Pharmacokinetic/Pharmacodynamic Parameters of NNG-DEPO (Stimus) With Aranesp® (Amgen) in Treatment of Anemia in CKD Patients on Dialysis (CKD)

Randomized, Double-blind, Parallel, Active Controlled Study to Compare Pharmacokinetic/Pharmacodynamic Parameters of Nanogen's Darbepoetin Alfa With Aranesp® (Amgen) in Treatment of Anemia in Chronic Kidney Disease Patients on Dialysis

This is a double-blind, randomized, active-control study with 2-study arms-darbepoetin alfa biosimilar and Aranesp, noninferiority trial design in dialysis patients. Dialysis patients will be randomized into 1:1 ratio to receive either Darbepoetin alfa or Aranesp 0.75 µg/kg by subcutaneous injection every other week for 24 weeks.

Pharmacokinetic/pharmacodynamic parameters for evaluation are assessed as per study endpoints at defined time points on all patients.

During the treatment, dose adjustments will be made as necessary to achieve a hemoglobin response, defined as maintaining Hb in target range 10 - 12 g/dL.

Study Overview

• Status: Active, not recruiting
• Conditions: Chronic Kidney Disease
• Intervention / Treatment: Biological: Stimus

Detailed Description

PHASE OF TRIAL: I SAMPLE SIZE: 43 for pharmacokinetic/pharmacodynamic parameters TARGET POPULATION: Patients with chronic kidney disease undergoing dialysis

STUDY GROUPS:

1. Darbepoetin alfa (Nanogen) SC 0.75 µg/kg Q2W, for 24 weeks.
2. Aranesp® (Amgen) SC 0.75 µg/kg Q2W, for 24 weeks.

PK ASSESSMENT: Blood samples for PK assessments will be collected at:

• IV: time zero (predose) before injection of study drug and then after 0.25, 0.5, 4, 12, 24, 48, 96, 144, 240 and 336 hours post-dose.
• SC: time zero (predose) before injection of study drug and then after 4, 12, 24, 48, 96, 144, 240 and 336 hours post-dose.

PD ASSESSMENT: Blood samples for PD assessments will be collected at time zero (predose) before injection of study drug and then after 24, 48, 96, 144, 240 and 336 hours post-dose.

SAFETY AND TOLERABILITY ASSESSMENT:

Safety and tolerability assessments will be performed at each visit. Following variables will be considered to define the safety and tolerability of investigational drugs:

• Clinical adverse events (AEs): frequency of AEs, overall and by intensity.
• Severe clinical adverse events (SAEs): frequency of AEs, overall and by intensity.
• Symptoms directed physical examination including body weight, and vital signs during treatment period: mean change from baseline and the frequency of clinically relevant changes from baseline.
• Laboratory tests: frequency of clinically relevant changes from baseline.
• The frequency of any concomitant medication administered to treat any adverse events.
• Presence of anti-bodies to darbepoetin alfa (immunogenicity).

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 1

Contacts and Locations

Study Locations

• Vietnam
  • Ho Chi Minh City, Vietnam
    • NANOGEN Pharmaceutical Biotechnology JSC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

• The patients signed the informe consent form and adhere to study visit schedule.
• Male or female patients aged from 18 to 65 years.
• Patients on hemodialysis or peritoneal dialysis for at least 3 months and have Hb baseline <10 g/dL during the screening period.
• Have transferrin saturation ≥ 20%, serum ferritin ≥ 200 ng/mL, vitamin B12 and folate within the normal range.
• Have expected survival of at least 6 months from time of enrollment (by investigator's assessment).
• Women childbearing age must agree to use medically acceptable methods of contraception during the study and for 6 months after the last study treatment.
• The patient does not have any serious medical conditions that may affect to study treatment compliance.

Exclusion Criteria

• Uncontrolled hypertension over 2 weeks prior to and within the screening period (BP ≥ 160/90 mmHg).
• Patients treated with Darbepoetin alfa or r-HuEPO within 4 weeks prior to enrollment.
• Patients with Uncontrolled diabetes mellitus with HbA1C ≥ 10%.
• Congestive Heart Failure of grade 3 or 4 as New York Heart Association classification.
• History of unstable angina or myocardial infarction within 6 months.
• History of Grand mal seizures in last 2 years.
• Present with severe hyperparathyroidism (iPTH >1500 pg/mL for Dialysis).
• History of major surgery within 12 weeks prior to screening.
• Systemic hematologic disorders including sickle cell anemia, myelodysplastic syndromes, hematological malignancy, myeloma and hemolytic anemia.
• Systemic infections, active inflammatory diseases and malignancies.
• Active liver disease or hepatic with liver enzymes AST and ALT raised > 2-times of laboratory normal values, child B or child C cirrhosis.
• Are being treated with androgen therapy within the 8 weeks prior to the screening period.
• Pregnant or suspected pregnant women, breast-feeding women.
• Patients scheduled for any transplant procedure within 6 months of screening or with a previous history of kidney transplantation.
• Patients who are hypersensitive to any of substances of investigational product.
• Patients using drugs that can affect the concentration of Hb in the blood (except blood-forming drugs such as iron, folic acid).
• Patients with seropositivity to HIV, HBV or anti-HCV.
• Patients having acute tuberculosis or any acute bacterial infection within 1 month prior to the screening.
• Patient has occult blood in stool or any other known source of internal bleeding and confirmed gastrointestinal bleeding by endoscopy.
• Patients with blood transfusion due to acute bleeding within 12 weeks prior to screening period.
• Patients with a history of immunosuppressive therapy within 1 month.
• The patient is suffering from advanced cancer.
• Patients having participated in any other clinical trial within 1 month prior to the screening period.
• The patient had any medical condition that the investigator assessed as affecting the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Stimus; Treatment: Nanogen's Darbepoetin alfa 10µg/0.4mL, 20µg/0.5mL, 40µg/0.4mL, 60µg/0.3mL, prefilled syringe	Biological: Stimus; NNG-DEPO (Darbepoetin alfa 10 mcg/0.4 mL, 20 mcg/0.5 mL, 40 mcg/0.4 mL, 60 mcg/0.3 mL) is available as a prefilled syringe in a sterile, colorless, glass tube.; Aranesp® (Darbepoetin alfa 10 mcg/ 0.4 mL, 20 mcg/ 0.5 mL, 40 mcg/ 0.4 mL, 60 mcg/ 0.3 mL) is manufactured by Amgen, as a pre-filled syringe in a sterile, glass tube, colourless. Storage: 2-8ºC, not frozen. The process of transporting and storing the drug must ensure the temperature in the range of 2-8ºC. NNG-DEPO/Aranesp is administered subcutaneously (or intravenously for patients with PK-PD in the previous IV group), at a dose of 0.75 g/kg initially, every 2 weeks at the second visit. IPs will be prepared according to standard procedure (SOP). Dosage adjustment guideline: Patients will have hemoglobin levels monitored every 2 weeks. The investigators will evaluate and adjust the dose of Darbepoetin alfa to maintain the Hb levels within the target range (10 - 12 g/dL)
Active Comparator: Aranesp; Control: Amgen's Aranesp® 10µg/0.4mL, 20µg/0.5mL, 40µg/0.4mL, 60µg/0.3mL, prefilled syringe	Biological: Stimus; NNG-DEPO (Darbepoetin alfa 10 mcg/0.4 mL, 20 mcg/0.5 mL, 40 mcg/0.4 mL, 60 mcg/0.3 mL) is available as a prefilled syringe in a sterile, colorless, glass tube.; Aranesp® (Darbepoetin alfa 10 mcg/ 0.4 mL, 20 mcg/ 0.5 mL, 40 mcg/ 0.4 mL, 60 mcg/ 0.3 mL) is manufactured by Amgen, as a pre-filled syringe in a sterile, glass tube, colourless. Storage: 2-8ºC, not frozen. The process of transporting and storing the drug must ensure the temperature in the range of 2-8ºC. NNG-DEPO/Aranesp is administered subcutaneously (or intravenously for patients with PK-PD in the previous IV group), at a dose of 0.75 g/kg initially, every 2 weeks at the second visit. IPs will be prepared according to standard procedure (SOP). Dosage adjustment guideline: Patients will have hemoglobin levels monitored every 2 weeks. The investigators will evaluate and adjust the dose of Darbepoetin alfa to maintain the Hb levels within the target range (10 - 12 g/dL)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK parameters comparison between NNG-DEPO and Aranesp®: Cmax	Serum peak concentrations (Cmax)	IV:Assessed predose and at 0.25; 0.5; 4;12;24;48;96;144;240;336 hours postdose/ SC: Assessed predose and at 4;12;24;48;96;144;240;336 hours postdose
PK parameters comparison between NNG-DEPO and Aranesp®: AUC(0, t)	Area under the curve from 0 to t (AUC 0-t)	IV:Assessed predose and at 0.25; 0.5; 4;12;24;48;96;144;240;336 hours postdose/ SC: Assessed predose and at 4;12;24;48;96;144;240;336 hours postdose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PD parameters comparison between NNG-DEPO and Aranesp®: Cmax of reticulocytes	Serum peak concentrations (Cmax) of reticulocytes	Assessed predose and at and at 24;48;96;144;240;336 hours postdose
PD parameters comparison between NNG-DEPO and Aranesp®: AUC(0, t) of reticulocytes	Area under the curve from 0 to t (AUC 0-t) of reticulocytes	Assessed predose and at and at 24;48;96;144;240;336 hours postdose
PD parameters comparison between NNG-DEPO and Aranesp®: Tmax of reticulocytes	Time for the drug to reach peak concentration (Tmax) of reticulocytes	Assessed predose and at and at 24;48;96;144;240;336 hours postdose
PK parameters comparison between NNG-DEPO and Aranesp®:Tmax	Time for the drug to reach peak concentration (Tmax)	IV:Assessed predose and at 0.25; 0.5; 4;12;24;48;96;144;240;336 hours postdose/ SC: Assessed predose and at 4;12;24;48;96;144;240;336 hours postdose
PK parameters comparison between NNG-DEPO and Aranesp®: AUC(0,∞)	Area under the curve from 0 to ∞ (AUC0-∞)	IV:Assessed predose and at 0.25; 0.5; 4;12;24;48;96;144;240;336 hours postdose/ SC: Assessed predose and at 4;12;24;48;96;144;240;336 hours postdose
PK parameters comparison between NNG-DEPO and Aranesp®:T1/2	Half-life (T1/2)	IV:Assessed predose and at 0.25; 0.5; 4;12;24;48;96;144;240;336 hours postdose/ SC: Assessed predose and at 4;12;24;48;96;144;240;336 hours postdose
PK parameters comparison between NNG-DEPO and Aranesp®: CL/F	CL/F	IV:Assessed predose and at 0.25; 0.5; 4;12;24;48;96;144;240;336 hours postdose/ SC: Assessed predose and at 4;12;24;48;96;144;240;336 hours postdose
PK parameters comparison between NNG-DEPO and Aranesp®:Vz/F	Vz/F	IV:Assessed predose and at 0.25; 0.5; 4;12;24;48;96;144;240;336 hours postdose/ SC: Assessed predose and at 4;12;24;48;96;144;240;336 hours postdose
PK parameters comparison between NNG-DEPO and Aranesp®: λz.	λz.	IV:Assessed predose and at 0.25; 0.5; 4;12;24;48;96;144;240;336 hours postdose/ SC: Assessed predose and at 4;12;24;48;96;144;240;336 hours postdose
Proportion of the adverse events (AE) including physical examinations, vital signs, and clinical laboratory investigations.	Rate of AE and SAE occurence	Week 0 (Assessed predose)- Week 24]

Collaborators and Investigators

• Sponsor: Nanogen Pharmaceutical Biotechnology Joint Stock Company
• Collaborators: Vietstar Biomedical Research; Clinical Research Consultants, Inc.; Clinical Research Viet Nam Skill Training And Consultant Company Limited

Study record dates

Study Major Dates

• Study Start (Actual): August 8, 2019
• Primary Completion (Anticipated): November 30, 2022
• Study Completion (Anticipated): December 31, 2022

Study Registration Dates

• First Submitted: October 13, 2022
• First Submitted That Met QC Criteria: November 23, 2022
• First Posted (Actual): December 5, 2022

Study Record Updates

• Last Update Posted (Actual): December 5, 2022
• Last Update Submitted That Met QC Criteria: November 23, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: dialysis; CKD; darbepoetin alfa; Nanogen; treatment of anemia
• Additional Relevant MeSH Terms: Urologic Diseases; Hematologic Diseases; Renal Insufficiency; Kidney Diseases; Renal Insufficiency, Chronic; Anemia
• Other Study ID Numbers: NNG06.1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No