E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of anemia with darbepoetin alfa in pediatric subjects with chronic kidney disease (CKD) receiving and not receiving dialysis |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064848 |
E.1.2 | Term | Chronic kidney disease |
E.1.2 | System Organ Class | 100000004857 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10002272 |
E.1.2 | Term | Anemia |
E.1.2 | System Organ Class | 100000004851 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To test if the proportion of subjects achieving a Hb value ≥ 10.0 g/dL at any time point after the first dose during the study is greater than 0.8 when administered de novo darbepoetin alfa QW for treatment of anemia in pediatric CKD subjects receiving and not receiving dialysis.
To test if the proportion of subjects achieving a Hb value ≥ 10.0 g/dL at any time point after the first dose during the study is greater than 0.8 when administered de novo darbepoetin alfa Q2W for treatment of anemia in pediatric CKD subjects receiving and not receiving dialysis |
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E.2.2 | Secondary objectives of the trial |
To assess the safety and tolerability of darbepoetin alfa administered QW and Q2W
To estimate Hb values over the duration of the study in the QW and Q2W arms
To estimate doses over the duration of the study in the QW and Q2W arms
To assess the health-related quality of life in pediatric CKD subjects ≥ 2 years old over the duration of the study in the QW and Q2W arms
To obtain pharmacokinetic (PK) data in subjects < 6 years of age |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Signed informed consent form/assent form (if applicable)
Diagnosis of CKD defined as CKD stage 3 – 5, with an estimated Glomerular Filtration Rate (GFR) < 60 mL/min/1.73 m2 (Schwartz equation) if not receiving dialysis, or: Receiving dialysis
Ages 1 year through 18 years
Two consecutive screening Hb values (taken at least 5 days apart during the screening period) must be < 10.0 g/dL
Transferrin saturation (Tsat) ≥ 20%
Clinically stable and suitable for participation in this study, in the judgment of the investigator |
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E.4 | Principal exclusion criteria |
Anticipating or scheduled for a living related-donor kidney transplant
Prior history (within 12 weeks before randomization) of cardiovascular events including:
- acute myocardial ischemia
- hospitalization for congestive heart failure
- myocardial infarction
- stroke or transient ischemic attack
Hematologic disease that is likely to affect red blood cell production or turnover (eg, hemolytic anemia, thalassemia, sickle cell disease, myelodysplastic syndromes, hematologic malignancy); myeloma; hemolytic anemia; thalassemia
Upper or lower GI bleeding within the 6 months prior to randomization
Uncontrolled hypertension defined as stage 2 hypertension or greater.
This is defined as a systolic or diastolic blood pressure value greater than the 99th percentile + 5 mmHg for a subject's age. See Appendix G.
(Blood Pressure Stages defined in the "The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents" Pediatrics 2004)
Use of any erythropoiesis stimulating agent (ESA) within the 8 weeks prior to randomization, and/or, previous use of an ESA for an unapproved indication or administered via an unapproved route at any time prior to randomization
History of non-febrile seizure
Major surgery within 1 week prior to randomization (excluding vascular access surgery)
Clinical evidence of current malignancy and/or receiving systemic chemotherapy/radiotherapy with the exception of localized basal cell or squamous cell carcinoma of the skin and cervical intraepithelial
neoplasia
RBC transfusions within 1 week prior to randomization
Androgen therapy within 8 weeks prior to randomization
Currently receiving antibiotic therapy for systemic infection
Prior history (within 6 months prior to randomization) of
thromboembolism (eg, deep vein thrombosis or pulmonary embolism)
Peritoneal dialysis subjects with an episode of peritonitis within 30 days prior to randomization
Pregnant or breast-feeding, or planning to become pregnant within four weeks after the end of treatment.
Females who have reached menarche must have a negative serum pregnancy test (or definitive evidence to
demonstrate lack of pregnancy) within 21 days prior to randomization, unless there is a documented
history of amenorrhea.
Not willing to use effective contraception during treatment and for 1 month after the end of treatment
Other investigational procedures are excluded
Treatment with an investigational product or device within 30 days before randomization or scheduled to receive an investigational product other than those specified by this protocol during the course of this
study
Has known sensitivity to any of the products to be administered during dosing
Subject or parent/legal guardian has any kind of disorder that compromises the ability of the subject or parent/legal guardian to give written informed consent and/or to comply with study procedures
Subject is receiving corticosteroids at a dose higher than 0.5 mg/kg body weight/day of prednis(ol)one (or equivalent dose of another steroid) for > 5 days within 4 weeks of enrollment. Subject is receiving any other immunosuppressive agent. |
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E.5 End points |
E.5.1 | Primary end point(s) |
For the QW arm: Achieving a Hb value ≥ 10.0 g/dL at any time point after the first dose without receiving any red blood cell transfusions after randomization and within 90 days prior to the hemoglobin measurement
For the Q2W arm: Achieving a Hb value ≥ 10.0 g/dL at any time point after the first dose without receiving any red blood cell transfusions after randomization and within 90 days prior to the hemoglobin measurement |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Achieving a Hb value ≥ 10.0 g/dL at any time point after the first dose during the study when administered de novo darbepoetin alfa QW: After the first dose, Hb assessed at weeks 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24 and 25. Achievement of a Hb value ≥ 10.0 g/dL evaluated at the end of the study.
- Achieving a Hb value ≥ 10.0 g/dL - Achieving a Hb value ≥ 10.0 g/dL at any time point after the first dose during the study when administered de novo darbepoetin alfa Q2W: After the first dose, Hb assessed at weeks 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24 and 25. Achievement of a Hb value ≥ 10.0 g/dL evaluated at the end of the study. |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints:
- Hb value at each scheduled time point
- Darbepoetin alfa doses over the duration of the study
- Time to first Hb value ≥ 10.0 g/dL
- Dose at first Hb value ≥ 10.0 g/dL
- Change from baseline at Week 13 and Week 25 in Pediatric Quality of Life Questionnaire (PedsQL) scores
Secondary safety endpoints:
- Adverse events
- Maximum Hb value increase over a 2 week period
- Blood pressure and changes in laboratory parameters during the study
- Hb rate of rise (ROR) during the study
- Excursions above 12.0 g/dL, above 13.0 g/dL and above 14.0 g/dL
- Anti-erythropoiesis antibodies at each scheduled time point
Additional secondary endpoint:
- Darbepoetin alfa serum concentrations for subjects < 6 years of age |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Hb value: Screening, Day 1, weeks 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24 and 25.
- Darbepoetin alfa doses over the duration of the study: Evaluated at the
end of the study
- Time to first Hb value ≥ 10.0 g/dL: Evaluated at the end of the study
- Dose at first Hb value ≥ 10.0 g/dL: Evaluated at the end of the study
- Change from baseline at Week 13 and Week 25 in Pediatric Quality of Life Questionnaire (PedsQL) scores: Day 1, weeks 13 and 25.
For remaining timepoints, please see the protocol |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
darbepoetin alfa QW and Q2W will be compared. Placebo injections used to maintain study blind |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
Will this trial be conducted at a single site globally?
| No |
E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
Mexico |
Russian Federation |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.2 | In all countries concerned by the trial years | 8 |