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

Achondroplasia Clinical Trial

Official title:

A PHASE 2 MULTIPLE DOSE, RANDOMIZED STUDY TO ASSESS THE SAFETY, TOLERABILITY, PHARMACOKINETICS AND EFFICACY OF RECIFERCEPT IN CHILDREN WITH ACHONDROPLASIA

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04638153
• Other study ID #: C4181005
• Secondary ID: 2020-001189-13
• Status: Terminated
• Phase: Phase 2
• Start date: December 2, 2020
• Est. completion date: March 27, 2023

Study information

• Verified date: January 2024
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 60
• Est. completion date: March 27, 2023
• Est. primary completion date: January 16, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Months to 10 Years

Eligibility

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).

Related Conditions & MeSH terms

• Achondroplasia

Intervention

Biological:
• Recifercept
Recifercept

Locations

Country	Name	City	State
Australia	Murdoch Children's Research Institute	Melbourne	Victoria
Australia	Murdoch Children's Research Institute	Parkville	Victoria
Belgium	Universitair Ziekenhuis Antwerpen	Edegem
Belgium	Universitaire Ziekenhuizen Leuven (UZ Leuven)	Leuven
Denmark	DanTrials ApS	Copenhagen NV
Italy	Fondazione Policlinico Universitario Agostino - Gemelli IRCCS	Roma
Japan	Okayama University Hospital	Okayama
Japan	Osaka University Hospital	Suita-city	Osaka
Portugal	Centro Hospitalar e Universitário de Coimbra - Hospital Pediátrico	Coimbra
Spain	Hospital Vithas San Jose	Vitoria-Gasteiz	Alava
United States	Ocean Sleep Medicine	Aliso Viejo	California
United States	Texas Children's Hospital	Houston	Texas
United States	Ocean Sleep Medicine	Irvine	California
United States	MemorialCare Sleep Disorders Center at Long Beach Memorial Medical Center	Long Beach	California
United States	Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center	Torrance	California
United States	Nemours Alfred I duPont Hospital for Children	Wilmington	Delaware

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Denmark,  Italy,  Japan,  Portugal,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Treatment Emergent Treatment-Related Adverse Events (AEs)	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).	The first dose up to 28 to 35 days after the last dose of study intervention (13 months)
Primary	Least Square Mean of Change From Baseline Height Growth at 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.	Baseline, Month 3, Month 6, Month 9, and Month 12
Secondary	Change From Baseline in Pulse Rate at Month 3, Month 6, Month 9, and Month 12	Pulse rate measurements were preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions (eg, television, cell phones) where possible (with consideration of the age of the child). Pulse rate was summarized by treatment in accordance with the sponsor reporting standards.	Baseline, Month 3, Month 6, Month 9, and Month 12
Secondary	Change From Baseline in Respiratory Rate at Month 3, Month 6, Month 9, and Month 12	Respiratory rate was obtained with participant in the seated position, after having sat calmly for at least 5 minutes. Respiratory rate was summarized by treatment in accordance with the sponsor reporting standards.	Baseline, Month 3, Month 6, Month 9, and Month 12
Secondary	Change From Baseline in Blood Pressure at Month 3, Month 6, Month 9, and Month 12	Blood pressure measurements were preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions (eg, television, cell phones) where possible (with consideration of the age of the child). Supine systolic blood pressure (SBP) and diastolic blood pressure (DBP) were summarized by treatment in accordance with the sponsor reporting standards.	Baseline, Month 3, Month 6, Month 9, and Month 12
Secondary	Change From Baseline in Temperature at Month 3, Month 6, Month 9, and Month 12	Temperature was obtained with participant in the seated position, after having sat calmly for at least 5 minutes. Temperature measurements were summarized by treatment in accordance with the sponsor reporting standards.	Baseline, Month 3, Month 6, Month 9, and Month 12
Secondary	Number of Participants With Abnormal Physical Examination Findings at Month 3, Month 6, Month 9, and Month 12	A physical examination included, at a minimum, assessments of the cardiovascular, respiratory, gastrointestinal systems and skin. Physical examination assessments were summarized by treatment in accordance with the sponsor reporting standards.	Month 3, Month 6, Month 9, and Month 12
Secondary	Number of Participants With Laboratory Abnormalities (Without Regard to Baseline Abnormality)	Participants with laboratory abnormalities that met pre-specified criteria included following parameters: hematology (corpuscular volume, corpuscular hemoglobin, corpuscular hemoglobin concentration, platelet, leukocytes, lymphocytes, neutrophils, eosinophils, and monocytes), and chemistry (bilirubin, alkaline phosphatase, albumin, urea nitrogen, urate, potassium, phosphate, bicarbonate).	Baseline to Month 12
Secondary	Pre-Dose Serum Concentration (Ctrough) of Recifercept	Ctrough was defined as pre-dose serum concentration during dosing and observed directly from data.	Pre-dose on Day(s) 4, 8, 15, 29, 61, 91, 183, 273, 365
Secondary	Number of Participants With Positive Anti-Drug Antibodies (ADA) and Neutralizing Antibody (NAb) of Recifercept	The immunogenicity was measured by presence of ADA and NAb in participants treated with recifercept and summarized by dose regimen.	The first dose up to 28 to 35 days after the last dose of study intervention (13 months)
Secondary	Change From Baseline in Sitting/Standing Height Ratio at Month 3, Month 6, Month 9, and Month 12	Sitting/standing height ratio was the ratio of sitting height to standing height.	Baseline, Month 3, Month 6, Month 9, and Month 12
Secondary	Least Square Mean of Change From Baseline Arm Span to Standing Height/Length Difference at Month 3, Month 6, Month 9, and Month 12	Arm span to standing height/length difference was the difference between arm span and standing height.	Baseline, Month 3, Month 6, Month 9, and Month 12
Secondary	Change From Baseline in Knee Height : Lower Segment Ratio at Month 3, Month 6, Month 9, and Month 12	Knee height : lower segment ratio was the ratio of knee to heel length to the difference between standing height and sitting height.	Baseline, Month 3, Month 6, Month 9, and Month 12
Secondary	Change From Baseline in Occipito-Frontal Circumference at Month 3, Month 6, Month 9, and Month 12	Head circumference or the occipito-frontal circumference is the greatest of the cranial dimensions which passes around the forehead anteriorly and the external occipital protruberance posteriorly. It is a routine part of the physical examination of a child and is of great importance in detecting abnormal patterns of cranial growth. Occipito-frontal circumference data were summarized for each treatment arm.	Baseline, Month 3, Month 6, Month 9, and Month 12
Secondary	Change From Baseline in Occipito-Frontal to Occipito-Mid-Face Ratio at Month 3, Month 6, Month 9, and Month 12	Ratio of occipito-frontal distance to occipito-mid-face measurements was summarized for each treatment arm.	Baseline, Month 3, Month 6, Month 9, and Month 12
Secondary	Change From Baseline in Height Standard Deviation Score (Z-Score) at Month 3, Month 6, Month 9, and Month 12	Height Standard Deviation Score (SDS) (z-score) was calculated as the difference between mean observed standing height at each visit and mean value of reference population divided by standard deviation of reference population. SDS indicates how similar the participant was to the reference population.	Baseline, Month 3, Month 6, Month 9, and Month 12
Secondary	Change From Baseline in Fixed Flexion Angles at Elbow at Month 3, Month 6, Month 9, and Month 12	Fixed flexion angles at elbow data were presented for each treatment arm. An average of a participant's elbow extension measurements over a visit was computed.	Baseline, Month 3, Month 6, Month 9, and Month 12
Secondary	Change From Baseline in Body Mass Index (BMI) at Month 3, Month 6, Month 9, and Month 12	Body Mass Index (BMI) = Weight (kg)/[(Standing Height (m))^2]. Standing height and weight were averaged over a visit before BMI was computed.	Baseline, Month 3, Month 6, Month 9, and Month 12
Secondary	Change From Baseline in Waist : Chest Circumference Ratio at Month 9 and Month 12	Waist : Chest Ratio = Waist Circumference / Chest Circumference. Waist and chest circumference were averaged over a visit before waist : chest circumference ratio was computed.	Baseline, Month 9, and Month 12
Secondary	Change From Baseline in Apnea-Hypopnea Index (AHI) at Month 12	The apnea-hypopnea index (AHI) is the average of the apneic and hypopneic episodes per hour of sleep, which is measured to assess obstructive sleep apnea (OSA). An AHI score of 1 to 4.9 events/hour is mild OSA, 5 to 9.9 events/hour is moderate, and more than 9 events/hour is severe in pediatric population.	Baseline and Month 12
Secondary	Change From Baseline in Desaturation Index at Month 12	Desaturation index is one of the polysomnography parameters to assess obstructive sleep apnea. It refers to the average number of desaturation episodes occurring per hour, where desaturation episodes are defined as a decrease in the mean oxygen saturation of =3% (over the last 120 seconds) that lasts for at least 10 seconds.	Baseline and Month 12
Secondary	Change From Baseline in Polysomnography Other Parameters at Month 12	Polysomnography refers to a systematic process used to collect physiologic parameters during sleep. Polysomnography other parameters included total sleep time spent with oxygen saturation (SaO2) < 90% (T90), total sleep time spent with end-tidal carbon dioxide (EtCO2) >50 mm Hg.	Baseline and Month 12
Secondary	Change From Baseline in SaO2 Nadir at Month 12	SaO2 measures the percentage of oxyhemoglobin (oxygen-bound hemoglobin) in the blood. SaO2 nadir refers to lowest SaO2.	Baseline and Month 12

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