A Phase 1 interventional study of Epoetin Alfa 40000 UNT/ML in Anemia, sponsored by Bio Sidus SA. Completed. Open to participants aged 21 Years to 55 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2020-02-12.
Sponsored by Bio Sidus SA · Phase 1, Interventional, and Other
Pharmacokinetic/Pharmacodynamic Study of 3 Epoetin Alfa Formulations in Single Subcutaneous Doses Administered to Healthy Volunteers
SPONSOR Biosidus S.A.
TITLE
Pharmacokinetic/ Pharmacodynamic Study of 3 Epoetin Alfa Formulations in Single Subcutaneous Doses Administered to Healthy Volunteers
SPONSOR
Biosidus S.A.
PRINCIPAL INVESTIGATOR
Guillermo Di Girolamo, M.D., National License No. 56857, domiciled at Congreso 3137 (Calle 75), San Andrés (1651), Telephone/Fax: 4753 - 8211, e - mail: gdigirolamo@arnet.com.ar
CO-INVESTIGATORS
Guillermo Alberto Keller, M.D., National License No.106.860, domiciled at Murgiondo 376, CABA. Cell Phone: 1563615376 - e-mail: drguillermokeller@yahoo.com.ar
Paola Czerniuk, M.D., National License No. 84280, domiciled at Paraguay 3559, Piso 6, Dto A, CABA. Cell Phone 1550189563, e - mail: pczerniuk@intramed.net.ar SITE Centro de Medicina Integral S.R.L. - Address: Avenida Belgrano 1844, CABA (C1094) - Telephone: (011) 4383 - 5145
LABORATORY
Laboratorio de Calidad de Biosidus SA - Constitución 4234 (C1254ABX) Buenos Aires, Argentina - Tel. 4909 8000 - Fax 4909 8055
OBJECTIVES
Primary: To compare the pharmacokinetic and pharmacodynamic behavior of three formulations of epoetin alfa after subcutaneous administration of 40,000 UI:
Secondary: To assess the pharmacological action, through quantification of blood reticulocytes at different time points as a surrogate pharmacodynamic marker. Assessment of adverse effects and tolerance.
TRIAL DESIGN
Open, randomized, 3 - arm, cross - over, sequential, and balanced
DISCONTINUATION SCHEME
The sponsor and the investigators can independently discontinue the study at any time if there is a mere possibility of or in case of occurrence of a serious adverse effect or situation that might affect the volunteer's health. If the Hb exceeds 18 g/ dl confirmed by repetition of the analysis at the pre - dose control in each phase, the volunteer will be excluded and 1 unit of blood will be collected. If, after the procedure, it is still above 18 g/ dl, another 0.5 or 1 Unit of blood will be collected, based on medical judgment.
NUMBER OF VOLUNTEERS
24 (twenty - four) at first. Since it is a sequential design, if the statistical analysis of the first 24 volunteers does not show biosimilarity, 12 additional volunteers will be included up to a total of 36 (thirty - six) volunteers.
DURATION OF THE STUDY
3 months
Selection and recruitment period: 2 (two) months
TIME THE STUDY WILL TAKE
Visit I: Selecting volunteers, obtaining informed consents, performing baseline tests.
Visits II, III, and IV: They will consist of 3 hospitalization phases -one for subcutaneous administration of Test Formulation Number 1 (T1), another for subcutaneous administration of Test Formulation Number 2 (T2), and a third one for subcutaneous administration of Reference Formulation (R), with a washout period of no fewer than 28 days between phases.
Sampling times for erythropoietin quantification in each phase, carried out by Biosidus SA, will be: pre - dose and 1, 2, 4, 6, 7, 8, 9, 10, 11, 12, 15, 24, 48, 72, 96, and 120 hours post - dose.
Telephone contact: The Principal Investigator or the healthcare staff assigned by the Principal Investigator will contact the volunteer by phone after the volunteer's discharge until the last (120 - hour) outpatient collection in order to ask about tolerance to the medication and presence of adverse effects.
Blood samples will be collected for red blood cell, Hb, and reticulocyte counting using flow cytometry performed by Biosidus SA, as an erythropoietin surrogate pharmacodynamic marker at the following time points: pre - dose (0 hours), 24, 48, 72, 96, 120, and 240 hours.
Another blood sample will be collected for red blood cell and Hb count after 504 hours (21 days after the dose), 7 days before starting the next treatment cycle, in order to determine whether the volunteer complies with one of the inclusion criteria for the next phase, i.e. not exceeding 18 g/ dl of Hg.
DOSE / ROUTE / REGIME / OF THE INVESTIGATION PRODUCTS
Single 40,000 UI dose of epoetin alfa. The following formulations will be assessed after administering 1 subcutaneous injection on the arm:
There will be 6 randomly assigned sequences:
COMPARISON DRUG
Erypo ® 40,000 UI, liquid without albumin, prefilled syringe, produced by Janssen - Cilag GmbH (Reference Formulation, "R")
COMPARATIVE PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENT BETWEEN THE FORMULATIONS
Based on the erythropoietin serum concentration results, at the different sampling times, the following variables will be calculated:
The difference between Tmax times in each test formulations and the reference formulation will be assessed, and the elimination rate constant and half - life of the drug in the body will be calculated.
The average results for each formulation will be presented, as well as each volunteer's individual results.
STATISTICAL ANALYSIS
CALCULATION OF THE SAMPLE SIZE:
The size of the sample (n:24) was established based on literature data and information from absolute and relative bioavailability studies performed with the drug before by Biosidus SA. Since it is a sequential design, if the statistical analysis of the first 24 volunteers does not show biosimilarity, 12 additional volunteers will be included up to a total of 36 (thirty - six) volunteers.
ANALYSIS PLAN
COMPARATIVE PHARMACOKINETIC ANALYSIS BETWEEN FORMULATIONS
COMPARATIVE PHARMACODYNAMIC ANALYSIS BETWEEN THE FORMULATIONS
Using ANOVA, the possible differences between subjects, treatments, and periods will be analyzed.
Outliers: In order to determine possible outliers, a selective - statistical method will be applied.
1,810 studies on the registry are indexed under Anemia; 215 are open to participants now.
This study's enrollment of 24 is below the median of 117 across 1,336 interventional studies indexed under Anemia.
Browse Anemia studies →Bio Sidus SA is the lead sponsor of 6 studies on the registry; none are open to participants now.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
EXCLUSION CRITERIA:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
A recording of the heart’s electrical activity, taken with stickers on the chest, arms and legs. It takes a few minutes and does not hurt.
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
A condition in which the immune system attacks the body’s own tissues, such as rheumatoid arthritis, lupus, psoriasis, type 1 diabetes or inflammatory bowel disease.
Immunotherapy studies often leave out active autoimmune disease, and some name exceptions, such as thyroid disease on replacement hormone. Check the exceptions this study lists.
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Hepatitis B is a virus that infects the liver. These are separate tests: HBsAg positive usually means a current infection (a recent vaccination can briefly cause it too); total anti-HBc (HBcAb) positive means an infection now or in the past; HBV DNA measures how much virus is in the blood.
Some studies accept a past infection if HBV DNA is undetectable, sometimes with antiviral medicine during the study. Check what this study allows.
Hepatitis C is a virus that infects the liver. An HCV antibody test can stay positive after an infection has cleared (and is occasionally positive without one); an HCV RNA test shows whether the virus is there now.
After treatment, hepatitis C counts as cured when HCV RNA is still undetectable 12 weeks or more after the treatment ended. Studies often accept people cured this way.
Hemoglobin (Hb)
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
BMI (body mass index)
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ECG (electrocardiogram)
A recording of the heart’s electrical activity, taken with stickers on the chest, arms and legs. It takes a few minutes and does not hurt.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Childbearing potential
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Clinically significant
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Autoimmune disease
A condition in which the immune system attacks the body’s own tissues, such as rheumatoid arthritis, lupus, psoriasis, type 1 diabetes or inflammatory bowel disease.
Immunotherapy studies often leave out active autoimmune disease, and some name exceptions, such as thyroid disease on replacement hormone. Check the exceptions this study lists.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HIV
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hepatitis B tests
Hepatitis B is a virus that infects the liver. These are separate tests: HBsAg positive usually means a current infection (a recent vaccination can briefly cause it too); total anti-HBc (HBcAb) positive means an infection now or in the past; HBV DNA measures how much virus is in the blood.
Some studies accept a past infection if HBV DNA is undetectable, sometimes with antiviral medicine during the study. Check what this study allows.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hepatitis C tests
Hepatitis C is a virus that infects the liver. An HCV antibody test can stay positive after an infection has cleared (and is occasionally positive without one); an HCV RNA test shows whether the virus is there now.
After treatment, hepatitis C counts as cured when HCV RNA is still undetectable 12 weeks or more after the treatment ended. Studies often accept people cured this way.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Epoetin Alfa 40000 UNT/ML subcutaneous single dose
Drug: Epoetin Alfa 40000 UNT/ML
Epoetin Alfa 40000 UNT/ML subcutaneous single dose
Drug: Epoetin Alfa 40000 UNT/ML
Epoetin Alfa 40000 UNT/ML subcutaneous single dose
Drug: Epoetin Alfa 40000 UNT/ML
Drug page: Epoetin Alfa
40.000 UI subcutaneous single dose
Also known as: Hemax, Hemax PFS, Erypo
AUC0-t
AUC0-t: Area under the serum concentration curve from time 0 to time t (in this case, 120 hours).
Time frame: 120 h
AUC0-∞
AUC0-∞: Area under the serum concentration curve resulting from extrapolation from time 0 to time ∞.
Time frame: 120hr
Cmax
Cmax: maximum serum concentration of epoetin alfa.
Time frame: 120hr
Tmax
Tmax: time to the maximum serum concentration of epoetin alfa
Time frame: 120hr
Reticulocyte Response: Cmax
Reticulocyte count by flow cytometry, as a surrogate marker of the pharmacodynamics of erythropoietin. Maximum reticulocyte concentration achieved.
Time frame: 120hr
Reticulocyte Response: AUC 0-120h
Time frame: 120hr
ADAs
Number of patients with antidrug antibodies after 3 months. Anti-erythropoietin antibodies screening was done using immunoprecipitation on the sample collected prior to the first dose of the first phase of the trial and on the 504-hour sample of the third phase
Time frame: 120hr
Adverse Events
Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0
Time frame: 120hr
| Milestone | Hemax PFS - Hemax - Eprex | Hemax PFS - Eprex - Hemax | Hemax - Hemax PFS - Eprex | Hemax - Eprex - Hemax PFS | Eprex - Hemax PFS - Hemax | Eprex - Hemax - Hemax PFS |
|---|---|---|---|---|---|---|
| Started | 4 | 4 | 4 | 4 | 4 | 4 |
| Completed | 4 | 4 | 4 | 4 | 3 | 4 |
| Not completed | 0 | 0 | 0 | 0 | 1 | 0 |
| Withdrew: Withdrawal by subject | 0 | 0 | 0 | 0 | 1 | 0 |
AUC0-t: Area under the serum concentration curve from time 0 to time t (in this case, 120 hours).
| mUI*h/mL | Hemax® PFS 40,000 UI | Hemax® 40,000 UI | Erypo ® 40,000 UI |
|---|---|---|---|
| AUC0-t | 37440.71 ± 16821.67 | 34483.73 ± 13513.69 | 41150.49 ± 17095.44 |
AUC0-∞: Area under the serum concentration curve resulting from extrapolation from time 0 to time ∞.
| mUI*h/mL | Hemax® PFS 40,000 UI | Hemax® 40,000 UI | Erypo ® 40,000 UI |
|---|---|---|---|
| AUC0-∞ | 42487.04 ± 19533.78 | 36907.41 ± 14363.66 | 43978.39 ± 18786.74 |
Cmax: maximum serum concentration of epoetin alfa.
| mUI / ml | Hemax® PFS 40,000 UI | Hemax® 40,000 UI | Erypo ® 40,000 UI |
|---|---|---|---|
| Cmax | 853.11 ± 386.49 | 808.29 ± 338.10 | 913.07 ± 429.19 |
Tmax: time to the maximum serum concentration of epoetin alfa
| h | Hemax® PFS 40,000 UI | Hemax® 40,000 UI | Erypo ® 40,000 UI |
|---|---|---|---|
| Tmax | 14.17 ± 5.53 | 15.04 ± 5.13 | 14.96 ± 5.16 |
Reticulocyte count by flow cytometry, as a surrogate marker of the pharmacodynamics of erythropoietin. Maximum reticulocyte concentration achieved.
| mUI / ml | Hemax® PFS 40,000 UI | Hemax® 40,000 UI | Erypo ® 40,000 UI |
|---|---|---|---|
| Reticulocyte Response: Cmax | 1.23 ± 0.46 | 1.33 ± 0.49 | 1.31 ± 0.48 |
| mUI*h/mL | Hemax® PFS 40,000 UI | Hemax® 40,000 UI | Erypo ® 40,000 UI |
|---|---|---|---|
| Reticulocyte Response: AUC 0-120h | 341.65 ± 162.98 | 344.49 ± 132.89 | 345.58 ± 150.13 |
Number of patients with antidrug antibodies after 3 months. Anti-erythropoietin antibodies screening was done using immunoprecipitation on the sample collected prior to the first dose of the first phase of the trial and on the 504-hour sample of the third phase
| Participants | Hemax® PFS 40,000 UI | Hemax® 40,000 UI | Erypo ® 40,000 UI |
|---|---|---|---|
| Anti-erythropoietin antibodies | 0 | 0 | 0 |
| No anti-erythropoietin antibodies detected | 24 | 24 | 24 |
Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0
| Participants | Hemax® PFS 40,000 UI | Hemax® 40,000 UI | Erypo ® 40,000 UI |
|---|---|---|---|
| Asthenia | 3 | 3 | 5 |
| Myalgia | 3 | 0 | 2 |
| Pruritus of trunk | 0 | 1 | 0 |
| Generalized myalgia | 0 | 1 | 1 |
| Arthralgia | 0 | 0 | 2 |
| Dorsal myalgia | 0 | 0 | 1 |
| Fracture | 1 | 0 | 1 |
| Headache | 2 | 0 | 0 |
| Pyrosis | 1 | 0 | 0 |
| Vomiting | 1 | 1 | 1 |
| Diarrhea | 0 | 0 | 1 |
| Nausea | 0 | 1 | 0 |
| No adverse events registered | 13 | 17 | 10 |
Collected over The security profile was determined in all 3 periods of drug administration. All the volunteers were planned to received 3 doses of rhEPO. The duration of all clinical phase was 75 days. so, safety information was collected during 75 days.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Hemax® PFS 40,000 UI | 0/24 (0%) | 1/24 (4.2%) | 11/24 (45.8%) |
| Hemax® 40,000 UI | 0/24 (0%) | 0/24 (0%) | 7/24 (29.2%) |
| Erypo ® 40,000 UI | 0/24 (0%) | 0/24 (0%) | 14/24 (58.3%) |
| Event | Hemax® PFS 40,000 UI | Hemax® 40,000 UI | Erypo ® 40,000 UI |
|---|---|---|---|
| Severe low back painMusculoskeletal and connective tissue disorders | 1/24 | 0/24 | 0/24 |
| Event | Hemax® PFS 40,000 UI | Hemax® 40,000 UI | Erypo ® 40,000 UI |
|---|---|---|---|
| AstheniaGeneral disorders | 3/24 | 3/24 | 5/24 |
| MyalgiaMusculoskeletal and connective tissue disorders | 3/24 | 0/24 | 2/24 |
| ArthralgiaMusculoskeletal and connective tissue disorders | 0/24 | 0/24 | 2/24 |
| HeadacheGeneral disorders | 2/24 | 0/24 | 0/24 |
| Pruritus of trunkSkin and subcutaneous tissue disorders | 0/24 | 1/24 | 0/24 |
| Generalized myalgiaMusculoskeletal and connective tissue disorders | 0/24 | 1/24 | 1/24 |
| Dorsal myalgiaMusculoskeletal and connective tissue disorders | 0/24 | 0/24 | 1/24 |
| FractureMusculoskeletal and connective tissue disorders | 1/24 | 0/24 | 1/24 |
| PyrosisGastrointestinal disorders | 1/24 | 0/24 | 0/24 |
| VomitingGastrointestinal disorders | 1/24 | 1/24 | 1/24 |
| Age, Continuous(years) | Hemax PFS - Hemax - Eprex | Hemax PFS - Eprex - Hemax | Hemax - Hemax PFS - Eprex | Hemax - Eprex - Hemax PFS | Eprex - Hemax PFS - Hemax | Eprex - Hemax - Hemax PFS | Total |
|---|---|---|---|---|---|---|---|
| Mean | 40.25 ± 12.71 | 44.25 ± 0.96 | 41.50 ± 13.77 | 37.50 ± 8.96 | 32.25 ± 12.69 | 41.50 ± 10.66 | 39.54 ± 10.37 |
| Sex: Female, Male(Participants) | Hemax PFS - Hemax - Eprex | Hemax PFS - Eprex - Hemax | Hemax - Hemax PFS - Eprex | Hemax - Eprex - Hemax PFS | Eprex - Hemax PFS - Hemax | Eprex - Hemax - Hemax PFS | Total |
|---|---|---|---|---|---|---|---|
| Female | 1 | 2 | 1 | 2 | 1 | 2 | 9 |
| Male | 3 | 2 | 3 | 2 | 3 | 2 | 15 |
| Weight(kg) | Hemax PFS - Hemax - Eprex | Hemax PFS - Eprex - Hemax | Hemax - Hemax PFS - Eprex | Hemax - Eprex - Hemax PFS | Eprex - Hemax PFS - Hemax | Eprex - Hemax - Hemax PFS | Total |
|---|---|---|---|---|---|---|---|
| Mean | 76.00 ± 14.02 | 72.00 ± 8.68 | 74.00 ± 6.32 | 74.25 ± 8.73 | 69.25 ± 11.93 | 72.00 ± 10.20 | 72.92 ± 9.36 |
| Height(cm) | Hemax PFS - Hemax - Eprex | Hemax PFS - Eprex - Hemax | Hemax - Hemax PFS - Eprex | Hemax - Eprex - Hemax PFS | Eprex - Hemax PFS - Hemax | Eprex - Hemax - Hemax PFS | Total |
|---|---|---|---|---|---|---|---|
| Mean | 177.50 ± 15.20 | 127.25 ± 4.79 | 173.25 ± 3.95 | 171.00 ± 13.74 | 171.00 ± 6.83 | 170.50 ± 8.54 | 172.58 ± 9.02 |
| Body Mass Index(kg/m^2) | Hemax PFS - Hemax - Eprex | Hemax PFS - Eprex - Hemax | Hemax - Hemax PFS - Eprex | Hemax - Eprex - Hemax PFS | Eprex - Hemax PFS - Hemax | Eprex - Hemax - Hemax PFS | Total |
|---|---|---|---|---|---|---|---|
| Mean | 24.01 ± 2.03 | 24.21 ± 1.63 | 24.67 ± 2.21 | 25.44 ± 1.33 | 23.39 ± 2.29 | 24.64 ± 1.33 | 24.39 ± 1.76 |
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Studies of the drug tested here: Epoetin Alfa
Bio Sidus SA