A PHASE 2 MULTIPLE DOSE, RANDOMIZED STUDY TO ASSESS THE SAFETY, TOLERABILITY, PHARMACOKINETICS AND EFFICACY OF RECIFERCEPT IN CHILDREN WITH ACHONDROPLASIA
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- Pfizer
- 入组人数
- 60
- 试验地点
- 30
- 主要终点
- Least Square Mean of Change From Baseline Height Growth at Month 3, Month 6, Month 9, and Month 12
研究概览
简要总结
Approximately 63 participants will be randomized to one of three doses to receive Recifercept either
- Low Dose
- Medium Dose
- High Dose
Participants will will attend the clinic at baseline and at Day 1, 4, 8, 15, 29 & then Month 2, 3 6, 9 & 12. Assessments include safety, blood sampling, physical examination, vital signs, anthropometric body measurements & patient/caregiver quality of life questionnaires
Participants will received treatment with Recifercept for 12 months. All participants who complete the study and in the opinion of the investigator, continue to have a positive risk:benefit profile, will be offered to enroll into an open-label extension (OLE) study.
A PK cohort will include 12 participants who will randomly receive a single dose of 3 mg/kg of Phase 2 study (process 1c) formulation and a single dose of 3 mg/kg of the proposed Phase 3 (process 2) study formulation in a cross over study. Dose of the cohort could be changed due to emerging safety and efficacy data in the study.
详细描述
This is a phase 2 randomized, 3 arm (3 active doses of Recifercept), parallel group dose finding study of safety, tolerability, PK and efficacy
The total number of participants is 63 in 2 age straified cohorts of 0-2 years and 6-10 years old.
The study will enroll approximately 54 children with achondroplasia aged 2-10 years (inclusive) who will be enrolled and randomized to receive one of three doses of recifercept
- Low Dose
- Medium Dose
- High Dose
A total of 18 participants will be enrolled per dose 18 per dosesuch that at least 15 participants per dose are evaluable. An interim analysis is planned when at least 15 participants per dose aged ≥2 to <11 years have received 6 months of treatment with recifercept. eDMC will review safety, PK and efficacy data to confirm ongoing positive benefit:risk in participants.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Single (Outcomes Assessor)
盲法说明
Anthropometric Measurements Assessor
入排标准
- 年龄范围
- 3 Months 至 10 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Main cohort: Aged ≥2 years to <11 years (up to the day before 11th birthday inclusive) at time of enrollment; or exploratory cohort: aged ≥3 months to <2 years (up to the day before 2nd birthday inclusive) at time of enrollment
- •Documented, confirmed genetic diagnosis of achondroplasia from historical medical records prior to entry into this trial (test must have been performed at a laboratory fully accredited for genetic testing under local regulations).
- •Completed the C4181001 natural history study with at least 2 valid height/length measurements (at least 3 months apart) prior to enrollment in this study. One of these measurement timepoints must be within the 3 months prior to enrollment in C
- •Tanner stage 1 based on investigator assessment during physical examination (must include assessment of breast development for females, testicular stage for males).
- •Able to stand independently for height measurements (if ≥2 years of age at enrollment).
- •If aged <2 years at enrollment, has a documented historical MRI brain/cervical spine performed in the previous 12 months.
排除标准
- •Presence of co-morbid conditions or circumstances that, in the opinion of the investigator, would affect interpretation of growth data or ability to complete the trial procedures.
- •Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study.
- •Presence of severe obesity (BMI >95th percentile on Hoover-Fong BMI charts) [Hoover-Fong et al, 2008].14
- •Known closure of long bone growth plates (cessation of height growth).
- •Body weight <7 kg or >30 kg.
- •Moderate or severe renal impairment CrCL GFR <60 mL/min/1.73m2 (Calculated GFR based on updated "bedside" Schwartz formula for pediatric patients (CrCL (mL/min/1.73 m2) = 0.413 * Height (cms)/ Serum cr (mg/dL) or hepatic impairment (AST/ALT >1.5 ULN).
- •History of hypersensitivity to study intervention or any excipients.
- •History of any prior treatment with human growth hormone or related products (including insulin-like growth factor 1 [IGF-1]).
- •History of receipt of any treatment that are known to potentially affect growth (including oral steroids >5 days in the last 6 months, high dose inhaled corticosteroids (>800 mcg/day beclametasone equivalent) and medication for attention deficit hyperactivity disorder).
- •History of limb lengthening surgery (defined as distraction osteogenesis/Ilizarov/callostasis technique following submetaphyseal osteotomy to extend bone length).
- •Any limb lengthening/corrective orthopaedic surgery planned at any point during the trial period.
- •Less than 6 months since fracture or surgical procedure of any bone determined from the screening visit date.
- •Presence of any internal guided growth plates/devices.
- •History of removal of internal guided growth plates/devices within less than 6 months.
- •History of receipt of any investigational product for achondroplasia or that may affect growth/interpretation of growth parameters.
- •History of receipt of an investigational product (not for achondroplasia/growth affecting) within the last 30 days or 5 half-lives (whichever is longer).
结局指标
主要结局
Least Square Mean of Change From Baseline Height Growth at Month 3, Month 6, Month 9, and Month 12
时间窗: Baseline, Month 3, Month 6, Month 9, and Month 12
Height growth was defined as the ratio of observed change from baseline in standing height to the expected change from baseline in the reference population.
Number of Participants With Treatment Emergent Treatment-Related Adverse Events (AEs)
时间窗: The first dose up to 28 to 35 days after the last dose of study intervention (13 months)
Treatment-related AE was any untoward medical occurrence attributed to study intervention in a participant who received study intervention. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AE is defined as an AE with onset date occurring during the on-treatment period. Relatedness to recifercept was assessed by the investigator (Yes/No).
次要结局
- Number of Participants With Laboratory Abnormalities (Without Regard to Baseline Abnormality)(Baseline to Month 12)
- Change From Baseline in SaO2 Nadir at Month 12(Baseline and Month 12)
- Number of Participants With Abnormal Physical Examination Findings at Month 3, Month 6, Month 9, and Month 12(Month 3, Month 6, Month 9, and Month 12)
- Change From Baseline in Occipito-Frontal to Occipito-Mid-Face Ratio at Month 3, Month 6, Month 9, and Month 12(Baseline, Month 3, Month 6, Month 9, and Month 12)
- Change From Baseline in Height Standard Deviation Score (Z-Score) at Month 3, Month 6, Month 9, and Month 12(Baseline, Month 3, Month 6, Month 9, and Month 12)
- Change From Baseline in Apnea-Hypopnea Index (AHI) at Month 12(Baseline and Month 12)
- Change From Baseline in Polysomnography Other Parameters at Month 12(Baseline and Month 12)
- Change From Baseline in Respiratory Rate at Month 3, Month 6, Month 9, and Month 12(Baseline, Month 3, Month 6, Month 9, and Month 12)
- Change From Baseline in Blood Pressure at Month 3, Month 6, Month 9, and Month 12(Baseline, Month 3, Month 6, Month 9, and Month 12)
- Change From Baseline in Temperature at Month 3, Month 6, Month 9, and Month 12(Baseline, Month 3, Month 6, Month 9, and Month 12)
- Change From Baseline in Pulse Rate at Month 3, Month 6, Month 9, and Month 12(Baseline, Month 3, Month 6, Month 9, and Month 12)
- Pre-Dose Serum Concentration (Ctrough) of Recifercept(Pre-dose on Day(s) 4, 8, 15, 29, 61, 91, 183, 273, 365)
- Change From Baseline in Occipito-Frontal Circumference at Month 3, Month 6, Month 9, and Month 12(Baseline, Month 3, Month 6, Month 9, and Month 12)
- Number of Participants With Positive Anti-Drug Antibodies (ADA) and Neutralizing Antibody (NAb) of Recifercept(The first dose up to 28 to 35 days after the last dose of study intervention (13 months))
- Least Square Mean of Change From Baseline Arm Span to Standing Height/Length Difference at Month 3, Month 6, Month 9, and Month 12(Baseline, Month 3, Month 6, Month 9, and Month 12)
- Change From Baseline in Knee Height : Lower Segment Ratio at Month 3, Month 6, Month 9, and Month 12(Baseline, Month 3, Month 6, Month 9, and Month 12)
- Change From Baseline in Waist : Chest Circumference Ratio at Month 9 and Month 12(Baseline, Month 9, and Month 12)
- Change From Baseline in Desaturation Index at Month 12(Baseline and Month 12)
- Change From Baseline in Sitting/Standing Height Ratio at Month 3, Month 6, Month 9, and Month 12(Baseline, Month 3, Month 6, Month 9, and Month 12)
- Change From Baseline in Fixed Flexion Angles at Elbow at Month 3, Month 6, Month 9, and Month 12(Baseline, Month 3, Month 6, Month 9, and Month 12)
- Change From Baseline in Body Mass Index (BMI) at Month 3, Month 6, Month 9, and Month 12(Baseline, Month 3, Month 6, Month 9, and Month 12)