Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12615000358549
Ethics application status
Approved
Date submitted
20/03/2015
Date registered
20/04/2015
Date last updated
17/01/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A double blind single-dose study to evaluate pharmacokinetics, safety and tolerability of Stelis Teriparatide [rh-PTH (1-34)] with innovator product Forsteo Registered Trademark (European Innovator) in healthy volunteers via subcutaneous administration of a single dose of 20 mcg .
Scientific title
A randomized, double blind, 2-treatment, 2-period, single-dose, cross over, comparative study to evaluate pharmacokinetics, safety and tolerability of Stelis Teriparatide [rh-PTH (1-34)] [teriparatide, Stelis Biopharma Pvt. Ltd., India] with ForsteoRegistered Trademark (teriparatide, Eli Lilly Nederland BV, Grootslag 1-5, NL-3991 RA Houten, The Netherlands) in healthy volunteers following subcutaneous administration of a single dose of 20 mcg Teriparatide
Secondary ID [1] 286387 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Osteoporosis 294531 0
Condition category
Condition code
Musculoskeletal 294840 294840 0 0
Osteoporosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Test Product (T): Stelis Teriparatide [rh-PTH (1-34)] [teriparatide, Stelis Biopharma Pvt. Ltd., India]
Reference Product (R): Forsteo Registered Trademark (teriparatide, Eli Lilly Nederland BV, Grootslag 1-5, NL-3991 RA Houten, The Netherlands)
The volunteers will be administered 20 mcg Teriparatide from Test product or reference product through subcutaneous injection on either side of anterior abdominal wall, alternating between opposite sites in the 2 periods by trained nursing staff in accordance with the randomization scheme according to the instructions for medication administration of injection in pre-filled pen.

The Test product Stelis Teriparatide rhPTH(1-34) is formulated as a multi-dose (28 dose) small volume parenteral containing 250 mcg teriparatide (r-DNA origin) as active ingredient, 0.41 mg Glacial Acetic Acid as buffering agent, 0.10 mg Sodium Acetate (Anhydrous) as buffering agent, 45.4 mg Mannitol as tonicity modifier, 3.0 mg Metacresol as preservative, Hydrochloric Acid Solution 10% q.s. and Sodium Hydroxide Solution 10% q.s. for pH adjustment, Water for Injection q.s. 1 mL. The sterile finished product solution is aseptically filled into pre-sterile cartridges. The sealed cartridges are then finally assembled in the pen-injector. Stelis teriparatide biosimilar is thus identical in composition and strength to the innovator reference product FORSTEO (Registered Trademark). Stelis finished product also does not contain any ingredients of animal or human origin.

The Formulation Components, intended dosage and route of administration of Stelis Biosimilar Teriparatide is identical to the innovator reference product FORSTEO.
The comparability criteria for Stelis teriparatide biosimilar is established for the finished product via a quality target product profile (QTPP). The QTPP was based on data collected on the reference medicinal product FORSTEO, including publicly available information and data obtained from extensive characterization of the reference medicinal product. QTPP formed the basis for the development of the biosimilar product and its manufacturing process.

Each of the 2 treatment periods will be separated by a washout period of at least 4 weeks between injections in Period 1 and Period 2
Intervention code [1] 291455 0
Treatment: Drugs
Comparator / control treatment
Forsteo Registered Trademark European teriparatide (rDNA origin) 20 mcg subcutaneous injection will be used as the comparator.
Control group
Active

Outcomes
Primary outcome [1] 294602 0
Primary parameters: AUC 0- inf.

Plasma assay.
Timepoint [1] 294602 0
Samples for estimation of Teriparatide will be drawn pre-dose (within 30 minutes prior to dosing), and post dose at 5, 10, 20, 30, 40, 50 minutes and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10 and 12 hours.
Primary outcome [2] 294709 0
Cmax.

Plasma assay.
Timepoint [2] 294709 0
Samples for estimation of Teriparatide will be drawn pre-dose (within 30 minutes prior to dosing), and post dose at 5, 10, 20, 30, 40, 50 minutes and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10 and 12 hours.
Secondary outcome [1] 313701 0
Secondary parameter: AUC0-t.

Plasma Assay
Timepoint [1] 313701 0
Samples for estimation of Teriparatide will be drawn pre-dose (within 30
minutes prior to dosing), and post dose at 5, 10, 20, 30, 40, 50 minutes
and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10 and 12 hours.
Secondary outcome [2] 313907 0
Secondary parameter: Tmax

Plasma assay.
Timepoint [2] 313907 0
Samples for estimation of Teriparatide will be drawn pre-dose (within 30
minutes prior to dosing), and post dose at 5, 10, 20, 30, 40, 50 minutes
and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10 and 12 hours.
Secondary outcome [3] 313908 0
Secondary parameter: Apparent clearance(CL/F).

Plasma assay
Timepoint [3] 313908 0
Samples for estimation of Teriparatide will be drawn pre-dose (within 30
minutes prior to dosing), and post dose at 5, 10, 20, 30, 40, 50 minutes
and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10 and 12 hours.
Secondary outcome [4] 313909 0
Secondary parameter: Apparent volume of distribution(Vz/F).

Plasma assay.
Timepoint [4] 313909 0
Samples for estimation of Teriparatide will be drawn pre-dose (within 30
minutes prior to dosing), and post dose at 5, 10, 20, 30, 40, 50 minutes
and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10 and 12 hours.
Secondary outcome [5] 313910 0
Secondary parameter: Kel

Plasma Assay
Timepoint [5] 313910 0
Samples for estimation of Teriparatide will be drawn pre-dose (within 30
minutes prior to dosing), and post dose at 5, 10, 20, 30, 40, 50 minutes
and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10 and 12 hours.
Secondary outcome [6] 313911 0
Secondary parameter: T half.

Plasma assay
Timepoint [6] 313911 0
Samples for estimation of Teriparatide will be drawn pre-dose (within 30
minutes prior to dosing), and post dose at 5, 10, 20, 30, 40, 50 minutes
and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10 and 12 hours.
Secondary outcome [7] 314128 0
Secondary parameter: Observed and change from baseline ionized serum calcium concentrations.

Plasma Assay
Timepoint [7] 314128 0
In Period 1, Samples for estimation of ionised serum calcium will be drawn on Day -1 at -24, -23, -22, -20, -18, -16, -14, and -12 hours, to time-matched clock times scheduled for Day 1. On day 1 of both study periods samples for estimation of ionised serum calcium will be drawn pre-dose (within 30 minutes prior to dosing), and post dose at hours 1, 2, 4, 6, 8, 10, 12, 24 (Day 2).
Secondary outcome [8] 314129 0
Endogenous intact PTH(1-84) will be assessed at baseline and at times points 0.5, 1, 2, 6, and 12 hrs after dosing. The intact PTH(1-84) will be done by plasma assay using ELISA methods.
Timepoint [8] 314129 0
Intact PTH (1-84) will be assessed at predose (duplicate),
and post dose at hours 0.5, 1, 2, 6 and 12.
Secondary outcome [9] 314131 0
Secondary parameter: time to Cmin (tmin).

Plasma Assay
Timepoint [9] 314131 0
Intact PTH (1-84) will be assessed at predose (duplicate),
and post dose at hours 0.5, 1, 2, 6 and 12.
Secondary outcome [10] 314132 0
Secondary parameter: Safety Endpoints: Adverse event (AE) and serious adverse event (SAE) incidence.
Timepoint [10] 314132 0
Incidence of Adverse Events (AEs) and serious adverse event (SAE) will be monitored throughout the study. 
Secondary outcome [11] 314133 0
Secondary parameter: Safety Endpoints: Incidence of grade 3-4 AEs
Timepoint [11] 314133 0
Incidence of grade 3-4 AEs will be monitored throughout the study.
Secondary outcome [12] 314134 0
Secondary parameter: Safety Endpoints: Local reaction incidence
Timepoint [12] 314134 0
The tolerability of the IP at local injection site will be assessed at 15 min prior to dosing and at 1, 2, 4, 6, 8, 10 12 and 24 hours after dosing in each period
Secondary outcome [13] 314135 0
Secondary parameter: Safety Endpoints: Incidence of anti-teriparatide antibodies
Timepoint [13] 314135 0
The Incidence of anti-teriparatide antibodies will be assessed at day 1(prior to dosing) and at days 7 (+/- 1), 14 (+/- 1) and 28 days after dosing in each period.

Eligibility
Key inclusion criteria
1. Male or non-pregnant female between the ages of 18-45 years.
2. Body Mass Index of 19 to 30 kg/m2, and a minimum body weight of 50 kg at screening.
3. Female subjects of childbearing potential must practice effective contraception during the study and be willing and able to continue contraception for 30 days after their last dose of study treatment.
4. Must be in general good health as determined by the Investigator based on comprehensive medical history, physical examination findings, vital sign measurements, and clinical laboratory tests, unless considered not clinically significant by the Investigator.
5. Ability to understand the purpose and risks of the study, and provide signed and dated study specific informed consent prior to any study-specific procedures.
6. Able and willing to participate in the study according to the protocol for the full length of expected term of follow-up
Minimum age
18 Years
Maximum age
45 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Known history of or positive test result for human immunodeficiency virus (HIV), hepatitis C virus [test for hepatitis C virus antibody (HCV Ab)] or hepatitis B virus [test for hepatitis B surface antigen (HBsAg)].
2. History of severe allergic reactions to any drug or anaphylactic reactions.
3. Known allergy to Teriparatide or any other components of the product (both Test & Reference products).
4. Subjects with a history of malignant disease, including solid tumors and hematologic malignancies (except basal cell and squamos cell carcinomas of the skin that have been completely excised and are considered cured).
5. Has undergone major surgery within the previous 12 months from screening visit or is planning to undergo a major surgery within 12 weeks of screening visit.
6. Female subjects who are pregnant or have a positive pregnancy test result currently breastfeeding, or planning to become pregnant during the course of the study.
7. Vaccinations within 4 weeks, prior to study medicine administration in period 1.
8. Blood donation (Greater than equal to 500 mL) within 30 days prior to screening.
9. History of any clinically significant cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, or other major disease, as determined by the Investigator.
10. History of alcohol or substance abuse.
11. Positive result for drugs of abuse on admission to the study center including amphetamines, barbiturates, cocaine, methadone, 3, 4 methylenedioxymethamphetamine (ecstasy), phencyclidine, tetrahydrocannabinol, and opiates.
12. Use of any tobacco product more than 5 times within 30 days prior to screening.
13. Positive testing for alcohol at check-in.
14. Alcohol use within 72 hours prior to dosing of period 01. Subjects must be willing to restrict alcohol use throughout their participation in the study.
15. Clinically significant abnormal clinical laboratory test values, as determined by the Investigator, or any values for alanine aminotransferase (ALT), aspartate aminotransferase (AST), or creatinine that are above the upper limit of normal, any values for platelets or hemoglobin that are below the lower limit of normal, or any out of normal range values for white blood cells, serum sodium, or serum potassium or as determined by the Investigator,
16. Clinically significant abnormalities in 12-lead ECG.
17. Any previous treatment with any parathormone/teriparatide product, including investigational use.
18. Prior treatment with any investigational drug within the 30 days prior to Day 1, or within 5 half-lives of the drug, whichever is longer.
19. Treatment with any medication prescribed within 30 days prior to Day 1 or longer if the medication has a long half-life, and over-the-counter (OTC) products including analgesics, herbal remedies, vitamin therapy within 14 days prior to Day 1 or longer if the medication has a long half-life, unless agreed as not clinically significant by the Investigator (vitamins, minerals, and nutrition supplements may be taken at the discretion of the Investigator). Exception: contraceptives.
20. Inability to comply with study requirements.
21. Other unspecified reasons that, in the opinion of the Investigator or sponsor, make the subject unsuitable for enrollment.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
This is a double blinded study. The randomization code will be provided by Pharmacokinetics & Biostatistics Department to the delegated un-blinded site staff. The delegated un-blinded site staff will refer the randomization code to determine the medication to be dispensed for each subject. This will be dispensed into a suitably labeled container.
Persons involved in this study i.e. investigator, physicians/nurses, analytical personnel, subjects will remain blinded at all times. Except for nominated individual(s) responsible for preparing the randomization code/code-break envelopes, the delegated un-blinded study staff who prepare, check and dispense the individual unit doses and drug administrator, will be the only staff who are not blind to the study drug and will not be involved
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
Pharmacokinetic and Pharmacodynamic concentrations and parameters will be presented descriptively using summary statistics and plots. Safety data will be summarized descriptively. All pharmacokinetic parameters, derived using non compartmental methods, and all statistical analyses will be performed using SAS v9.2.
The ln-transformed pharmacokinetic parameters Cmax and AUC0-inf of rh-PTH (1–34) in will be analyzed using an analysis of variance (ANOVA) model and the PROC GLM model statement will include the fixed effects of treatment, period, sequence and subjects nested within sequence. The sequence effect will be tested at the 0.10 level of significance using the subjects nested within sequence mean square from the ANOVA as the error term. All other main effects will be tested at the 0.05 level of significance against the residual error (mean square error/MSE) from the ANOVA as the error term.
Statistical tests of Analysis of variance (ANOVA), least square means for test and reference formulations, difference between test and reference formulations will be calculated for ln-transformed Cmax, and AUC0-inf Geometric least square means of test and reference formulations, its ratio, 90% confidence interval for geometric least square mean ratio will be calculated for Cmax, and AUC0-inf.
As this is a pilot study 24 subjects considered as this data will provide sufficient pharmacokinetic and safety data to plan the pivotal study. Sufficient healthy volunteers (at least 30 healthy volunteers) will be enrolled in the study to allow for at least 24 evaluable subjects who completes both the periods. Each volunteer will serve as his/her control and receive the test formulation in 1 of the study periods and the reference formulation in the other study period in a randomized fashion. No statistical calculations has been done to determine the number of subjects.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
5/06/2015
Actual
16/10/2015
Date of last participant enrolment
Anticipated
4/12/2015
Actual
19/11/2015
Date of last data collection
Anticipated
Actual
14/01/2016
Sample size
Target
24
Accrual to date
Final
30
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 290959 0
Commercial sector/Industry
Name [1] 290959 0
Stelis Biopharma Pvt. Ltd.
Country [1] 290959 0
India
Primary sponsor type
Commercial sector/Industry
Name
Stelis Biopharma Pvt. Ltd.
Address
Plot no. 293, Bommasandra-Jigani Link Road,
Jigani Industrial Area, Anekal Taluk,
Bangalore - 560105, Karnataka,
India.
Country
India
Secondary sponsor category [1] 289641 0
None
Name [1] 289641 0
None
Address [1] 289641 0
None
Country [1] 289641 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292557 0
The Alfred Health Human Ethics Commitee
Ethics committee address [1] 292557 0
Ethics committee country [1] 292557 0
Australia
Date submitted for ethics approval [1] 292557 0
23/03/2015
Approval date [1] 292557 0
24/09/2015
Ethics approval number [1] 292557 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 622 622 0 0
/AnzctrAttachments/368215-152-15 Certificate of Approval_Amend Sep15.pdf

Contacts
Principal investigator
Name 55918 0
Dr Jason Lickliter
Address 55918 0
Jason Lickliter MBBS PhD FRACP
Nucleus Network Limited
Level 5 Burnet Institute
AMREP Precinct
89 Commercial Road
Victoria 3004 Australia
Country 55918 0
Australia
Phone 55918 0
+ 613 9076 8960
Fax 55918 0
Email 55918 0
[email protected]
Contact person for public queries
Name 55919 0
Mohanlal Sayana
Address 55919 0
Stelis Biopharma Pvt. Ltd.
Plot no. 293, Bommasandra Jigani Link
Road Jigani Industrial Area, Anekal
Taluk Bangalore- 560 105 ,INDIA
Country 55919 0
India
Phone 55919 0
+91 80 67840 444
Fax 55919 0
Email 55919 0
[email protected]
Contact person for scientific queries
Name 55920 0
Mohanlal Sayana
Address 55920 0
Stelis Biopharma Pvt. Ltd.
Plot no. 293, Bommasandra Jigani Link
Road Jigani Industrial Area, Anekal
Taluk Bangalore- 560 105 ,INDIA
Country 55920 0
India
Phone 55920 0
+91 80 67840 444
Fax 55920 0
Email 55920 0
[email protected]

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