Phase 1
Completed N=154
Bioequivalence Study of Fixed Dose Versus Single Entities of Dolutegravir and Lamivudine
Infection, Human Immunodeficiency Virus
Source: ClinicalTrials.gov NCT03078556 ↗
Enrolled (actual)
154
Serious AEs
0.0%
Results posted
Feb 2019
Primary outcomePrimary: Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity [AUC (0-Inf)] of Plasma DTG and 3TC in the Fasted State: Part 1 — 43.1456; 54.8793; 12.3337; 12.7603 Hour*micrograms per milliliter
Summary
This study aims to compare the bioequivalence of two experimental fixed dose combination (FDC) tablets versus single entity products of dolutegravir (DTG) and lamivudine (3TC) in healthy adult subjects. The study will be carried out in two parts. Part 1 of the study will be open label, up to 3 periods design with a wash out period of at least 7 days between treatment periods. Subjects will be randomized to receive either single entities or formulation 1 FDC of DTG and 3TC in a crossover manner in first 2 periods. The first 16 subjects who complete the first two treatment periods and consent to continue will receive a single dose of FDC formulation 1 tablet administered with a high fat meal for a third treatment period. In Part 2 of the study, subjects will be randomized to receive either single entities or formulation 2 FDC of DTG and 3TC in a crossover manner in first 2 periods. Similarly the first 16 subjects will then receive FDC formulation 2 tablets with high fat meal in treatment period 3. Subjects will have a follow-up visit within 7-14 days after the last dose of study drug. Approximately 76 healthy subjects will be included in Part 1 of the study and if Part 2 of the study is conducted, another 76 healthy subjects will be included. The total duration will be approximately 11 weeks.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity [AUC (0-Inf)] of Plasma DTG and 3TC in the Fasted State: Part 1 |
43.1456; 54.8793; 12.3337; 12.7603 | — |
| PRIMARY AUC (0-Inf) of Plasma DTG and 3TC in the Fasted State: Part 2 |
47.2391; 54.5594; 12.7713; 13.5624 | — |
| PRIMARY Area Under the Concentration-time Curve From Time 0 to the Last Quantifiable Time Point (AUC[0-t]) of Plasma DTG and 3TC in the Fasted State: Part 1 |
41.4207; 52.8754; 12.1571; 12.6147 | — |
| PRIMARY AUC(0-t) of Plasma DTG and 3TC in the Fasted State: Part 2 |
45.2043; 52.3372; 12.4790; 13.3552 | — |
| PRIMARY Maximum Observed Concentration (Cmax) of Plasma DTG and 3TC in the Fasted State: Part 1 |
2.4065; 3.0817; 2.6650; 3.1885 | — |
| PRIMARY Cmax of Plasma DTG and 3TC in the Fasted State: Part 2 |
2.5531; 2.9132; 2.4428; 3.2185 | — |
| SECONDARY Absorption Lag Time (Tlag) of DTG and 3TC in Fasted State: Part 1 |
0.0000; 0.0000; 0.0000; 0.0000 | — |
| SECONDARY Tlag of DTG and 3TC in Fasted State: Part 2 |
0.0000; 0.0000; 0.0000; 0.0000 | — |
| SECONDARY Time to Reach Maximum Plasma Concentration (Tmax) of DTG and 3TC in the Fasted State: Part 1 |
2.0072; 2.0017; 1.0047; 1.0008 | — |
| SECONDARY Tmax of DTG and 3TC in the Fasted State: Part 2 |
2.5008; 2.5004; 1.0063; 1.0011 | — |
| SECONDARY Time of the Last Quantifiable Concentration (Tlast) of DTG and 3TC in the Fasted State: Part 1 |
72.0031; 71.9303; 71.9289; 71.9303 | — |
| SECONDARY Tlast of DTG and 3TC in the Fasted State: Part 2 |
71.6813; 71.8243; 71.7138; 71.8153 | — |
| SECONDARY Time to Reach Half the Maximum Plasma Concentration (t1/2) of DTG and 3TC in the Fasted State: Part 1 |
14.6917; 14.7557; 17.0395; 17.3436 | — |
| SECONDARY t1/2 of DTG and 3TC in the Fasted State: Part 2 |
15.1538; 14.7893; 17.8421; 18.1071 | — |
| SECONDARY Apparent Elimination Rate Constant (Lambda z) of DTG and 3TC in the Fasted State: Part 1 |
0.0472; 0.0470; 0.0407; 0.0400 | — |
| SECONDARY Lambda z of DTG and 3TC in in the Fasted State: Part 2 |
0.0457; 0.0469; 0.0388; 0.0383 | — |
| SECONDARY Percentage of Extrapolated AUC (0 to Inf) of DTG and 3TC in the Fasted State: Part 1 |
3.4967; 3.2582; 1.0287; 0.9052 | — |
| SECONDARY Percentage of Extrapolated AUC(0 to Inf) of DTG and 3TC in the Fasted State: Part 2 |
3.8923; 3.5773; 1.2518; 1.1432 | — |
| SECONDARY AUC of 0 to 24 Hours (AUC[0-24]) of DTG and 3TC in the Fasted State: Part 1 |
29.4257; 37.6112; 11.3960; 11.9418 | — |
| SECONDARY AUC(0-24) of DTG and 3TC in the Fasted State: Part 2 |
31.5664; 36.6126; 11.6419; 12.5810 | — |
| SECONDARY Apparent Oral Clearance (CL/F) of DTG and 3TC in the Fasted State: Part 1 |
1.1589; 0.9111; 24.3236; 23.5104 | — |
| SECONDARY CL/F of DTG and 3TC in the Fasted State: Part 2 |
1.0584; 0.9164; 23.4901; 22.1200 | — |
| SECONDARY Apparent Oral Volume of Distribution (Vz/F) of DTG and 3TC in the Fasted State: Part 1 |
24.6254; 19.3399; 616.7365; 598.8651 | — |
| SECONDARY Vz/F of DTG and 3TC in the Fasted State: Part 2 |
23.1159; 19.8124; 650.7952; 599.5525 | — |
| SECONDARY Concentration at 24 Hours Post-dose (C24) of DTG and 3TC in the Fasted State: Part 1 |
0.6373; 0.8059; 0.0331; 0.0318 | — |
| SECONDARY C24 of DTG and 3TC in the Fasted State: Part 2 |
0.7065; 0.8071; 0.0366; 0.0350 | — |
| SECONDARY Last Quantifiable Concentration (Clast) of DTG and 3TC in the Fasted State: Part 1 |
0.0702; 0.0832; 0.0056; 0.0050 | — |
| SECONDARY Clast of DTG and 3TC in the Fasted State: Part 2 |
0.0800; 0.0862; 0.0069; 0.0062 | — |
| SECONDARY AUC (0-Inf) of Plasma DTG and 3TC in the Fed State: Part 1 |
62.3435; 71.9777; 13.4357; 12.8668 | — |
| SECONDARY AUC (0-Inf) of Plasma DTG and 3TC in the Fed State: Part 2 |
57.6561; 76.4283; 14.6420; 13.3443 | — |
| SECONDARY AUC (0-t) of Plasma DTG and 3TC in the Fed State: Part 1 |
60.3212; 69.2560; 13.2818; 12.6491 | — |
| SECONDARY AUC (0-t) of Plasma DTG and 3TC in the Fed State: Part 2 |
55.2176; 72.7545; 14.4706; 13.0923 | — |
| SECONDARY Cmax of Plasma DTG and 3TC in the Fed State: Part 1 |
3.5068; 3.7900; 3.5413; 2.5132 | — |
| SECONDARY Cmax of Plasma DTG and 3TC in the Fed State: Part 2 |
3.1015; 3.7516; 3.5824; 2.4453 | — |
| SECONDARY Tlag of DTG and 3TC in Fed State: Part 1 |
0.0000; 0.2522; 0.0000; 0.0000 | — |
| SECONDARY Tlag of DTG and 3TC in Fed State: Part 2 |
0.0000; 0.1253; 0.0000; 0.0000 | — |
| SECONDARY Tmax of DTG and 3TC in the Fed State: Part 1 |
1.5013; 5.0006; 1.0001; 3.5003 | — |
| SECONDARY Tmax of DTG and 3TC in the Fed State: Part 2 |
1.5007; 5.0019; 1.0003; 2.7508 | — |
| SECONDARY T1/2 of DTG and 3TC in the Fed State: Part 1 |
14.5843; 14.5816; 18.3614; 19.8579 | — |
| SECONDARY T1/2 of DTG and 3TC in the Fed State: Part 2 |
14.9828; 15.1718; 17.2250; 19.7311 | — |
| SECONDARY Lambda z of DTG and 3TC in in the Fed State: Part 1 |
0.0475; 0.0475; 0.0378; 0.0349 | — |
| SECONDARY Lambda z of DTG and 3TC in in the Fed State: Part 2 |
0.0463; 0.0457; 0.0403; 0.0351 | — |
| SECONDARY Clast of DTG and 3TC in in the Fed State: Part 1 |
0.1060; 0.1190; 0.0048; 0.0066 | — |
| SECONDARY Clast of DTG and 3TC in in the Fed State: Part 2 |
0.0975; 0.1310; 0.0059; 0.0091 | — |
| SECONDARY Percentage of Extrapolated AUC (0-inf) in the Fed State: Part 1 |
3.3305; 3.8870; 0.8856; 1.4830 | — |
| SECONDARY Percentage of Extrapolated AUC (0-inf) in the Fed State: Part 2 |
3.6835; 3.8790; 1.0443; 1.7467 | — |
| SECONDARY AUC(0-24) of DTG and 3TC in the Fed State: Part 1 |
43.1879; 46.8555; 12.6113; 11.8076 | — |
| SECONDARY AUC(0-24) of DTG and 3TC in the Fed State: Part 2 |
38.6325; 48.2012; 13.7012; 12.1065 | — |
| SECONDARY CL/F of DTG and 3TC in the Fed State: Part 1 |
0.8020; 0.6947; 22.3285; 23.3159 | — |
| SECONDARY CL/F of DTG and 3TC in the Fed State: Part 2 |
0.8672; 0.6542; 20.4890; 22.4815 | — |
| SECONDARY Tlast of DTG and 3TC in the Fed State: Part 1 |
71.8265; 71.9758; 71.8265; 71.9758 | — |
| SECONDARY Tlast of DTG and 3TC in the Fed State: Part 2 |
72.0292; 71.8711; 72.0292; 71.8711 | — |
| SECONDARY Vz/F of DTG and 3TC in the Fed State: Part 1 |
16.7520; 14.4964; 593.2054; 643.0977 | — |
| SECONDARY Vz/F of DTG and 3TC in the Fed State: Part 2 |
19.0954; 14.6215; 535.8125; 641.3744 | — |
| SECONDARY C24 of DTG and 3TC in the Fed State: Part 1 |
0.9216; 1.1916; 0.0304; 0.0366 | — |
| SECONDARY C24 of DTG and 3TC in the Fed State: Part 2 |
0.8355; 1.2273; 0.0350; 0.0417 | — |
| SECONDARY Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP): Part 1 and 2 |
0.1; 0.2; -2.1; -0.5; -0.3; 0.0 | — |
| SECONDARY Change From Baseline in Heart Rate (HR): Part 1 and 2 |
0.6; 0.4; 4.9; 0.1; -0.3; 3.0 | — |
| SECONDARY Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs): Part 1 and 2 |
14; 18; 1; 15; 12; 1 | — |
Eligibility Criteria
Inclusion Criteria
- Between 18 and 55 years of age inclusive, at the time of signing the informed consent.
- Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac evaluation (history, electrocardiogram [ECG]).
- 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 the Medical Monitor if required, agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
- Subject must be able to swallow 2 tablets at the same time (Reference tablets only).
- Body weight >=50 kilogram (kg) for men and >=45 kg for women and body mass index (BMI) within the range 18.5-31.0 kg per meter square (kg/m^2).
- Male or Female. Female subject: is eligible to participate if she is not pregnant (as confirmed by a negative serum or urine human chorionic gonadotrophin [hCG] test), not lactating, and at least one of the following conditions applies: 1. non-reproductive potential defined as: pre-menopausal females with one of the following: documented tubal ligation; documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion; hysterectomy; documented bilateral Oophorectomy. Postmenopausal defined as 12 months of spontaneous amenorrhea; in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. 2. Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from 30 days prior to the first dose of study medication and until at least five terminal half-lives OR until any continuing pharmacologic effect has ended, whichever is longer after the last dose of study medication and completion of the follow-up visit.
- Capable of giving signed informed consent which includes compliance with the requirements and restrictions.
Exclusion Criteria
- Alanine aminotransferase (ALT) and bilirubin >1.5x upper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin 450 milliseconds (msec).
- Unable to refrain from the 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 ViiV 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 >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 gram (g) of alcohol: 12 ounces [360 milliliter (mL)] of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
- Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 1 month prior to screening.
- 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.
- Creatinine cl
Data sourced from ClinicalTrials.gov (NCT03078556). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.