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

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

57

Of the 57 participants in full analysis set (FAS), 33 (57.9%) were male participants and 24 (42.1%) were female participants. The study populations were generally comparable across the 3 dose groups with respect to age, race and ethnicity. * The median (range) of age was 5.0 (1-10) years. Of the 57 participants in FAS, 3 participants were 1 year, 27 participants were 2-5 years, and 27 participants were 6-10 years of age. The number of participants of 2-10 years of age was 18 in each of the 3 dose groups. * Most of the participants were White (84.2%) and not Hispanic or Latino (87.7%). In recifercept 1 mg/kg once weekly (QW) group, recifercept 2 mg/kg twice weekly (BIW) group and recifercept 1.5 mg/kg once daily (QD) group, the mean standing height was 92.53 cm, 89.23 cm and 93.24 cm, respectively. The mean weight was 16.33 kg, 16.01 kg and 19.23 kg, respectively. The mean body mass index was 19.83 kg/m2, 20.18 kg/m2 and 21.57 kg/m2, respectively.

This was a phase 2, randomized, 3-arm (3 active doses of recifercept), parallel group dose-finding study of safety, tolerability, pharmacokinetics (PK) and efficacy. The main cohort: The study was planned to enroll approximately 54 children with achondroplasia aged 2-10 years (inclusive) who were enrolled and randomized to receive one of 3 doses of recifercept (1 mg/kg QW, 2 mg/kg BIW or 1.5 mg/kg QD, n=18 per dose) such that approximately 45 participants were evaluable (up to 15 participants per dose). Additionally, an exploratory cohort of approximately 9 children with achondroplasia, aged 3 months to 2 years, was planned to be enrolled later in the study (n=3 per dose). All these 63 participants in this part of the study were planned to receive recifercept for 12 months. Enrollment followed 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. An interim analysis was performed when approximately 45 participants (up to 15 participants per dose) aged >=2 to <11 years had received 6 months of treatment with recifercept. The external data monitoring committee reviewed safety, PK and efficacy data to confirm ongoing positive benefit:risk in participants. The decision of terminating this study was made by the sponsor based on the interim analysis results that the pre-specified 6-month efficacy criteria were not met. All participants who completed the study prior to the early termination and in the opinion of the investigator, continued to have a positive risk:benefit profile, were offered to enroll into an open-label extension study.

Most participants experienced at least 1 treatment-emergent adverse event (TEAE) (85.0% in recifercept 1 mg/kg QW group, 100% in recifercept 2 mg/kg BIW group, and 88.9% in recifercept 1.5 mg/kg QD group). Treatment-related adverse events (AEs) were reported in 35.0% in recifercept 1 mg/kg QW group, 78.9% in recifercept 2 mg/kg BIW group, and 77.8% in recifercept 1.5 mg/kg QD group. * The most frequently reported all-causality TEAEs were severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test positive (14 [24.6%] participants), Injection site erythema (13 [22.8%] participants), Nasopharyngitis (12 [21.1%] participants), and Injection site rash (10 [17.5%] participants). The most frequently reported treatment-related TEAEs were Injection site erythema (13 [22.8%] participants), and Injection site rash (10 [17.5%] participants). Most of the TEAEs were mild in severity. No events of death were reported in the study. One serious adverse event of Sinus bradycardia was reported for 1 (5.0%) participant in recifercept 1 mg/kg QW group, with onset day on Day 50 and resolved on the same day. The event was severe and considered not related to treatment. No participants discontinued from study or study intervention due to AE. Injection site reactions were considered AE of special interest. Most injection site reactions were mild in severity. The mean time from the most recent dosing to occurrence of injection site reaction was 0.5 day, 0.3 day, and 0.1 day in recifercept 1 mg/kg QW group, recifercept 2 mg/kg BIW group, and recifercept 1.5 mg/kg QD group, respectively. The mean duration for injection site reaction was 2.3 days, 2.8 days, and 6.9 days in recifercept 1 mg/kg QW group, recifercept 2 mg/kg BIW group, and recifercept 1.5 mg/kg QD group, respectively. No clinically significant trends were noted for laboratory test. No clinically meaningful findings in the vital signs measurements, electrocardiograms, physical examination assessments, or other observations related to safety were observed in this study.

Increase in Height Growth Above Expected in Reference Population: 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. An Mixed-Effect Repeated Measures (MMRM) method was used to analyze height growth at Months 3, 6, 9 and 12 relative to the reference population in the FAS. The least-square (LS) mean height growth compared to the reference population as the ratio was 1.1 in recifercept 1 mg/kg QW group, 0.9 in recifercept 2 mg/kg BIW group, and 0.6 in recifercept 1.5 mg/kg QD group at Month 3. At Month 12, the LS mean height growth compared to the reference population as the ratio was 1.0 in recifercept 1 mg/kg QW group, 1.0 in recifercept 2 mg/kg BIW group, and 0.9 in recifercept 1.5 mg/kg QD group. The LS mean height growth was comparable across the 3 dose groups at Months 6, 9 and 12, with the greatest LS mean difference of 0.1 across the dose groups. PK Results: Intact PK of recifercept were assessed as trough serum concentration (pre-dose) at visits of Day 8, Day 15 and Months 1, 2, 3, 6, 9 and 12 in all 3 dose groups. PK samples were also collected 20 hours post-dose at Month 2 and 40 hours post-dose at Month 3 for recifercept 1 mg/kg QW and 2 mg/kg BIW groups. As expected, recifercept concentration increased from 1 mg/kg QW to 1.5 mg/kg QD dose. Looking at the pre-dose (trough) concentration at steady-state (trough serum concentration [Ctrough]), it appeared that recifercept concentrations were stable over 12 months of dosing. Observed steady-state serum recifercept exposures in achondroplasia participants at dosing regimens of 1 mg/kg QW, 2 mg/kg BIW and 1.5 mg/kg QD were consistent with the exposures predicted earlier (at the start of the study) by a Population PK model developed using healthy participants data.

The 3 recifercept regimens were safe and well-tolerated in participants aged>=3 months to<11 years with achondroplasia. The study did not meet the 6 month efficacy criteria at interim analysis. Recifercept did not demonstrate the efficacy endpoints at 12 months. Observed steady-state serum recifercept exposures were consistent with the healthy participants study results. Majority of the participants had anti-drug antibody and neutralizing antibody positive (>80% and >65%) at least 1 visit post baseline.

Mar. 22, 2024

Yes

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.

https://jrct.mhlw.go.jp/latest-detail/jRCT2061220040

Kawai Norisuke

Pfizer R&D Japan G.K.

Shinjuku Bunka Quint Bldg., 3-22-7 Yoyogi, Shibuya-ku, Tokyo

clinical-trials@pfizer.com

Clinical Trials Information Desk

Pfizer R&D Japan G.K.

Shinjuku Bunka Quint Bldg., 3-22-7 Yoyogi, Shibuya-ku, Tokyo

+81-3-5309-7000

clinical-trials@pfizer.com

Complete

Sept. 14, 2022

Interventional

randomized controlled trial

single blind

dose comparison control

parallel assignment

prevention purpose

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 x 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).

Both

Achondroplasia

Intervention: Recifercept
Arms: Low Dose, Medium Dose, High Dose,
PK cohort: Phase 2 formulation [process 1c] 3 mg/kg, Phase 3 formulation [process 2] 3 mg/kg

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

July. 20, 2021

Australia/Belgium/Denmark/Italy/Portugal/Spain/United States