Clinical trial NCT03969329: A Phase 3 Study of Etelcalcetide in Children With Secondary Hyperparathyroidism Receiving Hemodialysis
Official title: Phase 3, Single-arm, Open-label, Multidose, Titration, Pharmacokinetic, Pharmacodynamic, and Safety Study of Etelcalcetide in Children and Adolescents ≥ 2 to < 18 Years of Age With Secondary Hyperparathyroidism and Chronic Kidney Disease Receiving Maintenance Hemodialysis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Secondary Hyperparathyroidism
Keywords: Secondary hyperparathyroidism (sHPT)
Chronic kidney disease (CKD)
Paediatric
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2019-05-31
Enrollment: 24
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Subjects will remain on treatment for 26 weeks from day 1 or until the time of renal transplant or parathyroidectomy, whichever occurs first. Subjects will receive a starting dose of etelcalcetide 0.07 mg/kg or 5 mg, whichever is lower, 3 times a week (TIW) intravenously. The dose of etelcalcetide will be titrated every 4 weeks (weeks 5, 9, 13, and 17) based on intact parathyroid hormone (iPTH), calcium, and safety to a maximum dose of 0.21 mg/kg or 15 mg, whichever is lower. The lowest protocol specified dose (PSD) for this study is 0.035 mg/kg or 2.5 mg, whichever is lower.
Primary purpose: TREATMENT

Brief summary: Assess the efficacy, safety, pharmacokinetics (PK) and pharmacodynamics (PD) of etelcalcetide in the treatment of secondary hyperparathyroidism (SHPT) in pediatric subjects between ≥ 2 to \< 18 years of age, with chronic kidney disease (CKD) on hemodialysis


Eligibility criteria: Inclusion Criteria:

* Subject's legally acceptable representative has provided informed consent when the subject is legally too young to provide informed consent and the subject has provided written assent based on local regulations and/or guidelines prior to any study-specific activities/procedures being initiated.
* Male or female subjects greater than or equal to 2 to less than 18 years of age at the time of enrollment.
* Targeted Dry weight greater than or equal to 7 kg at the time of screening Week -1.
* Diagnosed with chronic kidney disease (CKD) and secondary hyperparathyroidism (SHPT) undergoing hemodialysis/hemodiafiltration three times per week (TIW) at the time of screening greater than or equal to 1 month.
* Diagnosis of secondary hyperparathyroidism (SHPT) with the mean of the 2 consecutive central laboratory intact parathyroid hormone (iPTH) values greater than 300 pg/mL during screening, on separate days and within 2 weeks of enrollment obtained from the central laboratory during screening.
* Serum corrected calcium (cCa) value greater than or equal to 9.0 mg/dL obtained from the central laboratory during screening.
* Dialysate calcium (Ca) level greater than or equal to 2.5 mEq/L for at least 1 month prior to screening and throughout the duration of the study.
* Subject receiving active vitamin D sterols must have had no more than a maximum dose change of 50% within the 2 weeks prior to screening laboratory assessments, remain stable through enrollment, and be expected to maintain stable doses for the duration of the study, except for adjustments allowed per protocol.
* Subject receiving phosphate binders must have had no more than a maximum dose change of 50% within the 2 weeks prior to screening laboratory assessments, remain stable through enrollment, and be expected to maintain stable dose for the duration of the study, except for adjustments allowed per protocol.
* Subject receiving calcium (Ca) supplements must have had no more than a maximum dose change of 50% within the 2 weeks prior to screening laboratory assessments, remain stable through enrollment, and be expected to maintain stable dose for the duration of the study, except for adjustments allowed per protocol.
* Secondary hyperparathyroidism (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, history of symptomatic ventricular dysrhythmias Torsades de Pointes or other conditions associated with prolonged QT interval.
* Anticipated or scheduled parathyroidectomy during the study period.
* Anticipated or scheduled kidney transplant during the study period.
* Subject has received a parathyroidectomy within 6 months prior to enrollment.
* Other Medical Conditions:
* Current malignancy or history of other malignancy, except non-melanoma skin cancers within the last 5 years.
* Prior/Concomitant Therapy:
* Use of concomitant medications that may prolong the QTc (eg, ondansetron, albuterol, sotalol, amiodarone, erythromycin, or clarithromycin). Refer to CredibleMeds.org for guidance.
* Receipt of cinacalcet therapy within 30 days prior to screening and through enrollment.
* Receipt of etelcalcetide therapy within 6 months prior to screening and through enrollment.
* All herbal medicines (eg, St. John's wort), vitamins, and supplements consumed by the subject within the 30 days prior to enrollment, 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 subject participation.
* Use of any over-the-counter or prescription medications within the 14 days or 5 half-lives (whichever is longer) prior to enrollment that are not established therapies for subjects 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 subject participation. Paracetamol for analgesia will be allowed.
* Prior/Concurrent Clinical Study Experience:
* Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(ies). Other investigational procedures while participating in this study are excluded.
* Diagnostic Assessments During Screening:
* Subject 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 \[SGOT\]) greater than 1.5 times the upper limit of normal (ULN).
* Corrected QT interval greater than 500 ms, using Bazett's formula.
* Corrected QT interval greater than or equal to 450 to less than or equal to 500 ms, using Bazett's formula, unless written permission to enroll is provided by the investigator after consultation with a pediatric cardiologist.
* Subject has a clinically significant electrocardiogram (ECG) abnormality (eg, unstable arrhythmia) during screening that, in the opinion of the investigator, could pose a risk to subject safety or interfere with the study evaluation.
* Within the 3 Months Prior to Screening:
* New onset or worsening of a pre-existing seizure disorder.
* Subjects on anti-convulsant medication must be on a stable and therapeutic dose for 3 months prior to screening (if blood level monitoring is clinically available, then the subject must have a therapeutic blood level within 1 week of enrollment).

Other Exclusions:

* Female subject 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 study 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 subjects of childbearing potential unwilling to use 1 highly effective or acceptable method of effective contraception during treatment and for an additional 3 months after the last dose of investigational product. Refer to Appendix 5 for additional contraceptive information.
* Female subjects of childbearing potential with a positive pregnancy test assessed at screening by a serum pregnancy test.
* Subject has known sensitivity to etelcalcetide or excipients to be administered during dosing.
* Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator's knowledge.
* History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) or unacceptable physical findings, that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation procedures or completion.
* Subject previously has entered this study.
* Anemia, which in the opinion of the investigator makes it not advisable to undergo sequential blood draws.
* History of unstable chronic heart failure within the last 1 year prior to screening.

Primary outcomes:
measure: Percent change in intact parathyroid hormone (iPTH) from baseline during the efficacy assessment period (EAP) at weeks 20 to 26
timeFrame: 20 to 26 weeks
Secondary outcomes:
measure: Achievement of a greater than 30% reduction from baseline in mean intact parathyroid hormone (iPTH) during the efficacy assessment period (EAP)
timeFrame: 20 to 26 weeks
measure: Percent change from baseline in corrected total serum calcium (Ca) and serum phosphorus from baseline during the EAP
timeFrame: 20 to 26 weeks
measure: Proportion of subjects achieving corrected serum calcium (Ca) levels less than 8.0 mg/dL (2.0 mmol/L) at any time during the study
timeFrame: During the treatment period
measure: Proportion of subjects with hypocalcemia (corrected serum calcium levels less than 8.4 mg/dL)
timeFrame: During the treatment period
measure: Etelcalcetide plasma concentrations before and at the end of dialysis after single and multiple doses
timeFrame: During the treatment period
measure: Etelcalcetide PK parameter of maximum-observed concentration (Cmax)
timeFrame: During the treatment period
measure: Etelcalcetide pharmacokinetic (PK) parameter of plasma trough concentrations (Cmin)
timeFrame: During the treatment period
measure: Subject incidence of all treatment-emergent adverse events
timeFrame: During the treatment period
Other outcomes:
Locations:
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Praha 5
country: Czechia
facility: Fakultni nemocnice v Motole
city: Bron cedex
country: France
facility: Hospices Civils de Lyon Hopital Femme Mere Enfant
city: Paris
country: France
facility: Hôpital Armand Trousseau
city: Bonn
country: Germany
facility: Kindernierenzentrum Bonn
city: Hamburg
country: Germany
facility: Universitaetsklinikum Hamburg Eppendorf
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Universitaetsklinikum Heidelberg, Zentrum fuer Kinder und Jugendmedizin
city: Koeln
country: Germany
facility: Universitaetsklinikum Koeln
city: Athens
country: Greece
facility: General Children Hospital Panagioti and Aglaias Kyriakou
city: Thessaloniki
country: Greece
facility: Ippokrateio General Hospital of Thessaloniki
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Szeged
country: Hungary
facility: Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont Altalanos Orvostudomanyi Kar
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Meyer
city: Vilinus
country: Lithuania
facility: Childrens Hospital, Affiliate of Vilnius University Hospital Santaros Klinikos
city: Krakow
country: Poland
facility: Uniwersytecki Szpital Dzieciecy w Krakowie
city: Porto
country: Portugal
facility: Unidade Local de Saude de Santo Antonio, EPE - Hospital de Santo Antonio
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
state: Andalucía
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d Hebron
state: Cataluña
city: Glasgow
country: United Kingdom
facility: Royal Hospital for Sick Children
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hospitals NHS Trust
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children
city: Southampton
country: United Kingdom
facility: University Hospital Southampton NHS Foundation Trust
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References: