidence of AEs, SAEs, and clinically significant changes in vital signs, physical examination, Tanner stage, ECG, echocardiogram, bone morphology/quality assessed by X-rays/DXA, and laboratory test results (urinalysis, chemistry, hematology). Additionally, imaging, hip monitoring, immunogenicity, salivary cortisol, serum prolactin, and FSH/LH levels (FSH/LH will be monitored for all subjects >8 years of age, and for subjects at Tanner stage 2, whichever is earlier); and anxiety, motor and cognitive assessment with the Childhood Behavioral Checklist (CBCL) and WeeFIM will be utilized for safety-related reviews and analysis. Additional assessments will be conducted to evaluate changes from baseline in bone metabolism and BMN 111 activity biomarkers. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Anthropometric measurements: 111-301 Week52/302 BL, Weeks 13, 26,39, 52, 65, 78, 91, 104, every 26 weeks up to 260
Clinical labs; Vital signs/AEs; Physical exam; Anti-BMN 111 immunogenicity; bone metabolism biomarkers: 111-301 Week 52/302 BL, Day 1, Weeks 13, 26, 39, 52, 65, 78, 91, 104, every 26 weeks up to 260,
ECG; X-Ray/DXA: 111-301, 302BL, Day 1, Weeks 52, 104, 156, 208, 260,
Clinical hip assessment: 111-301 Week 52/302 BL, Weeks 26, 52, 78, 104, every 26 weeks up to 260
Salivary cortisol; serum prolactin; FSH/LH: 111-301 Week 52/302 BL, 26, 52, 78, 26 weeks up to week 260
CBCL and WeeFIM: 111-301 Week 52/302 BL, 26, 52, 78, 104, every 52 weeks up to 260
BMN 111 activity biomarkers: 111-301 Week 52/302 BL, Day1, Weeks 52, 104, every 26 weeks up to 260 |
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E.5.2 | Secondary end point(s) |
1)The secondary efficacy endpoints include the change from baseline in height Z-score and the change from baseline in upper:lower body segment ratio.
2)PK sampling will be carried out over the study period.
3)Health-related Quality of Life (HRQoL) and ADL questionnaires will be administered to assess quality of life and daily activities performance of study subjects. 4) Evaluate immunogenicity of BMN 111 and assess impact on safety, PK and efficacy measures 5) Evaluate change from baseline in body proportion ratios of the extremities 6) Evaluate effect of BMN 111 on bone morphology/quality by X-ray and DXA |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Anthropometric measurements: 111-301 Week 52/302 BL, Weeks 13, 26, 39, 52, 65, 78, 91, 104, every 26 weeks up to Week 260
PK: 301 Week 52/302 BL, Day 1, Week 26, Week 52, Week 104 and every 52 weeks up to Week 260
Health-related Quality of Life (PedsQL, QoLISSY), Functional Independence Assessment (Wee FIM), and CBCL: 111-301 Week 52/302 BL, Week 26, Week 52, Week 78, Week 104, every 26 weeks up to Week 260
DXA (BMD and BMC of whole body less head, spine): Week 52/302 BL, Week 52, Week 104, Week 156, Week 208, Week 260
Anti-BMN 111 immunogenicity: Week 52/302 BL, Day 1. Week 13, Week 26, Week 39, Week 52, Week 65, Week 78, Week 91, Week 104, every 26 week up to Week 260
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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 | 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 | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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
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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 | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |