NCT02055157已完成2 期
A Phase 2, Open-label, Sequential Cohort Dose-escalation Study of BMN 111 in Children With Achondroplasia
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 35
- 试验地点
- 9
- 主要终点
- Overall Summary of Adverse Events During Entire Study Period
研究概览
简要总结
This is a Phase 2, open-label, sequential cohort dose-escalation study of BMN 111 in children with achondroplasia. The primary objective is to assess the safety and tolerability of daily BMN 111 administered to children with achondroplasia.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 5 Years 至 14 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Parent(s) or guardian(s) are willing and able to provide written, signed informed consent
- •5 to 14 years old at end of study
- •ACH, documented by clinical grounds, confirmed by genetic testing
- •At least 6-month of pretreatment growth assessment in Study 111-901 before study entry, and one standing height at least 6 months prior to screening for 111-202
- •Negative pregnancy test at the Screening Visit for females ≥ 10 years old or who have begun menses
- •If sexually active, willing to use a highly effective method of contraception while participating in the study
- •Ambulatory, able to stand without assistance
- •Willing and able to perform all study procedures as physically possible
- •Parents/caregivers willing to administer daily injections to the subjects
- •Additional inclusion Criteria Optional, Open-label Extension Phase:
- •Appropriate written informed consent
排除标准
- •Hypochondroplasia or short stature condition other than ACH
- •Have any of the following:
- •Hypothyroidism or hyperthyroidism
- •Insulin-requiring diabetes mellitus
- •Autoimmune inflammatory disease
- •Inflammatory bowel disease
- •Autonomic neuropathy
- •Recent acute illness associated with volume dehydration not completely resolved prior to the first dose of study drug
- •Unstable condition requiring surgical intervention during the study
- •Growth plates have fused
- •Have a history of any of the following:
- •Renal insufficiency, defined as creatinine > 2 mg/dl
- •Baseline systolic BP < 75 mm Hg or recurrent symptomatic hypotension or recurrent symptomatic hypotension, recurrent symptomatic orthostatic hypotension
- •Cardiac or vascular disease, including the following:
- •Cardiac dysfunction (abnormal echocardiogram [ECHO] including left ventricle [LV] mass) at Screening Visit
- •Hypertrophic cardiomyopathy
- •Pulmonary Hypertension
- •Congenital heart disease with ongoing cardiac dysfunction
- •Cerebrovascular disease
- •Aortic insufficiency
- •Clinically significant atrial or ventricular arrhythmias
- •Have an ECG showing any of the following:
- •Right or left atrial enlargement or ventricular hypertrophy
- •PR (period of time from the beginning of atrial depolarization until the beginning of ventricular depolarization) interval > 200 msec
- •QRS (The Q, R, and S heart waves that are measured on an electrocardiogram) interval > 110 msec
- •Corrected QTc-F (Measure of the corrected time between the start of the Q wave and end of the T wave in the heart's electrical cycle) > 450 msec
- •Second- or third-degree atrioventricular block
- •Documented Vitamin D deficiency
- •Require any investigational agent prior to completion of study period
- •Have received another investigational product or investigational medical device within 30 days before the Screening visit
- •Use of any other investigational product or investigational medical device for the treatment of ACH or short stature
- •Current chronic therapy with antihypertensive medications, angiotensin-converting enzyme (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
- •Treatment with growth hormone, IGF-1 (Insulin-like growth factor), or anabolic steroids in the previous 6 months or long-term treatment (> 3 months) at any time
- •Long-term treatment (> 1 month) with oral corticosteroids
- •Concomitant medication that prolongs the QT/QTc-F interval within 14 days or 5 half-lives, whichever is longer, before the Screening visit
- •Pregnant or breastfeeding at the Screening Visit or planning to become pregnant (self or partner) at any time during the study
- •Limb-lengthening or bone-related surgery < 18 months prior to study enrollment
- •Had a fracture of the long bones or spine within 6 months prior to screening (except for fracture of digits or toes)
- •AST (Aspartate Transaminase) or ALT (Alanine Transaminase) at least 3x upper limit of normal (ULN) or total bilirubin at least 2x ULN
- •Evidence of severe sleep apnea requiring surgery or new initiation of CPAP (Continuous positive airway pressure).
- •History of malignancy and chemotherapy/radiation or currently under work-up for suspected malignancy
- •Known hypersensitivity to BMN 111 or its excipients
- •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
- •Concurrent disease or condition that would interfere with study participation or safety
- •Have abnormal findings on baseline clinical hip exam or imaging assessments that are determined to be clinically significant as determined by the PI.
- •Have a history of hip surgery or severe hip dysplasia
- •Have a history of clinically significant hip injury in the 30 days prior to screening.
- •History of slipped capital femoral epiphysis or avascular necrosis of the femoral head.
- •Are unable to lie flat when in prone position
- •Additional Exclusion Criteria for Optional, Open-label Extension Phase:
- 另有 2 项未显示
研究组 & 干预措施
Cohort 1
Experimental
Cohort 1: 2.5 ug/kg
干预措施: BMN 111 (Drug)
Cohort 2
Experimental
Cohort 2: 7.5 ug/kg,
干预措施: BMN 111 (Drug)
Cohort 3
Experimental
Cohort 3: 15 ug/Kg
干预措施: BMN 111 (Drug)
Cohort 4
Experimental
Cohort 4: 30 ug/kg
干预措施: BMN 111 (Drug)
结局指标
主要结局
Overall Summary of Adverse Events During Entire Study Period
时间窗: Up to Month 25 ± 7 Days
A treatment-emergent Adverse Events (TEAE) is any Adverse Events that newly appeared, increased in frequency or worsened in severity following initiation of study drug administration. TEAE - Treatment-emergent adverse event. SAE - Serious adverse event.
Overall Summary of Adverse Events During Initial 6-Month Period
时间窗: Up to Month 6 ± 7 Days
A treatment-emergent Adverse Events (TEAE) is any Adverse Events that newly appeared, increased in frequency or worsened in severity following initiation of study drug administration. Serious adverse event (SAE).
次要结局
- Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Initial 6-months(At month 6 (Day 183))
- Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Entire Study Period - Cohort 3 and 4(At month 24)
- Change From Baseline in Height Z-Scores Using CDC Reference Standard During Entire Study Period - Cohort 3 and 4(At month 24)
- Change From Baseline in Annualized Growth Velocity (AGV) During Initial 6-Month(At 6 month (Day 183))
- Change From Baseline in Upper to Lower Body Ratios During Initial 6-Months(At month 6 (Day 183))
- Change From Baseline in Upper Arm to Lower Arm Length Ratio During Entire Study Period - Cohort 3 and 4(At month 24)
- Change From Baseline in Arm Span to Height Ratio During Entire Study Period - Cohort 3 and 4(At month 24)
- Change From Baseline in Annualized Growth Velocity (AGV) During Entire Study Period - Cohort 3 and 4(At month 24)
- Change From Baseline in Upper to Lower Body Ratios During Entire Study Period - Cohort 3 and 4(At month 24)
- Change From Baseline in Upper to Lower Body Ratios During Entire Study Period - Cohort 1 and 2 Switchers(At month 24)
- Change From Baseline in Upper Arm to Lower Arm Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers(At month 24)
- Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers(At month 24)
- Change From Baseline in Annualized Growth Velocity (AGV) During Entire Study Period - Cohort 1 and 2 Switchers(At month 24)
- Change From Baseline in Height Z-Scores Using Centers for Disease Control and Prevention (CDC) Reference Standard During Initial 6-Months(At month 6 (Day 183))
- Change From Baseline in Height Z-Scores Using CDC Reference Standard During Entire Study Period - Cohort 1 and 2 Switchers(At month 24)
- Change From Baseline in Upper Arm Length to Lower Arm (Forearm) Length Ratio During Initial 6-Months(At month 6 (Day 183))
- Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Initial 6-months(At month 6 (Day 183))
- Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers(At month 24)
- Change From Baseline in Arm Span to Height Ratio During Initial 6-months(At month 6 (Day 183))
- Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Entire Study Period - Cohort 3 and 4(At month 24)
- Change From Baseline in Arm Span to Height Ratio During Entire Study Period - Cohort 1 and 2 Switchers(At month 24)
研究者
研究点 (9)
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