Continuation Study of Long-term Safety, Tolerability, Pharmacokinetics and Efficacy of Recifercept in Achondroplasia

Study Overview
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Brief Summary
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All participants who completed the prior study to assess long-term safety, tolerability, pharmacokinetics and efficacy, and in the opinion of the investigator, continue to have a positive risk:benefit profile, will be offered to enroll in this open-label extension (OLE) study for up to an additional 24 months of treatment. Approximately 63 participants will be offered to continue at the previously received dose of Recifercept either Low Dose Medium Dose High Dose or at the therapeutic dose once it is identified. Participants will attend the clinic monthly for 24 months. Assessments include safety, blood sampling, physical examination, vital signs, anthropometric body measurements & patient/caregiver quality of life questionnaires.

Official Title
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A PHASE 2 OPEN LABEL EXTENSION STUDY TO ASSESS THE LONG-TERM SAFETY, TOLERABILITY, PHARMACOKINETICS AND EFFICACY OF RECIFERCEPT IN CHILDREN WITH ACHONDROPLASIA

Conditions
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Achondroplasia

Intervention / Treatment
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* Biological: Recifercept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female participants between the ages of >15 months to <12 years inclusive, at Visit 1 (Screen 1). Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests lifestyle considerations and other study procedures. Completed the C4181005 Phase 2 study. Able to stand independently for height measurements (if ≥2 years of age at enrollment). 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 (body mass index (BMI) >95th percentile on Hoover-Fong BMI charts) [Hoover-Fong et al, 2008]. Known closure of long bone growth plates (cessation of height growth). Body weight >45 kg. 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 beclometasone 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 other (except recifercept) investigational product for achondroplasia or that may affect growth/interpretation of growth parameters. History of receipt of an investigational drug (not for achondroplasia/growth affecting) within the last 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer).

Ages Eligible for Study
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Minimum Age: 15 Months
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low Dose<br>Low Dose | Biological: Recifercept<br>* Recifercept<br>|
| Experimental: Medium Dose<br>Medium Dose | Biological: Recifercept<br>* Recifercept<br>|
| Experimental: High Dose<br>High Dose | Biological: Recifercept<br>* Recifercept<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Treatment-Related Adverse Events (AEs) | Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. 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 are events between first dose of study drug and up to 24 months after last dose that were absent before treatment or that worsened relative to pretreatment state. Relatedness to Recifercept was assessed by the investigator (Yes/No). Participants with multiple occurrences of an AE within a category were counted once within the category. | Baseline (Day 0) up to 24 months after last dose of study medication | 
| Height | Increase in height growth above expected in reference population | Change in height from baseline up to 24 months after last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics - Apparent Clearance (CL/F) | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Month(s) 3, 6, 9, 12, 15, 18, 21 & 24 | 
| Change from Baseline in Standing & Sitting Height | Sitting height/standing height ratio | Baseline, 3, 6, 9, 12, 15, 18, 21, & 24 Months | 
| Change from Baseline in Arm Span | Arm span to height/length difference | Baseline, 3, 6, 9, 12, 15, 18, & 24 Months | 
| Change from Baseline in Lower Leg Length | Knee height:lower segment ratio | Baseline, 3, 6, 9, 12, 15, 18, 21, & 24 Months | 
| Change from Baseline in Cranial Face Measurements | Occipito-frontal circumference | Baseline, 3, 6, 9, 12, 15, 18 & 24 Months | 
| Change from Baseline in Cranial Face Measurements | Ratio of occipito-frontal distance to occipito-mid-face measurements | Baseline, 3, 6, 9, 12, 15, 18, 21, & 24 Months | 
| Change from Baseline in Height | z-score of the above height to arm span proportionality and skull morphology where achondroplasia reference datasets exist | Baseline, 3, 6, 9, 12, 15, 18, 21 & 24 Months | 
| Change from Baseline in Elbow Range of Motion | Fixed flexion angles at elbow | Baseline, 3, 6, 9, 12, 15, 18, 21, & 24 Months | 
| Change from Baseline in Polysomnography | Apnea-hypopnea index (obstructive and total) | Baseline, 3, 6, 9, 12, 15, 18, 21, & 24 Months | 
| Change from Baseline in Polysomnography | Desaturation index (number of desaturations per hour >3% from baseline) | Baseline, 3, 6, 9, 12, 15, 18, 21, & 24 Months | 
| Change from Baseline in Polysomnography | Percentage time spent <90% oxygen saturation (SaO2) | Baseline, 3, 6, 9, 12, 15, 18, 21, & 24 Months | 
| Change from Baseline in Polysomnography | Percentage time spent with end-tidal carbon dioxide >50 mmHg | Baseline, 3, 6, 9, 12, 15, 18, 21, & 24 Months | 
| Change from Baseline in Polysomnography | SaO2 nadir | Baseline, 3, 6, 9, 12, 15, 18, 21, & 24 Months | 
| Change from Baseline in Body Mass Index | Body mass index (BMI) | Baseline, 3, 6, 9, 12, 15, 18, 21, & 24 Months | 
| Change from Baseline in Waist & Chest Circumference | Waist:chest circumference ratio | Baseline, 3, 6, 9, 12, 15, 18, 21, & 24 Months | 
| Number of Participants With Laboratory Abnormalities | Following parameters were analyzed for laboratory examination: hematology (hemoglobin, hematocrit, red blood cell count, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); blood chemistry (blood urea nitrogen, creatinine, glucose, calcium, sodium, potassium, chloride, total bicarbonate, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, uric acid albumin, total protein) | Baseline up to end of treatment (24 months) | 
| Number of Participants With Change From Baseline in Vital Signs | Following parameters were analyzed for examination of vital signs: systolic and diastolic blood pressure, respiratory rate, radial pulse and body temperature. | Baseline up to end of treatment (24 months) | 
| Number of Participants With Change From Baseline in Physical Examination | Following parameters were analyzed for examination of systems; A physical examination will include, at a minimum, assessments of the cardiovascular, respiratory, gastrointestinal systems and skin. | Baseline up to end of treatment (24 months) | 
| Number of Participants With Anti-Drug Antibody (ADA) | The percentage of participants with positive ADA and neutralizing antibodies will be summarized for each treatment arm. | Baseline up to end of treatment (24 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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achondroplasia, dwarfism, bone diseases, development, bone diseases, Musculoskeletal Diseases, Osteochondrodysplasias, Genetic Diseases, Inborn, Skeletal Dysplasia