Study to Compare PK & Safety of Advixa With Humira in Healthy, Adult Subject Followed by Efficacy & Safety Study in RA Patients (ACT)

This study will have two parts, Part A and Part B. Part A will be conducted in apparently healthy, adult human subjects to evaluate the safety between test and reference products and to assess the Pharmacokinetic (PK) parameters. After the Part A completed the result will be reviewed by DSMB. Then only after successful DSMB favorable opinion the Part B of the study will start. Part B will be conducted in patients with moderate to severe rheumatoid arthritis (RA) to assess efficacy, tolerability and safety between test and reference products.

Descriptions for Part A and Part B of the study are as follows-

PART A

A Prospective, Randomized, Double blind, Parallel-group, Active controlled, Pk and safety study in Healthy, Adult, Human Subject by single subcutaneous injection. The sample size is 40. Single subcutaneous injection of 40 mg/ 0.4 ml dose of test or reference product will be administered as per the randomization schedule. In patient facility will be at least 12 hours prior to drug administration until 48 hrs post dose. The duration of the study will be 3 months. Housing 2 days, active / solicited safety follow-up for Adverse Events (either home visit or telephone call) will be performed from day 3 to day 8 and passive / un-solicited safety follow-up (spontaneous AE reporting by subject) will be performed for day 9 to day 64. Clinic visit at day 64 and day 90 for Safety evaluation.

Subjects will be screened for the inclusion/exclusion criteria based on: Demographic data, BMI, clinical history, physical examination (including vital signs), Haemogram, Random blood sugar, Serum bilirubin Total/Direct/Indirect, BUN, Serum urea, ALT (SGPT) blood, AST (SGOT) blood, Alkaline phosphatase serum, Serum creatinine, ECG, BNP, Chest X-ray (P/A view) (if required based on any significant past medical history and/or positive finding in respiratory system examination), Quantiferon TB gold plus, serology (HIV, hepatitis B and hepatitis C), Urinalysis, Amphetamines urine, Benzodiazepines urine, COVID-19 qRT-PCR. Breath alcohol test will be done during the screening.

For female volunteers: In addition to the above tests, urine pregnancy test will be done at the time of screening.

Any other test(s) if required will be done as per the suggestion given by the principal investigator or co-investigator.

Blood samples will be collected for serum drug concentration measurements at Time points: Pre-dose (-15 min) and post-dose 04, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 360, 528, 696, 864, 1032, 1200, 1536 hours.

Blood samples for biochemistry and hematology tests: Screening, day 64 and day 90 post dose.13 Ambulatory blood samples will be collected at 72, 96, 120, 144, 168, 192, 360, 528, 696, 864, 1032, 1200 and 1536 hours post-dose will be collected through fresh vein puncture.

ANOVA will be performed on log transformed Cmax, AUC0-t and AUC0-inf by using SAS or other statistical software.

The following standards for bioequivalence will be applied: The 90% confidence interval of the relative mean Cmax, AUC0-t and AUC0-inf of the test and reference product of Adalimumab should be between 80% and 125% for log-transformed data.

Bearing in mind the complexity of performing a PK profile in subjects in phase I, it is not realistic to establish pre-defined rules for bioequivalence on the basis of the limited blood sampling opportunities and number of subjects in each treatment group.

Pharmacokinetic (PK) Parameters: For Cmax and AUC0-t the 90% confidence interval for the ratio of the test and reference products should be contained within the acceptance interval of 80.00-125.00%.

• Safety assessment: Evaluation and comparison between references vs. test drug in terms of safety end point.

Post study assessment will be done. Physical examination including vital examination, well being assessment, biochemistry and hematology will be done at 64 days and 90 days post dose or on discontinuation of subject from the study.

Part B Part B will be conducted to assess efficacy, tolerability and safety of biosimilar adalimumab (Advixa, Incepta) in compared with reference adalimumab (Humira, AbbVie) in patients with moderate to severe rheumatoid arthritis (RA). Total 160 adult human subjects with moderate to severe active rheumatoid arthritis will be enrolled. 40 mg of either test adalimumab (Advixa) or reference adalimumab (Humira) by subcutaneous route in every two weeks.

The duration of the study will be 12 weeks. A total of eight visits (8) will be scheduled during this study including: screening visit (Visit 0); following screening enrolment Visit 1 (Day 1); Visit 2, Day 15 ± 1; Visit 3, Day 28 ± 3; Visit 4, Day 42 ± 3; Visit 5, Day 56 ± 3; Visit 6, Day 70 ± 3 and Visit 7, Day 84 ± 3.

After each dosage administration, Active/solicited safety follow-up for Adverse Events (either home visit or telephone call 2 times) will be performed for 2 days and passive/un-solicited safety follow-up (spontaneous AE reporting by subject) will be performed for remaining 11 days. This will be repeated after each dosage up to completion of study.

Subjects will be screened for the inclusion/exclusion criteria based on: Demographic data, BMI, clinical history, physical examination (including vital signs), Quantiferon TB gold plus, BNP, ECG, CBC, Chest X-ray (P/A view) (if required based on any significant past medical history and/or positive finding in respiratory system examination), CRP (C- reactive protein), Random blood sugar, Serum bilirubin Total/Direct/Indirect, BUN, Serum urea, ALT (SGPT) blood, AST (SGOT) blood, Alkaline phosphatase serum, Serum creatinine, Serology (hepatitis B, hepatitis C), Urinalysis will be done during the screening.

For female volunteers: In addition to the above tests, urine pregnancy test will be done at the time of screening.

Any other test(s) if required will be done as per the suggestion given by the principal investigator or co-investigator. Blood sample will be collected- For Screening: Before enrollment. For CRP and ESR tests: Day 1, 28, 56 and day 84. For CBC, SGPT, S. Creatinine: Day 28, 56 and day 84 For study completion: Day 84 post dose. Physical examination including vital examination, well-being assessment, Bio-chemistry and hematology tests will be done at day 84 post dose or on discontinuation of subject from the study. For safety evaluation, physical examination and vital examination (Blood pressure, pulse rate, oral temperature and respiratory rate) and Well-being assessment will be done at Screening, day 01, 15 ± 1, 28 ± 3, 42 ± 3, 56 ± 3, 70 ± 3 and day 84 ± 3 post-dose of scheduled time. Bio-chemistry and hematology tests will be reviewed to assess safety of the test drug.