Ascertain the Optimal Starting Dose of Mircera Given Subcutaneously for Maintenance Treatment of Anemia in Pediatric Patients With Chronic Kidney Disease on Dialysis or Not Yet on Dialysis.

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03552393
• Collaborator: (none)
• Enrollment: 40
• Locations: 22
• Arm: 1
• Actual Duration (Months): 35.5
• Patients Per Site: 1.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Ascertain the starting dose of Mircera given subcutaneously for the maintenance treatment of anemia in pediatric participants with chronic kidney disease (CKD) on dialysis or not yet on dialysis when switching from stable subcutaneous (SC) maintenance treatment with epoetin alfa, epoetin beta, or darbepoetin alfa.

Condition or Disease	Intervention/Treatment	Phase
Anemia; Renal Insufficiency, Chronic	Drug: Mircera	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Single-Arm, Multicenter Study to Ascertain the Optimal Starting Dose of MIRCERA® Given Subcutaneously for the Maintenance Treatment of Anemia in Pediatric Patients With Chronic Kidney Disease on Dialysis or Not Yet on Dialysis.
• Actual Study Start Date: Aug 3, 2018
• Actual Primary Completion Date: Jul 19, 2021
• Actual Study Completion Date: Jul 19, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Mircera Mircera will be administered subcutaneously once every 4 weeks	Drug: Mircera; The initial dose of Mircera will be one of nine starting doses corresponding to the prefilled syringe strengths based on the total weekly erythropoiesis-stimulating agent (ESA) dose during the screening period.; Other Names: Methoxy polyethylene glycol-epoetin beta

Outcome Measures

Primary Outcome Measures

1. Change in Hemoglobin (Hb) Concentration Between the Baseline and the Evaluation Period for Each Patient [Baseline up to Week 21]

   The Hb change from baseline was calculated on a per-participant basis using an individual's average for both the baseline and evaluation periods and taking the difference. The baseline period was defined as the time between the day of first study dose and the previous 35 days. The evaluation period was defined as the period between Week 17 and Week 21, inclusive.

Secondary Outcome Measures

1. Number of Participants With an Average Hb Concentration During the Evaluation Period Within ± 1 g/dL of Their Baseline Hb and Above, Within or Below the Range of 10-12 g/dL [Week 17 up to Week 21]

   Number of participants with an average Hb concentration during the evaluation period within ± 1 g/dL of their baseline Hb is reported as well as the number of participants with an average Hb concentration above, within or below the range of 10-12 g/dL. The evaluation period was defined as the period between Week 17 and Week 21 inclusive.

2. Mean Hb Values and Change From Baseline [Baseline, Weeks 3, 5, 9, 13, 17, 19, 21, 25, 29, 33, 37, 41, 45]

   The mean Hb concentration over time and the mean change in Hb from baseline over time are presented.

3. Change in Mircera Dose Over Time [Week 1 to Week 17]

   A dose change was defined as a change in the administered dose strength compared to the preceding dose.

4. Ratio of Mircera Starting Dose (Week 1) to the Dose at Week 17 [Week 1, Week 17]

   The ratio of Mircera dose was calculated as the median (min-max) ratio of starting dose (Week 1) to the dose at Week 17. Participants who withdrew before Week 17 or who were not administered a Mircera dose at Week 17 visit due to the applicable dose adjustment rules were excluded from the ratio computation.

5. Number of Participants With Adverse Events by Severity as Assessed by Highest World Health Organization (WHO) Toxicity Grade [Baseline up to Week 45]

   An adverse event is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product, any new disease, or exacerbation of existing disease (a worsening in the character, frequency, or severity of a known condition), recurrence of an intermittent medical condition or any deterioration in a laboratory value or other clinical test.

6. Bioavailability (F) of Mircera in Pediatric Participants Based on Population PK Model [Pre-dose at Week 1, 9, 17; Post-dose at Week 3, Week 19 and additional sample taken between 24 hours and 5 days at participant's convenience]

   Bioavailability (F) is defined as the percentage of the administered drug, that reaches the systemic circulation. A population PK model was developed for Mircera that adequately describes pediatric data: a 1-compartment model with first order absorption and elimination processes. The bioavailability (F) was estimated using all the data points listed under time frame using the population PK model.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Months to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Pediatric participants 3 months to 17 years of age with clinically stable chronic renal anemia

• CKD with estimated glomerular filtration rate (eGFR) of < 45 mL/min/1.73 m2 (determined by the Bedside Schwartz formula) or dialysis treatment for at least 8 weeks before the first dose of Mircera

• For participants on peritoneal dialysis (PD): a weekly Kt/V≥ 1.8

• For participants on hemodialysis (HD): adequate HD, urea reduction ratio (URR) > 65% or Kt/V > 1.2 for participants on HD three times per week.

Participants with fewer than or more than three HD sessions per week should have a weekly Kt/V≥ 3.6.

• Baseline Hb concentration 10.0-12.0 g/dL determined from the mean of two Hb values measured at Visit 1 (Week -3) and Visit 2 (Week -1)

• Stable SC maintenance treatment with epoetin alfa, epoetin beta, or darbepoetin alfa with the same dosing interval for at least 6 weeks before the first dose of Mircera

• Stable dose of epoetin alfa, epoetin beta, or darbepoetin alfa treatment with no weekly dose change > 25% (increase or decrease) for at least 4 weeks before the first dose of Mircera

• Adequate iron status defined as ferritin≥100 ng/mL or transferrin saturation (TSAT)≥ 20% (or percentage of hypochromic red cells < 10%); mean of two values measured during screening.

Exclusion Criteria:

• Overt gastrointestinal bleeding within 8 weeks before screening or during the screening period

• RBC transfusions within 8 weeks before screening or during the screening period

• Hemoglobinopathies (e.g., homozygous sickle-cell disease, thalassemia of all types) Hemolytic anemia, Active malignant disease

• PD subjects with an episode of peritonitis within the past 30 days prior to screening and/or during the screening period

• Uncontrolled or symptomatic inflammatory disease (e.g., systemic lupus erythematosus)

• Uncontrolled hypertension as assessed by the investigator

• Epileptic seizures within 3 months prior to screening and during the screening period

• Administration of any investigational drug within 4 weeks prior to screening or planned during the study

• Severe hyperparathyroidism (intact parathyroid hormone [PTH]≥ 1000 pg/mL or whole PTH≥ 500 pg/mL) or biopsy-proven bone marrow fibrosis

• Kidney transplant with use of immunosuppressive therapies known to exacerbate anemia

• Known hypersensitivity to recombinant human erythropoietin (EPO), polyethylene glycol, or any constituent of the study drug formulation

• Anti-EPO antibody (AEAB)-mediated pure red cell aplasia (PRCA) or history of AEAB mediated PRCA or positive AEAB test result in the absence of PRCA

• High likelihood of early withdrawal or interruption of the study (e.g., planned living donor kidney transplant within 5 months of study start)

• Planned elective surgery during the entire study period

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham; Pediatric Nephrology	Birmingham	Alabama	United States	35233
2	Loma Linda University health	Loma Linda	California	United States	92354
3	Emory University School of Med; Pediatrics	Atlanta	Georgia	United States	30322
4	Children'S Mercy Hospital; Pediatric Nephrology	Kansas City	Missouri	United States	64108
5	RWJBarnabas Health	West Orange	New Jersey	United States	07052
6	East Carolina University; Brody School of Medicine	Greenville	North Carolina	United States	27834
7	UT Southwestern Medical Center; Pediatrics Dept.	Dallas	Texas	United States	75390
8	Hopital Jeanne De Flandre; Pediatrie	Lille		France	59037
9	Gh Necker Enfants Malades; Nephrologie	Paris		France	75743
10	Höpital Hautepierre; Pediatrie 1	Strasbourg		France	67098
11	Semmelweis University; 1st Department of Pediatrics, Pediatric Nephrology Center	Budapest		Hungary	1083
12	Debreceni Egyetem Klinikai Központ; Gyermekklinika	Debrecen		Hungary	4032
13	Clinica Pediatrica II De Marchi	Milano	Lombardia	Italy	20122
14	Ospedale Infantile Regina Margherita; U.O. Autonoma di Nefrologia, Dialisi e Trapianto	Torino	Piemonte	Italy	10126
15	Vilnius University Children's Hospital	Vilnius		Lithuania	LT-08406
16	Uniwersyteckie Centrum Kliniczne; Klinika Chorob Nerek i Nadciśnienia Dzieci i Mlodziezy	Gdansk		Poland	80-952
17	Uniwersytecki Szpital Dziecięcy w Krakowie; Oddz.Nefrologii i Nadciśnienia Tętniczego/Stacja Dializ	Kraków		Poland	30-663
18	Instytut "Centrum Zdrowia Matki Polki; Klinika Pediatrii i Immunologii i Nefrologii	Lodz		Poland	93-338
19	Szpital Specjalistyczny dla Dzieci i Doroslych; Oddzial Kliniczny Pediatrii i Nefrologii	Torun		Poland	87-100
20	Szpital Kliniczny nr 1 im. prof. Szyszko; Oddz. Nefrologii Dzieciecej z Pododdziałem Dializoterapii	Zabrze		Poland	41-800
21	Hospital Universitari Vall d'Hebron; Servicio de Nefrologia	Barcelona		Spain	08035
22	Hospital Universitario Virgen del Rocio; Servicio de Nefrologia Pediatrica	Sevilla		Spain	41013

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol - Dec 7, 2018
• Statistical Analysis Plan - Mar 4, 2021

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT03552393
• Other Study ID Numbers: NH19708; 2016-004779-39
• First Posted: Jun 11, 2018
• Last Update Posted: Mar 7, 2022
• Last Verified: Mar 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Renal Insufficiency; Anemia

Study Results

Participant Flow

Recruitment Details	The core study was 23 weeks and consisted of three periods: screening (3 weeks), dose titration (16 weeks) and evaluation (4 weeks). Participants completing the 20 weeks of treatment with hemoglobin (Hb) within +/- 1g/dL of their baseline and within the target range of 10-12 g/dL were eligible to enter an optional 24-week safety extension period.
Pre-assignment Detail	A total of 40 pediatric participants (ages 3 months to 17 years) with a diagnosis of anemia due to chronic kidney disease (CKD) who may or may not have been on dialysis at the time of study start were switched from stable subcutaneous (SC) maintenance treatment with epoetin alfa/beta or darbepoetin to methoxy polyethylene glycol-epoetin beta (Mircera).

Arm/Group Title	Mircera
Arm/Group Description	Mircera was administered subcutaneously once every 4 weeks.
Period Title: Core Period
STARTED	40
COMPLETED	38
NOT COMPLETED	2
Period Title: Core Period
STARTED	25
COMPLETED	21
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Mircera
Arm/Group Description	Mircera was administered subcutaneously once every 4 weeks.
Overall Participants	40
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	10.32 (5.69)
Sex: Female, Male (Count of Participants)
Female	17 42.5%
Male	23 57.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 10%
Not Hispanic or Latino	27 67.5%
Unknown or Not Reported	9 22.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 7.5%
White	30 75%
More than one race	0 0%
Unknown or Not Reported	7 17.5%

Outcome Measures

1. Primary Outcome

Title	Change in Hemoglobin (Hb) Concentration Between the Baseline and the Evaluation Period for Each Patient
Description	The Hb change from baseline was calculated on a per-participant basis using an individual's average for both the baseline and evaluation periods and taking the difference. The baseline period was defined as the time between the day of first study dose and the previous 35 days. The evaluation period was defined as the period between Week 17 and Week 21, inclusive.
Time Frame	Baseline up to Week 21

Outcome Measure Data

Analysis Population Description

ITT population included all participants enrolled in the study. Number analyzed is the number of participants with Hb concentration assessment at specified time points.

Arm/Group Title	Mircera
Arm/Group Description	Mircera was administered subcutaneously once every 4 weeks.
Measure Participants	38
Baseline	11.05 (0.51)
Change at Evaluation Period	0.48 (1.03)

2. Secondary Outcome

Title	Number of Participants With an Average Hb Concentration During the Evaluation Period Within ± 1 g/dL of Their Baseline Hb and Above, Within or Below the Range of 10-12 g/dL
Description	Number of participants with an average Hb concentration during the evaluation period within ± 1 g/dL of their baseline Hb is reported as well as the number of participants with an average Hb concentration above, within or below the range of 10-12 g/dL. The evaluation period was defined as the period between Week 17 and Week 21 inclusive.
Time Frame	Week 17 up to Week 21

Outcome Measure Data

Analysis Population Description

ITT population included all participants enrolled in the study. Hb values within 21 days after blood transfusion(s) were excluded from analysis. Number analyzed is the number of participants with Hb concentration assessment at specified time points.

Arm/Group Title	Mircera
Arm/Group Description	Mircera was administered subcutaneously once every 4 weeks.
Measure Participants	38
Hb Above 1 g/dL of Baseline	15 37.5%
Hb Maintained Within ± 1 g/dL of Baseline	19 47.5%
Hb Below 1 g/dL of Baseline	4 10%
Hb Above 12 g/dL	12 30%
Hb Maintained Within 10-12 g/dL	24 60%
Hb Below 10 g/dL	2 5%

3. Secondary Outcome

Title	Mean Hb Values and Change From Baseline
Description	The mean Hb concentration over time and the mean change in Hb from baseline over time are presented.
Time Frame	Baseline, Weeks 3, 5, 9, 13, 17, 19, 21, 25, 29, 33, 37, 41, 45

Outcome Measure Data

Analysis Population Description

ITT population included all participants enrolled in the study. Number analyzed signifies number of participants evaluable at specified time points.

Arm/Group Title	Mircera
Arm/Group Description	Mircera was administered subcutaneously once every 4 weeks.
Measure Participants	40
Baseline	11.02 (0.53)
Week 3	11.69 (0.97)
Change at Week 3	0.67 (0.74)
Week 5	11.21 (1.02)
Change at Week 5	0.19 (0.94)
Week 9	11.68 (1.42)
Change at Week 9	0.64 (1.21)
Week 13	11.56 (1.17)
Change at Week 13	0.51 (1.10)
Week 17	11.46 (1.33)
Change at Week 17	0.42 (1.39)
Week 19	11.81 (1.11)
Change at Week 19	0.77 (1.14)
Week 21	11.10 (0.91)
Change at Week 21	0.05 (0.99)
Week 25	11.29 (1.04)
Change at Week 25	0.21 (1.12)
Week 29	11.22 (1.18)
Change at Week 29	0.15 (1.11)
Week 33	11.09 (1.11)
Change at Week 33	0.02 (1.24)
Week 37	11.04 (0.77)
Change at Week 37	-0.03 (0.90)
Week 41	10.83 (0.83)
Change at Week 41	-0.22 (1.03)
Week 45	10.68 (1.02)
Change at Week 45	-0.35 (1.13)

4. Secondary Outcome

Title	Change in Mircera Dose Over Time
Description	A dose change was defined as a change in the administered dose strength compared to the preceding dose.
Time Frame	Week 1 to Week 17

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least one dose of study drug regardless of whether they withdrew prematurely or not. Number analyzed signifies number of participants evaluable at specified time points.

Arm/Group Title	Mircera
Arm/Group Description	Mircera was administered subcutaneously once every 4 weeks.
Measure Participants	40
Week 1	75.00
Week 5	75.00
Change at Week 5	0.00
Week 9	50.00
Change at Week 9	0.00
Week 13	50.00
Change at Week 13	-25.00
Week 17	50.00
Change at Week 17	-20.00

5. Secondary Outcome

Title	Ratio of Mircera Starting Dose (Week 1) to the Dose at Week 17
Description	The ratio of Mircera dose was calculated as the median (min-max) ratio of starting dose (Week 1) to the dose at Week 17. Participants who withdrew before Week 17 or who were not administered a Mircera dose at Week 17 visit due to the applicable dose adjustment rules were excluded from the ratio computation.
Time Frame	Week 1, Week 17

Outcome Measure Data

Analysis Population Description

Participants who received a dose of study drug on Week 1 and Week 17 were included in the analysis.

Arm/Group Title	Mircera
Arm/Group Description	Mircera was administered subcutaneously once every 4 weeks.
Measure Participants	33
Median (Full Range) [ratio]	1.44

6. Secondary Outcome

Title	Number of Participants With Adverse Events by Severity as Assessed by Highest World Health Organization (WHO) Toxicity Grade
Description	An adverse event is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product, any new disease, or exacerbation of existing disease (a worsening in the character, frequency, or severity of a known condition), recurrence of an intermittent medical condition or any deterioration in a laboratory value or other clinical test.
Time Frame	Baseline up to Week 45

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least one dose of study drug regardless of whether they withdrew prematurely or not.

Arm/Group Title	Mircera
Arm/Group Description	Mircera was administered subcutaneously once every 4 weeks.
Measure Participants	40
Grade 1-2	25 62.5%
Grade 3-4	8 20%

7. Secondary Outcome

Title	Bioavailability (F) of Mircera in Pediatric Participants Based on Population PK Model
Description	Bioavailability (F) is defined as the percentage of the administered drug, that reaches the systemic circulation. A population PK model was developed for Mircera that adequately describes pediatric data: a 1-compartment model with first order absorption and elimination processes. The bioavailability (F) was estimated using all the data points listed under time frame using the population PK model.
Time Frame	Pre-dose at Week 1, 9, 17; Post-dose at Week 3, Week 19 and additional sample taken between 24 hours and 5 days at participant's convenience

Outcome Measure Data

Analysis Population Description

PK population included all participants enrolled in the study.

Arm/Group Title	Mircera
Arm/Group Description	Mircera was administered subcutaneously once every 4 weeks.
Measure Participants	40
Number [percentage]	67

Adverse Events

Time Frame	Up to Week 45
Adverse Event Reporting Description	Safety population included all participants who received at least one dose of study drug regardless of whether they withdrew prematurely or not.
Arm/Group Title	Mircera
Arm/Group Description	Mircera was administered subcutaneously once every 4 weeks.
All Cause Mortality
	Mircera
	Affected / at Risk (%)	# Events
Total	0/40 (0%)
Serious Adverse Events
	Mircera
	Affected / at Risk (%)	# Events
Total	13/40 (32.5%)
Congenital, familial and genetic disorders
Hydrocele	1/40 (2.5%)	1
Gastrointestinal disorders
Diarrhoea	1/40 (2.5%)	1
Vomiting	1/40 (2.5%)	2
General disorders
Device related thrombosis	1/40 (2.5%)	1
Infections and infestations
Appendicitis	1/40 (2.5%)	1
Device related infection	1/40 (2.5%)	2
Enterovirus infection	1/40 (2.5%)	1
Gastroenteritis	1/40 (2.5%)	1
Peritonitis	3/40 (7.5%)	3
Pharyngotonsillitis	1/40 (2.5%)	1
Pneumonia	1/40 (2.5%)	1
Pyelonephritis	1/40 (2.5%)	1
Respiratory syncytial virus bronchiolitis	1/40 (2.5%)	1
Rhinovirus infection	1/40 (2.5%)	1
Upper respiratory tract infection	1/40 (2.5%)	1
Viral infection	1/40 (2.5%)	1
Injury, poisoning and procedural complications
Anaemia postoperative	2/40 (5%)	2
Musculoskeletal and connective tissue disorders
Back pain	1/40 (2.5%)	1
Product Issues
Device malfunction	1/40 (2.5%)	1
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/40 (2.5%)	1
Vascular disorders
Hypotension	2/40 (5%)	2
Other (Not Including Serious) Adverse Events
	Mircera
	Affected / at Risk (%)	# Events
Total	28/40 (70%)
Blood and lymphatic system disorders
Anaemia	2/40 (5%)	2
Gastrointestinal disorders
Abdominal pain	3/40 (7.5%)	3
Diarrhoea	3/40 (7.5%)	4
General disorders
Injection site pain	2/40 (5%)	2
Pyrexia	5/40 (12.5%)	5
Infections and infestations
Bronchitis	2/40 (5%)	2
Conjunctivitis	3/40 (7.5%)	3
Gastroenteritis	2/40 (5%)	2
Nasopharyngitis	2/40 (5%)	2
Pharyngitis	2/40 (5%)	3
Rhinitis	3/40 (7.5%)	3
Upper respiratory tract infection	6/40 (15%)	6
Urinary tract infection	2/40 (5%)	2
Injury, poisoning and procedural complications
Accidental overdose	5/40 (12.5%)	5
Metabolism and nutrition disorders
Hyperkalaemia	2/40 (5%)	2
Hyperphosphataemia	2/40 (5%)	2
Musculoskeletal and connective tissue disorders
Muscle spasms	2/40 (5%)	2
Nervous system disorders
Headache	3/40 (7.5%)	6
Renal and urinary disorders
Haematuria	2/40 (5%)	2
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	3/40 (7.5%)	3
Rhinorrhoea	2/40 (5%)	3
Vascular disorders
Hypertension	2/40 (5%)	3
Hypotension	2/40 (5%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.