A Trial of Etelcalcetide in Pediatric Participants With Secondary Hyperparathyroidism and Chronic Kidney Disease on Hemodialysis

Официальное название

Phase 3, Randomized, Open-label, Controlled, Multiple Dose, Efficacy, Safety, Pharmacokinetic, and Pharmacodynamic Study of Etelcalcetide in Pediatric Subjects 28 Days to < 18 Years of Age With Secondary Hyperparathyroidism and Chronic Kidney Disease Receiving Maintenance Hemodialysis

Обзор

This is a phase 3 trial of etelcalcetide in pediatric participants with secondary hyperparathyroidism (SHPT) and chronic kidney disease (CKD) on hemodialysis.

Подробное описание

SHPT is a common and serious co-morbidity that develops relatively early in the course of CKD, worsens with declining kidney function, and is associated with serious complications in children on dialysis. Children on dialysis experience a wide spectrum of bone abnormalities and growth retardation, in addition to increased risk for cardiovascular morbidity and mortality that manifests early in their adulthood. Traditional therapies for SHPT (eg, vitamin D sterols) are widely used in the pediatric dialysis population, and have the potential to aggravate complications of the disease by increasing serum calcium (Ca), serum phosphorus, and serum Ca times serum phosphorus product.

Etelcalcetide has been shown to be safe and efficacious in treating adult CKD patients with SHPT by simultaneously controlling intact parathyroid hormone (iPTH), Ca, and phosphorus, and has recently been approved for use in adult patients with SHPT treated with hemodialysis in both the United States and Europe. Although no previous trials have been conducted in pediatric patients with etelcalcetide (one single dose pharmacokinetic \[PK\] trial is currently ongoing), Amgen anticipates minimal to moderate risk with a possibility of direct benefit to the pediatric participants (age 28 days to 18 years) in this trial. The burden of complications of SHPT in the pediatric dialysis population and the limitations of current standard therapy, underscore the need for trials of etelcalcetide in these patients to address this unmet medical need and inform the pediatric nephrology community of the potential use of etelcalcetide in children on hemodialysis with critical safety and efficacy data.

Вмешательства

• Препарат Etelcalcetide
  Etelcalcetide has been shown to be safe and efficacious in treating adult CKD patients with SHPT by simultaneously controlling iPTH, Ca, and phosphorus and has recently been approved for use in adult patients with SHPT treated with hemodialysis in both the United States and Europe
• Другое Standard of Care
  Standard of care, which can include therapy with vitamin D sterols, Ca supplementation, and/or phosphate binders

Первичные конечные точки

• Percentage of Participants Achieving a ≥ 30% Reduction from Baseline in Mean iPTH During the Efficacy Assessment Period (EAP) [Срок оценки: Baseline and Weeks 20-27]
• Percentage Change from Baseline in Mean iPTH During the EAP [Срок оценки: Baseline and Weeks 20-27]

Вторичные конечные точки (12)

• Maximum Serum Concentration (Cmax) of Etelcalcetide [Срок оценки: 10-30 minutes post dose on Day 1 and 10-30 minutes post dose on Weeks 5, 9, 13, 17, and 21]
• Minimum Serum Concentration (Cmin) of Etelcalcetide [Срок оценки: 10-30 minutes post dose on Day 1 and 10-30 minutes post dose on Weeks 5, 9, 13, 17, and 21]
• Number of Participants who Experienced Adverse Events (AEs) [Срок оценки: Day 1 to 30 days after last dose of etelcalcetide (up to approximately 30 weeks)]
• Frequency of Hypocalcemia [Срок оценки: Up to approximately 30 Weeks]
• Number of Participants with Corrected Serum Ca Levels at any Time During the Trial [Срок оценки: Up to approximately 30 Weeks]
• Number of Participants with Serum Phosphorous Levels Below Normal by Age Group [Срок оценки: Up to approximately 30 Weeks]
• Number of Participants with Predialysis iPTH Levels Below Normal by Age Group [Срок оценки: Up to approximately 30 Weeks]
• Change from Baseline in Systolic Blood Pressure [Срок оценки: Week -2, Week -1, Day1, and Weeks 4, 8, 12, 16, 20, 24, and 27]
• Change from Baseline in Diastolic Blood Pressure [Срок оценки: Week -2, Week -1, Day1, and Weeks 4, 8, 12, 16, 20, 24, and 27]
• Change from Baseline in Heart Rate [Срок оценки: Week -2, Week -1, Day1, and Weeks 4, 8, 12, 16, 20, 24, and 27]
• Change in Tanner Stage [Срок оценки: Week -2 and Week 27]
• Change in Height [Срок оценки: Day 1 and Week 27]

Критерии участия

Критерии включения

• Age of 28 days < 18 years.
• Dry weight ≥ 7 kg during screening.
• Diagnosed with CKD and SHPT undergoing hemodialysis at the time of screening.
• Diagnosis of SHPT with the mean of the 2 consecutive central laboratory iPTH values ≥ 300 pg/mL (32 pmol/L) during screening, on separate days and within 2 weeks of enrolment.
• Serum corrected calcium (cCa) value ≥ 9.0 mg/dL (2.25 mmol/L) for participants ≥ 2 years of age and older and serum cCa value ≥ 9.6 mg/dL (2.4 mmol/L) for participants 28 days to < 2 years of age obtained from the central laboratory during screening.
• Dialysate Ca level ≥ 2.5 mEq/L during screening for at least 4 weeks prior to screening and throughout the duration of the trial.
• No more than a maximum prescribed dose change of 50% for active vitamin D sterols/phosphate binders/Ca supplements within the 2 weeks prior to screening assessments and remain stable.
• SHPT not due to vitamin D deficiency, per investigator assessment.

Exclusion Criteria Disease Related

• History of congenital long QT syndrome, second or third degree heart block, ventricular tachyarrhythmia's or other conditions associated with prolonged QT interval.
• Anticipated or scheduled parathyroidectomy during the trial period.
• Anticipated or scheduled kidney transplant during the trial period.
• Participant has received a parathyroidectomy within 6 months prior to randomization.

Other Medical Conditions

• History of other malignancy, except non-melanoma skin cancers, cervical or breast ductal carcinoma in situ within the last 5 years.

Prior/Concomitant Therapy

• Use of concomitant medications that may prolong the corrected QT interval (eg, ondansetron, albuterol, sotalol, amiodarone, erythromycin, or clarithromycin). Refer to CredibleMeds.org for guidance. Certain medications may be allowed based on review by the medical monitor and require additional electrocardiogram (ECG) monitoring and potential electrolyte monitoring.
• Receipt of cinacalcet therapy within 30 days prior to screening assessments and through randomization.
• Receipt of etelcalcetide within 6 months prior to screening assessments and through randomization.
• All herbal medicines (eg, St. John's wort), vitamins, and supplements consumed by the participant within the 30 days prior to randomization, and continuing use if applicable, will be reviewed by the Principal Investigator and the Amgen Medical Monitor. Written documentation of the review and Amgen acknowledgment is required for participant participation.
• Use of any over-the-counter or prescription medications within the 14 days or 5 half-lives (whichever is longer) prior to randomization that are not established therapies for participants with renal disease or other conditions secondary to renal disease will be reviewed by the Principal Investigator and the Amgen Medical Monitor. Written documentation of the review and Amgen acknowledgment is required for participant participation. Paracetamol for analgesia will be allowed.

Prior/Concurrent Clinical Trial Experience • Currently receiving treatment in another investigational device or drug trial, or less than 30 days or 5 half-lives (whichever is longer) since ending treatment on another investigational device or drug trial(s). Other investigational procedures while participating in this trial are excluded.

Diagnostic Assessments During Screening

• Participant has significant abnormalities on the most recent central laboratory test during the screening period prior to enrollment per the Investigator including but not limited to the following: a. Serum transaminase (alanine aminotransferase \[ALT\] or serum glutamic pyruvic transaminase \[SGPT\], aspartate aminotransferase \[AST\] or serum glutamic oxaloacetic transaminase \[SGOT\]) > 2.0 times the upper limit of normal (ULN).
• Corrected QT interval (QTc) > 500 ms, using Bazett's formula.
• QTc ≥ 450 to ≤ 500 ms, using Bazett's formula, unless written permission to enroll is provided by the investigator after consultation with a pediatric cardiologist.
• Participant has a clinically significant ECG abnormality during screening that, in the opinion of the investigator, could pose a risk to participant safety or interfere with the trial evaluation.

Within the 60 days prior to enrollment

• New onset or worsening of a pre-existing seizure disorder.

Other Exclusions

• Participants aged 28 days to 6 months of age who were born prematurely at < 36 weeks gestational age.
• Female participant is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 3 months after the last dose of etelcalcetide. (Females of childbearing potential should only be included in the trial after a confirmed menstrual period and a negative highly sensitive serum pregnancy test within 7 days prior to the first dose of investigational product).
• Female participants of childbearing potential unwilling to use 1 highly-effective or acceptable method of contraception during treatment and for an additional 3 months after the last dose of investigational product.
• Participant has known sensitivity to etelcalcetide or excipients to be administered during dosing.
• Participant likely to not be available to complete all protocol-required trial visits or procedures, and/or to comply with all required trial procedures (eg, to the best of the participant and investigator's knowledge).
• History or evidence of any other clinically significant disorder, condition, or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to participant safety or interfere with the trial evaluation, procedures, or completion.
• Participant has previously entered this trial.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 10 центров

• Childrens Hospital of Los Angeles — Los Angeles
• Childrens Hospital Colorado — Aurora
• Childrens Mercy Hospital — Kansas City
• Mount Sinai Kidney Center - B1 Renal Treatment — New York
• Cincinnati Childrens Hospital Medical Center — Cincinnati
• Cleveland Clinic Foundation — Cleveland
• The Childrens Hospital at Oklahoma University Medical Center — Oklahoma City
• Childrens Hospital of Philadelphia — Philadelphia
• … и ещё 2 центра

Turkey (Türkiye) · 9 центров

• Hacettepe Universitesi Tip Fakultesi Hastanesi — Ankara
• Baskent Universitesi Ankara Hastanesi — Ankara
• Gazi Universitesi Saglik Arastirma ve Uygulama Merkezi Gazi Hastanesi — Ankara
• Ankara Bilkent Sehir Hastanesi — Ankara
• Firat Universitesi Tip Fakultesi Hastanesi — Elâzığ
• Istanbul Universitesi Cerrahpasa Tip Fakultesi — Istanbul
• Marmara Universitesi Tip Fakultesi Hastanesi — Istanbul
• Ege Universitesi Tip Fakultesi Hastanesi — Izmir
• … и ещё 1 центр

Индия · 6 центров

• Manipal Hospital — Bangalore
• KLES Dr Prabhakar Kore Hospital and Medical Research Centre — Belagavi
• Fortis Flt Lt Rajan Dhall Hospital — New Delhi
• All India Institute of Medical Sciences — New Delhi
• Sir Ganga Ram Hospital — New Delhi
• NRS Medical College and Hospital — Kolkata

Тайвань · 4 центра

• Kaohsiung Veterans General Hospital — Kaohsiung City
• National Cheng Kung University Hospital — Tainan
• National Taiwan University Hospital — Taipei
• Linkou Chang Gung Memorial Hospital — Taoyuan

Аргентина · 3 центра

• Fresenius Escobar — Belen de Escobar
• Hospital Italiano — Cuidad Autonoma de Buenos Aires
• Centro Infantil Del Rinon — San Miguel de Tucumán

Малайзия · 3 центра

• Hospital Raja Perempuan Zainab II — Kota Bharu
• Hospital Wanita Dan Kanak-Kanak Kuala Lumpur — Kuala Lumpur
• Hospital TuanKu Jaafar — Seremban

Россия · 3 центра

• SBHI Pediatrics city clinical hospital of Saint Vladimir — Moscow
• SBHI Children's City Multidisciplinary Clinical Specialized Center of High Medical Technol — Saint Petersburg
• State Budgetary Healthcare Institution Samara Regional Clinical Hospital na V D Seredavin — Samara

South Korea · 3 центра

• Asan Medical Center — Seoul
• Seoul National University Hospital — Seoul
• Pusan National University Yangsan Hospital — Yangsan-si, Gyeongsangnam-do

Сингапур · 1 центр

• National University Hospital — Singapore

Украина · 1 центр

• National Childrens Specializated Hospital Okhmadit — Kyiv

Идентификаторы

NCT: NCT03633708 · 20140315 · 2017-002411-34

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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