A Study Of Safety, Tolerability And Effectiveness Of Recifercept In Children With Achondroplasia

• ClinicalTrials.gov Identifier: NCT04638153
• Recruitment Status: Recruiting
• First Posted: November 20, 2020
• Last Update Posted: November 21, 2022
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Achondroplasia	Biological: Recifercept	Phase 2

Detailed Description:

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.

Additionally, an exploratory cohort of approximately 9 children with achondroplasia, ages 0-2 years, will be enrolled later in the study (n=3 per dose).

Enrollment will follow an age and dose-staggered approach (descending age and ascending dose) with review of safety and PK data by the study team before progression to the next enrollment block If certain pre-defined safety signals occur then a meeting of the eDMC will be convened to make a decision on progression of enrollment. The PK data collected in block A will be used in the PopPK model (developed using healthy adult data) to confirm the dosing for younger children (ie, ≥2 to <6 years and 0-<2 years).

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

All participants will receive 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.

PK Cohort:

Multiple changes have been made in the manufacturing process of the drug product (process 2) which will be used in Phase 3. Therefore, an additional PK cohort (at selected sites only) has been added, to evaluate the PK of Phase 2 formulation (process 1c) and Phase 3 formulation (process 2).

PK Cohort:

At selected sites only, an additional PK cohort has been added to evaluate the PK of two recifercept formulations. A total of 12 children with achondroplasia aged 2- <11 years will be enrolled in the PK cohort (6 in each treatment sequence). Each participant will receive 2 treatments (3 mg/kg Phase 2 formulation [process 1c] and 3 mg/kg Phase 3 formulation [process 2]) in a randomized manner. Dose of the cohort could be changed due to emerging safety and efficacy data in the study.

PK samples collected following each dose will be analyzed to evaluate the exposures of two formulations.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 63 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Masking Description: Anthropometric Measurements Assessor
• Primary Purpose: Prevention
• Official Title: A PHASE 2 MULTIPLE DOSE, RANDOMIZED STUDY TO ASSESS THE SAFETY, TOLERABILITY, PHARMACOKINETICS AND EFFICACY OF RECIFERCEPT IN CHILDREN WITH ACHONDROPLASIA
• Actual Study Start Date: December 2, 2020
• Estimated Primary Completion Date: January 4, 2024
• Estimated Study Completion Date: January 4, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Low Dose; Low Dose	Biological: Recifercept; Recifercept
Experimental: Medium Dose; Medium Dose	Biological: Recifercept; Recifercept
Experimental: High Dose; High Dose	Biological: Recifercept; Recifercept
Experimental: PK Phase 2 Formulation; Phase 2 formulation [process 1c] 3mg/kg	Biological: Recifercept; Recifercept
Experimental: PK Phase 3 Formulation; Phase 3 formulation [process 2] 3mg/kg	Biological: Recifercept; Recifercept

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Treatment Emergent Treatment-Related Adverse Events (AEs) [ Time Frame: Baseline (Day 0) up to 365 days after last dose of study medication ]
   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 365 days 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.
2. Height [ Time Frame: Change in height from baseline up to 365 days after last dose ]
   Increase in height growth above expected in reference population
3. PK Cohort: PK after single doses of 2 formulations [ Time Frame: Baseline to Day 57 ]
   To evaluate the PK of single subcutaneous doses of 2 formulations (process 1c and process 2) of recifercept

Secondary Outcome Measures :

1. Number of Participants With Change From Baseline in Vital Signs [ Time Frame: Baseline up to end of treatment (Day 365) ]
   Following parameters were analyzed for examination of vital signs: systolic and diastolic blood pressure, respiratory rate, radial pulse and body temperature.
2. Number of Participants With Change From Baseline in Physical Examination [ Time Frame: Baseline up to end of treatment (Day 365) ]
   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.
3. Number of Participants With Laboratory Abnormalities [ Time Frame: Baseline up to end of treatment (Day 365) ]
   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)
4. Pharmacokinetics - Apparent Clearance (CL/F) [ Time Frame: Day(s) 4, 8, 15, 29, 61, 91, 183, 365 ]
   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.
5. Number of Participants With Anti-Drug Antibody (ADA) [ Time Frame: Baseline up to end of treatment (Day 365) ]
   The percentage of participants with positive ADA and neutralizing antibodies will be summarized for each treatment arm.
6. Change from Baseline in Standing & Sitting Height [ Time Frame: Baseline, 3, 6, 9 & 12 Months ]
   Sitting height/standing height ratio
7. Change from Baseline in Arm Span [ Time Frame: Baseline, 3, 6, 9 & 12 Months ]
   Arm span to height/length difference
8. Change from Baseline in Lower Leg Length [ Time Frame: Baseline, 3, 6, 9 & 12 Months ]
   Knee height:lower segment ratio
9. Change from Baseline in Cranial Face Measurements [ Time Frame: Baseline, 3, 6, 9 & 12 Months ]
   Occipito-frontal circumference
10. Change from Baseline in Cranial Face Measurements [ Time Frame: Baseline, 3, 6, 9 & 12 Months ]
    Ratio of occipito-frontal distance to occipito-mid-face measurements
11. Change from Baseline in Height [ Time Frame: Baseline, 3, 6, 9 & 12 Months ]
    z-score of the above height to arm span proportionality and skull morphology where achondroplasia reference datasets exist
12. Change from Baseline in Elbow Range of Motion [ Time Frame: Baseline, 3, 6, 9 & 12 Months ]
    Fixed flexion angles at elbow
13. Change from Baseline in Body Mass Index [ Time Frame: Baseline, 3, 6, 9 & 12 Months ]
    Body mass index (BMI)
14. Change from Baseline in Waist & Chest Circumference [ Time Frame: Baseline, 3, 6, 9 & 12 Months ]
    Waist:chest circumference ratio
15. Change from baseline CHAQ questionnaire [ Time Frame: Baseline up to end of treatment (Day 365) in CHAQ component and index scores ]
    The Childhood Health Assessment Questionnaire (CHAQ) is a 36-item measure of health status and physical function.
16. Change from baseline QoLISSY Brief Questionnaire [ Time Frame: Baseline up to end of treatment (Day 365) in QoLISSY Brief total score ]
    QoLISSY Brief measures health-related quality of life (HRQoL) in children 4-18 years old from the participant and parent perspectives.The 9 items on the QoLISSY Brief were selected from the full QoLISSY physical, social and emotional HRQoL dimensions. The QoLISSY Brief questions ask the participant or caregiver about their status currently. Intended for children or caregivers of children, the instrument uses a 5-point Likert Scale ranging from 'not at all/never' to 'extremely/always'. The QoLISSY Brief total score is the 0-100 transformed sum of the 9 item scores, with higher scores representing better quality of life.
17. Change from Baseline in Polysomnography [ Time Frame: Baseline, 3, 6, 9 & 12 Months ]
    Clinical summary of findings (including reported diagnosis);
18. Change from Baseline in Polysomnography [ Time Frame: Baseline, 3, 6, 9 & 12 Months ]
    Whether study was performed in room air/oxygen/on continuous positive airway pressure;
19. Change from Baseline in Polysomnography [ Time Frame: Baseline, 3, 6, 9 & 12 Months ]
    Apnea-hypopnea index (obstructive and total)
20. Change from Baseline in Polysomnography [ Time Frame: Baseline, 3, 6, 9 & 12 Months ]
    Desaturation index (number of desaturations per hour >3% from baseline)
21. Change from Baseline in Polysomnography [ Time Frame: Baseline, 3, 6, 9 & 12 Months ]
    Percentage time spent <90% oxygen saturation (SaO2)
22. Change from Baseline in Polysomnography [ Time Frame: Baseline, 3, 6, 9 & 12 Months ]
    Percentage time spent with end-tidal carbon dioxide >50 mmHg
23. Change from Baseline in Polysomnography [ Time Frame: Baseline, 3, 6, 9 & 12 Months ]
    SaO2 nadir
24. PK Cohort Adverse Event Monitoring [ Time Frame: Baseline to Day 57 ]
    To assess the safety and tolerability of single SC doses of 2 formulations (process 1c and process 2) of recifercept

Eligibility Criteria

• Ages Eligible for Study: 3 Months to 10 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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).

Contacts and Locations

Contacts

Contact: Pfizer CT.gov Call Center; 1-800-718-1021; ClinicalTrials.gov_Inquiries@pfizer.com

Locations

United States, California

Ocean Sleep Medicine; Active, not recruiting

Aliso Viejo, California, United States, 92656

MemorialCare Sleep Disorders Center at Long Beach Memorial Medical Center; Active, not recruiting

Long Beach, California, United States, 90806

Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center; Active, not recruiting

Torrance, California, United States, 90502

United States, Delaware

Nemours Alfred I duPont Hospital for Children; Active, not recruiting

Wilmington, Delaware, United States, 19803

United States, Texas

Texas Children's Hospital; Active, not recruiting

Houston, Texas, United States, 77030

Australia, Victoria

Nemours Children's Health - Delaware; Active, not recruiting

Parkville, Victoria, Australia, 3052

Belgium

Universitair Ziekenhuis Antwerpen; Active, not recruiting

Edegem, Belgium, 2650

Universitaire Ziekenhuizen Leuven (UZ Leuven); Active, not recruiting

Leuven, Belgium, 3000

Denmark

DanTrials ApS; Active, not recruiting

Copenhagen NV, Denmark, DK-2400

Italy

Fondazione Policlinico Universitario Agostino - Gemelli IRCCS; Active, not recruiting

Roma, Italy, 00168

Japan

Osaka Women's and Children's Hospital; Not yet recruiting

Izumi, Osaka, Japan, 594-1101

Osaka University Hospital; Recruiting

Suita-city, Osaka, Japan, 565-0871

Okayama University Hospital; Active, not recruiting

Okayama, Japan, 700-8558

Portugal

Centro Hospitalar e Universitário de Coimbra - Hospital Pediátrico; Active, not recruiting

Coimbra, Portugal, 3000-602

Spain

Hospital Vithas San Jose; Active, not recruiting

Vitoria-Gasteiz, Alava, Spain, 01008

Sponsors and Collaborators

Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

More Information

Additional Information:

To obtain contact information for a study center near you, click here. 

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT04638153
• Other Study ID Numbers: C4181005; 2020-001189-13 ( EudraCT Number )
• First Posted: November 20, 2020
• Last Update Posted: November 21, 2022
• Last Verified: November 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
• URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Pfizer:

Skeletal Dysplasia

Additional relevant MeSH terms:

Achondroplasia; Dwarfism; Bone Diseases, Developmental; Bone Diseases; Musculoskeletal Diseases; Osteochondrodysplasias; Genetic Diseases, Inborn