A Phase 1 Relative Bioavailability Study of Ambrisentan and Tadalfil Fixed Dose Combination Tablets in Healthy Subjects

Hypertension, Pulmonary Clinical Trial

Official title:

A Phase 1 Study to Demonstrate the Relative Bioavailability of Fixed Dose Combinations of Ambrisentan and Tadalafil in Healthy Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02688387
• Other study ID #: 201964
• Status: Completed
• Phase: Phase 1
• Start date: March 18, 2016
• Est. completion date: August 4, 2017

Study information

• Verified date: July 2018
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is designed to understand the relative bioavailability (proportion of the administered dose that is absorbed into the bloodstream) of several fixed dose combinations (FDCs) tablets of ambrisentan and tadalafil for further development and to provide pharmacokinetic (PK - what the body does to the drug) data to enable a pivotal bioequivalence (BE - the relationship between two preparations of the same drug in the same dosage form that have a similar bioavailability) study. Depending on formulation work, the study will allow up to 8 new FDCs to be compared with the reference of ambrisentan and tadalafil monotherapies. The study will also evaluate up to 2 of the new formulations, that may be taken in to a BE study, to be tested for any effect on pharmacokinetics of the FDC in both fed and fasted state. This is a single centre, Phase 1, single dose, randomised, open label crossover study with 3 study parts; each study part will have up to a 5 way crossover in healthy subjects. Part 1 of the study will evaluate four formulations of the FDC (ambrisentan 10 milligram [mg] + tadalafil 40 mg) and the reference of the 2 monotherapy components taken concurrently (ambrisentan 10 mg and tadalafil 40 mg) in the fasted stated. If successful formulations are identified in this part of the study, then they will be re-formulated and tested in part 2. If no successful formulations are identified in part 1 of the study, then part 2 will be utilized to look at up to 4 new FDC formulations. However, if only two formulations, or less, are evaluated in part 2 then the FDC formulations may be tested both fed and fasted to assess food effect and part 3 will not be required. If successful formulations are identified in this study part, then up to 2 of these may be tested, for food effect, in Part 3 if not already assessed in this part. Therefore, part 3 is optional and utility is dependent on the results of the previous study parts.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 112
• Est. completion date: August 4, 2017
• Est. primary completion date: August 4, 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

• Between 18 and 60 years of age inclusive, at the time of signing the informed consent.

• Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests, vital signs and cardiac monitoring (ECG and 24 hour Holter). A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the Investigator, in consultation with Medical Monitor if required, judges and documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.

• Body weight >= 50 Kilogram (kg) (110 pounds [lbs]) for men and >= 45 kg (99lbs) for women and body mass index (BMI) within the range 18 - 30 kg per square metre (m^2) (inclusive)

• Male or Female. Female with non-reproductive potential defined as, Pre-menopausal females with one of the following: Documented tubal ligation or Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion or Hysterectomy or Documented Bilateral Oophorectomy, Documented Postmenopausal defined as 12 months of spontaneous amenorrhea

• Capable of giving signed informed consent.

Exclusion Criteria:

• A blood pressure <100/55 millimetre of Mercury (mm Hg).

• Haemoglobin (Hb) below normal range: Hb <133 (gram per litre) g/L for males and Hb <114 g/L for females

• Alanine amino transferase (ALT) and bilirubin >1.5 x upper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin is <35 percentage [%]).

• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)

• Corrected QT (QTc) >450 milliseconds (msec). The QTc is the QT interval corrected for heart rate according to Bazett's formula (QTcB), Fridericia's formula (QTcF), and/or another method, machine-read or manually over-read.

• Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.

• History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 gram (g) of alcohol: a half-pint (~240 millilitre [mL]) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.

• Smoking more than 5 cigarettes per week and subjects must be able to abstain from smoking for a 24 hour period prior to dose and any time whilst in the clinical unit.

• History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator or Medical Monitor, contraindicates their participation.

• Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at Screening or within 3 months prior to first dose of study treatment.

• A positive test for human immuno-deficiency virus (HIV) antibody

• A positive pre-study drug/alcohol screen.

• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within previous 3 months

• The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 3 months, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).

• Exposure to more than four new chemical entities within 12 months prior to the first dosing day.

Related Conditions & MeSH terms

• Hypertension, Pulmonary

Intervention

Drug:
• FDC (ambrisentan 10 mg-tadalafil 40 mg) single dose
The four FDCs in part 1 will have the following formulation designation: FDC1, FDC2, FDC3 and FDC4. They are film-coated tablets. The dose will be administered orally. Study treatment for Part2 and Part 3 will be amended after Part 1 study
• Reference (ambrisentan 10 mg + tadalafil 40 mg given concurrently)
Ambrisentan is a film-coated tablet. Each tablet of ambrisentan contains 10 mg of ambrisentan, approximately 95 mg of lactose (as monohydrate), 0.25 mg of lecithin and 0.11 mg of Allura red AC Aluminium Lake. Tadalafil is also a film-coated tablet. Each tablet of Tadalafil contains 20 mg tadalafil and 233 mg lactose. Both the tablets will be administered orally concurrently.

Locations

Country	Name	City	State
United Kingdom	GSK Investigational Site	London

Sponsors (3)

Lead Sponsor	Collaborator
GlaxoSmithKline	Covance Harrogate, Hammersmith Medicines Research

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Observed Concentration (Cmax) of Ambrisentan and Tadalafil in FDC (Ambrisentan 10 mg + Tadalafil 40 mg) and Montherapies (Ambrisentan 10 mg & Tadalafil 40 mg) - Part 1	Cmax is defined as the maximum (or peak) plasma concentration that the drug achieves, after the drug has been administered. Blood samples were collected at the indicated time points for analysis of ambrisentan and tadafil. The analysis was done under fasting condition post single dose. There is no formal hypotheses tested for Part 1 of the study. The analysis was performed on Pharmacokinetic (PK) parameter population, which included all participants who provided PK parameter data.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Primary	Area Under the Plasma Concentration Time Curve (AUC) From Time Zero to Infinite (Inf) Time, AUC (0-inf) of Ambrisentan and Tadalafil in FDC (Ambrisentan 10 mg + Tadalafil 40 mg) and Montherapies (Ambrisentan 10 mg & Tadalafil 40 mg) - Part 1	AUC (0- inf), is defined as area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity for ambrisentan and tadafil. Blood samples were collected at the indicated time-points. The analysis was done under fasting condition post single dose. There is no formal hypothesis tested for Part 1 of the study.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Primary	AUC From Time of Dose to Last Measurable Concentration (AUC [0-t]), in FDC, (Ambrisentan 10 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 10 mg & Tadalafil 40 mg), Under Fasting- Part 1	AUC (0-t), was defined as, the AUC measured from the time of dose to the last measurable concentration. Blood samples of 2.7 mL and 2 mL, were collected for ambrisentan and tadafil respectively. The plasma samples at Part 1, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours. The analysis was done under fasting condition post single dose. The PK Parameter Population was used for analysis. There is no formal hypotheses tested for Part 1 of the study.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Primary	Cmax of Ambrisentan and Tadalafil in FDC (Ambrisentan 10 mg + Tadalafil 40 mg) and Montherapies (Ambrisentan 10 mg & Tadalafil 40 mg) - Part 2	Cmax is defined as the maximum (or peak) plasma concentration that the drug achieves, after the drug has been administered. Blood samples were collected at the indicated time-points, of Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose. The analysis was done under fasting condition post single dose. There is no formal hypotheses tested for Part 2 of the study. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Primary	AUC (0 - Inf) for FDC, (Ambrisentan 10 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 10 mg & Tadalafil 40 mg), Under Fasting- Part 2	AUC (0- inf), is defined as area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity for ambrisentan and tadafil. Blood samples of 2.7 mL and 2 mL were collected for ambrisentan and tadafil respectively. The plasma samples for Part 2, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours post-dose. The analysis, was done under fasting condition post single dose. PK parameter Populatio was used for analysis. There is no formal hypotheses tested for Part 2 of the study. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Primary	AUC (0-t) for FDC, (Ambrisentan 10 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 10 mg & Tadalafil 40 mg), Under Fasting- Part 2	AUC (0-t), was defined as, the AUC measured from the time of dose to the last measurable concentration. Blood samples of 2.7 mL and 2 mL, were collected for ambrisentan and tadafil respectively. The plasma samples for Part 2, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours. The analysis was done under fasting condition post single dose. PK parameter Population was used for analysis. There is no formal hypotheses tested for Part 2 of the study. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Primary	Cmax for Ambrisentan and Tadalafil, Following Candidate FDC (Ambrisentan 10 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 10 mg & Tadalafil 40 mg), Under Fed and Fasted Conditions-Part 3A	Cmax is defined as the maximum (or peak) plasma concentration that the drug achieves, after the drug has been administered. Blood samples of 2.7 mL and 2 mL were collected for ambrisentan and tadafil respectively. The plasma samples for Part 3A, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours post-dose. The analysis was done under fed and fasting condition post single dose. PK parameter population was used.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Primary	AUC (0-inf) for Ambrisentan and Tadalafil, Following Candidate FDC (Ambrisentan 10 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 10 mg & Tadalafil 40 mg), Under Fed and Fasted Conditions-3A	AUC (0- inf), is defined as area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity for ambrisentan and tadafil. Blood samples of 2.7 mL and 2 mL were collected for ambrisentan and tadafil respectively. The plasma samples for Part 3A, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 48 and 72 hours post-dose. The analysis, was done under fed and fasting conditions post single dose. PK parameter population was used.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Primary	AUC (0-t) for Ambrisentan and Tadalafil, Following Candidate FDC (Ambrisentan 10 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 10 mg & Tadalafil 40 mg), Under Fed and Fasted Conditions-Part 3A	AUC (0-t), was defined as, the AUC measured from the time of dose to the last measurable concentration. Blood samples of 2.7 mL and 2 mL, were collected for ambrisentan and tadafil respectively. The plasma samples for Part 3A, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours post-dose. The analysis was done under fed and fasting condition post single dose. PK parameter population was used.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Primary	Cmax for Ambrisentan and Tadalafil, FDCs (Ambrisentan 5 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 5 mg & Tadalafil 40 mg) Under Fasted Conditions-3B	Cmax is defined as the maximum (or peak) plasma concentration that the drug achieves, after the drug has been administered. Blood samples of 2.7 mL and 2 mL were collected for ambrisentan and tadafil respectively. The plasma samples for Part 3B, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours post-dose. The analysis was done under fasting condition post single dose.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Primary	AUC (0-inf) for Ambrisentan and Tadalafil, FDCs (Ambrisentan 5 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 5 mg & Tadalafil 40 mg) Under Fasted Conditions-3B	AUC (0- inf), is defined as area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity for ambrisentan and tadafil. Blood samples of 2.7 mL and 2 mL were collected for ambrisentan and tadafil respectively. The plasma samples for Part 3B, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36,48 and 72 hours post-dose. The analysis was done under fasting condition post single dose. PK Parameter Population was used for analysis.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Primary	AUC (0-t) for Ambrisentan and Tadalafil, FDCs (Ambrisentan 5 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 5 mg & Tadalafil 40 mg) Under Fasted Conditions-3B	AUC (0-t), was defined as, the AUC measured from the time of dose to the last measurable concentration. Blood samples of 2.7 mL and 2 mL, were collected for ambrisentan and tadafil respectively. The plasma samples for Part 3B, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours post-dose. The analysis was done under fasting condition post single dose. PK parameter population was used for analysis.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Primary	Cmax for Ambrisentan and Tadalafil, FDCs (Ambrisentan 5 mg + Tadalafil 20 mg) Relative to Reference Monotherapies Tested (Ambrisentan 5 mg & Tadalafil 20 mg) Under Fasted Conditions-3B	Cmax is defined as the maximum (or peak) plasma concentration that the drug achieves, after the drug has been administered. Blood samples of 2.7 mL and 2 mL were collected for ambrisentan and tadafil respectively. The plasma samples for Part 3B, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours post-dose. The analysis was done under fasting condition post single dose. PK parameter population was used.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Primary	AUC (0-inf) for Ambrisentan and Tadalafil, FDCs (Ambrisentan 5 mg + Tadalafil 20 mg) Relative to Reference Monotherapies Tested (Ambrisentan 5 mg & Tadalafil 20 mg) Under Fasted Conditions-3B	AUC (0- inf), is defined as area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity for ambrisentan and tadafil. Blood samples of 2.7 mL and 2 mL were collected for ambrisentan and tadafil respectively. The plasma samples for Part 3B, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours post-dose. The analysis, was done under fasting conditions post single dose. PK parameter population was used for analysis.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Primary	AUC (0-t) for Ambrisentan and Tadalafil, FDCs (Ambrisentan 5 mg + Tadalafil 20 mg) Relative to Reference Monotherapies Tested (Ambrisentan 5 mg & Tadalafil 20 mg) Under Fasted Conditions- Part 3B	AUC (0-t), was defined as, the AUC measured from the time of dose to the last measurable concentration. Blood samples of 2.7 mL and 2 mL, were collected for ambrisentan and tadafil respectively. The plasma samples for Part 3B, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours post-dose. The analysis was done under fasting condition post single dose. PK parameter population was used for analysis.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Secondary	Time Taken to Reach Maximum Concentration (Tmax) for Ambrisentan and Tadalafil in FDC and Reference Treatment - Part 1	Serial blood samples were collected at the indicated time-points. In Part 3A, tmax was determined for ambrisentan and tadalafil when administered in FDC (10mg/40mg) under fed state and fasted state and as reference monotherapies (ambrisentan 10 mg and tadalafil 40 mg). PK parameter population was used to measure the tmax.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Secondary	Time Taken to Reach Maximum Concentration (Tmax) for Ambrisentan and Tadalafil in FDC and Reference Treatment - Part 2	Serial blood samples were collected at the indicated time-points. In Part 3A, tmax was determined for ambrisentan and tadalafil when administered in FDC (10mg/40mg) under fed state and fasted state and as reference monotherapies (ambrisentan 10 mg and tadalafil 40 mg). PK parameter population was used to measure the tmax. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Secondary	Time Taken to Reach Maximum Concentration (Tmax) for Ambrisentan and Tadalafil in FDC and Reference Treatment - Part 3A	Serial blood samples were collected at the indicated time-points. In Part 3A, tmax was determined for ambrisentan and tadalafil when administered in FDC (10mg/40mg) under fed state and fasted state and as reference monotherapies (ambrisentan 10 mg and tadalafil 40 mg). PK parameter population was used to measure the tmax.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Secondary	Time Taken to Reach Maximum Concentration (Tmax) for Ambrisentan and Tadalafil in FDC and Reference Treatment - Part 3B	Serial blood samples were collected at the indicated time-points. In Part 3B, tmax was determined for ambrisentan and tadalafil when administered in FDC (10mg/40mg) under fed state and fasted state and as reference monotherapies (ambrisentan 10 mg and tadalafil 40 mg). PK parameter population was used to measure the tmax.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Secondary	Plasma Half Life (t1/2) for Ambrisentan and Tadalafil in FDC and Reference Treatment Under Fed and Fasted Condition- Part1	t1/2 is defined as the time required by the concentration of the drug to reach half of its original value.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Secondary	Plasma t1/2 for Ambrisentan and Tadalafil in FDC and Reference Treatment Under Fed and Fasted Condition- Part 2	t1/2 is defined as the time required by the concentration of the drug to reach half of its original value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Secondary	Plasma t1/2 for Ambrisentan and Tadalafil in FDC and Reference Treatment Under Fed and Fasted Condition- Part 3A	t1/2 is defined as the time required by the concentration of the drug to reach half of its original value. The serial blood samples were assessed at specified timepoints.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Secondary	Plasma t1/2 for Ambrisentan and Tadalafil in FDC and Reference Treatment Under Fed and Fasted Condition- Part 3B	t1/2 is defined as the time required by the concentration of the drug to reach half of its original value. The serial blood samples were assessed at specified timepoints.	Pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48, and 72 hours postdose
Secondary	Change From Baseline in Vital- Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP), Part 1	Vital signs were measured in semi-supine position after 5 minutes rest and were assessed for SBP and DBP. Change from Baseline, was defined as value at post-Baseline visit minus the Baseline value. Baseline, was defined as Day 1. Safety population included all the participants enrolled into the study who received atleast one dose of investigational product.	Baseline and Up to Day 3
Secondary	Change From Baseline in Vital Signs-Heart Rate, Part 1	Vital signs were measured in semi-supine position after 5 minutes rest and were assessed for Heart rate. Change from Baseline, was defined as value at post-Baseline visit minus the Baseline value. Baseline, was defined as Day 1.	Baseline and Up to Day 3
Secondary	Change From Baseline in Vital- Temperature, Part 1	Vital signs were measured in semi-supine position after 5 minutes rest and were assessed for temperature. Change from Baseline, was defined as value at post-Baseline visit minus the Baseline value. Baseline, was defined as Day 1.	Baseline and Up to Day 3
Secondary	Change From Baseline in Vital Signs-Respiratory Rate, Part 1	Vital signs were measured in semi-supine position after 5 minutes rest and were assessed for Respiratory rate. Change from Baseline, was defined as value at post-Baseline visit minus the Baseline value. Baseline, was defined as Day 1.	Baseline and Up to Day 3
Secondary	Change From Baseline in Vital- SBP and DBP, Part 2	Vital signs were measured in semi-supine position after 5 minutes rest and were assessed for SBP and DBP. Change from Baseline, was defined as value at post-Baseline visit minus the Baseline value. Baseline, was defined as Day 1.	Baseline and Up to Day 3
Secondary	Change From Baseline in Vital Signs-Heart Rate, Part 2	Vital signs were measured in semi-supine position after 5 minutes rest and were assessed for Heart rate. Change from Baseline, was defined as value at post-Baseline visit minus the Baseline value. Baseline, was defined as Day 1. Safety population included all the participants enrolled into the study who received atleast one dose of investigational product.	Baseline and Up to Day 3
Secondary	Change From Baseline in Vital- Temperature, Part 2	Vital signs were measured in semi-supine position after 5 minutes rest and were assessed for temperature. Change from Baseline, was defined as value at post-Baseline visit minus the Baseline value. Baseline, was defined as Day 1. Safety population included all the participants enrolled into the study who received atleast one dose of investigational product.	Baseline and Up to Day 3
Secondary	Change From Baseline in Vital Signs-Respiratory Rate, Part 2	Vital signs were measured in semi-supine position after 5 minutes rest and were assessed for Respiratory rate. Change from Baseline, was defined as value at post-Baseline visit minus the Baseline value. Baseline, was defined as Day 1.	Baseline and Up to Day 3
Secondary	Change From Baseline in Vital- SBP and DBP, Part 3A	Vital signs were measured in semi-supine position after 5 minutes rest and were assessed for SBP, DBP. Change from Baseline, was defined as value at post-Baseline visit minus the Baseline value. Baseline, was defined as Day 1.	Baseline and Up to Day 3
Secondary	Change From Baseline in Vital Signs-Heart Rate, Part 3A	Vital signs were measured in semi-supine position after 5 minutes rest and were assessed for Heart rate. Change from Baseline, was defined as value at post-Baseline visit minus the Baseline value. Baseline, was defined as Day 1.	Baseline and Up to Day 3
Secondary	Change From Baseline in Vital- Temperature, Part 3A	Vital signs were measured in semi-supine position after 5 minutes rest and were assessed for temperature. Change from Baseline, was defined as value at post-Baseline visit minus the Baseline value. Baseline, was defined as Day 1.	Baseline and Up to Day 3
Secondary	Change From Baseline in Vital Signs-Respiratory Rate, Part 3A	Vital signs were measured in semi-supine position after 5 minutes rest and were assessed for Respiratory rate. Change from Baseline, was defined as value at post-Baseline visit minus the Baseline value. Baseline, was defined as Day 1.	Baseline and Up to Day 3
Secondary	Change From Baseline in Vital- SBP and DBP, Part 3B	Vital signs were measured in semi-supine position after 5 minutes rest and were assessed for SBP and DBP. Change from Baseline, was defined as value at post-Baseline visit minus the Baseline value. Baseline, was defined as Day 1.	Baseline and Up to Day 3
Secondary	Change From Baseline in Vital Signs-Heart Rate, Part 3B	Vital signs were measured in semi-supine position after 5 minutes rest and were assessed for HR. Change from Baseline, was defined as value at post-Baseline visit minus the Baseline value. Baseline, was defined as Day 1.	Baseline and Up to Day 3
Secondary	Change From Baseline in Vital- Temperature, Part 3B	Vital signs were measured in semi-supine position after 5 minutes rest and were assessed for temperature. Change from Baseline, was defined as value at post-Baseline visit minus the Baseline value. Baseline, was defined as Day 1.	Baseline and Up to Day 3
Secondary	Change From Baseline in Vital Signs-Respiratory Rate, Part 3-B	Vital signs were measured in semi-supine position after 5 minutes rest and were assessed for Respiratory rate. Change from Baseline, was defined as value at post-Baseline visit minus the Baseline value. Baseline, was defined as Day 1.	Baseline and Up to Day 3
Secondary	Number of Participants With Abnormal Electrocardiogram (ECG) Findings, -Part 1	12-lead ECG, was measured in semi-supine position after 5 minutes rest. The data for worst case post-baseline has been reported. Data values for the participants with abnormal clinically significant values are reported. Safety population was used for analysis.	Up to Day 3
Secondary	Number of Participants With Abnormal ECG Findings, -Part 2	12-lead ECG, were measured in semi-supine position after 5 minutes rest. It was conducted as triplicate at screen and baseline, whereas single measure at other times, unless out of range then triplicates were performed. The data for worst case post-baseline has been reported. Data values for the participants with abnormal clinically significant values are reported. Safety population was used for analysis.	Up to Day 3
Secondary	Number of Participants With Abnormal ECG Findings, -Part 3A	12-lead ECG, were measured in semi-supine position after 5 minutes rest. It was conducted as triplicate at screen and baseline, whereas single measure at other times, unless out of range then triplicates were performed. The data for worst case post-baseline has been reported. Data values for the participants with abnormal clinically significant values are reported. Safety population was used for analysis.	Up to Day 3
Secondary	Number of Participants With Abnormal ECG Findings, -Part 3B	12-lead ECG, were measured in semi-supine position after 5 minutes rest. It was conducted as triplicate at screen and baseline, whereas single measure at other times, unless out of range then triplicates were performed. The data for worst case post-baseline has been reported. Data values for the participants with abnormal clinically significant values are reported. Safety population was used for analysis.	Up to Day 3
Secondary	Number of Participants With Hematology Values of Potential Clinical Importance (PCI)- Part1	Blood samples were collected from the participants for analysis of hematology parameters like hematocrit, hemoglobin, lymphocytes, neutrophils, platelets and leukocytes. The data for number of participants, with low and high values of PCI have been reported. Safety population was used for analysis.	Up to Day 3
Secondary	Number of Participants With Hematology Values of PCI - Part 2	Blood samples were collected from the participants for analysis of hematology parameters like hematocrit, hemoglobin, lymphocytes, neutrophils, platelets and leukocytes. The data for number of participants, with low and high values of PCI have been reported. Safety population was used for analysis.	Day 2
Secondary	Number of Participants With Hematology Values of PCI - Part 3A	Blood samples of 2 mL, via a cannula for were collected from the participants for analysis of hematology parameters like hematocrit, hemoglobin, lymphocytes, neutrophils, platelets and leukocytes. It was conducted at Day 2 (48 hours). The data for number of participants, with low and high values of PCI have been reported. Safety population was used for analysis.	Day 2
Secondary	Number of Participants With Hematology Values of PCI - Part 3B	Blood samples of 2 mL, via a cannula for were collected from the participants for analysis of hematology parameters like hematocrit, hemoglobin, lymphocytes, neutrophils, platelets and leukocytes. It was conducted at Day 2 (48 hour). The data for number of participants, with low and high values of PCI have been reported. Safety population was used for analysis.	Day 2
Secondary	Number of Participants With Clinical Chemistry Values of PCI- Part1	Blood samples of 2 mL, via a cannula for were collected from the participants for analysis of clinical chemistry parameters like glucose, calcium, albumin, sodium and potassium. The data for number of participants, with low and high values of PCI have been reported. Safety population was used for analysis.	Day 2
Secondary	Number of Participants With Clinical Chemistry Values of PCI- Part 2	Blood samples of 2 mL, via a cannula for were collected from the participants for analysis of clinical chemistry parameters like glucose, calcium, albumin, sodium and potassium. It was collected at Day 2 (48 hour). The data for number of participants, with low and high values of PCI have been reported. Safety population was used for analysis.	Day 2
Secondary	Number of Participants With Clinical Chemistry Values of PCI- Part 3A	Blood samples of 2 mL, via a cannula for were collected from the participants for analysis of clinical chemistry parameters like glucose, calcium, albumin, sodium and potassium. It was collected at (48 hour). The data for number of participants, with low and high values of PCI have been reported. Safety population was used for analysis.	Day 2
Secondary	Number of Participants With Clinical Chemistry Values of PCI- Part 3B	Blood samples of 2 mL, via a cannula for were collected from the participants for analysis of clinical chemistry parameters like glucose, calcium, albumin, sodium and potassium. It was collected at Day 2 (48 hour). The data for number of participants, with low and high values of PCI have been reported. Safety population was used for analysis.	Day 2
Secondary	Number of Participants With Abnormal Urinalysis Results by Dipstick Method-Part 1	Urine samples were collected at Day -1 (Baseline) and 48 hour, from the participants for urinalysis, by standard dipstick method. The parameters analyzed were ketones, glucose, occult blood, and protein. The number of participants with parameters detected as trace-lysed, trace-intact, trace, 2+ and 1+ was reported. Safety Population was used for analysis.	Up to Day 2
Secondary	Number of Participants With Urinalysis Results by Dipstick Analysis-Part 2	Urine samples were collected at Day -1 (Baseline) and 48 hour, from the participants for urinalysis, by standard dipstick method. The parameters analyzed were ketones, glucose, occult blood, and protein. The number of participants with parameters detected as trace-lysed, trace-intact, trace, 2+ and 1+ was reported. Safety Population was used for analysis	Up to Day 2
Secondary	Number of Participants With Urinalysis Results by Dipstick Analysis-Part 3A	Urine samples were collected at Day -1 (Baseline) and 48 hour, from the participants for urinalysis, by standard dipstick method. The parameters analyzed were ketones, glucose, occult blood, and protein. The number of participants with parameters detected as trace-lysed, trace-intact, trace, 2+ and 1+ was reported. Safety Population was used for analysis.	Up to Day 2
Secondary	Number of Participants With Urinalysis Results by Dipstick Analysis-Part 3B	Urine samples were collected at Day -1 (Baseline) and 48 hour, from the participants for urinalysis, by standard dipstick method. The parameters analyzed were ketones, glucose, occult blood, and protein. The number of participants with parameters detected as trace-lysed, trace-intact, trace, 2+ and 1+ was reported. Safety Population was used for analysis.	Up to Day 2
Secondary	Number of Participants With Serious Adverse Events (SAEs) and Adverse Events (AEs)-Part 1	An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or is associated with liver injury and impaired liver function. Safety population was used for analysis.	Up to 42 days
Secondary	Number of Participants With SAEs and AEs-Part 2	An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or is associated with liver injury and impaired liver function. Safety population was used for analysis.	Up to 35 days
Secondary	Number of Participants With SAEs and AEs-Part 3A	An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or is associated with liver injury and impaired liver function. Safety population was used for analysis.	Up to 44 days
Secondary	Number of Participants With SAEs and AEs-Part 3B	An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or is associated with liver injury and impaired liver function. Safety population was used for analysis.	Up to 44 days