A Study Of Safety, Tolerability And Effectiveness Of Recifercept In Children With Achondroplasia
Condition: Achondroplasia
MeSH terms: Achondroplasia
Intervention: Recifercept
Intervention description: Recifercept
Phase: Phase 2
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Masking description: Anthropometric Measurements Assessor
Enrollment: 60.0
Sex: All
Minimum age: 3 Months
Maximum age: 10 Years
Healthy volunteers: No
Keywords: Skeletal Dysplasia

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  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 C4181005.

          -  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.

        Exclusion Criteria:

          -  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).