| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Human immunodeficiency virus type 1 (HIV-1) infection (Healthy participants) |
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| E.1.1.1 | Medical condition in easily understood language |
| HIV-1 infection (Healthy participants) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10020161 |
| E.1.2 | Term | HIV infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to evaluate the single-dose pharmacokinetics (PK) and bioequivalence of DRV 675 mg in the presence of COBI 150 mg when administered as a scored FDC tablet (DRV/COBI) compared to the co-administration as the separate available tablet formulations (DRV 1×600 mg and 1×75 mg tablet and COBI 1×150 mg tablet), under fed conditions in healthy participants. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
• To evaluate the single-dose PK and relative bioavailability of COBI 150 mg in the presence of DRV 675 mg when administered as a scored FDC tablet (DRV/COBI) compared to co-administration as the separate available tablet formulations (DRV 1×600 mg and 1×75 mg tablet and COBI 1×150 mg tablet), under fed conditions in healthy participants.
• To evaluate the short-term safety and tolerability of co-administration of DRV 675 mg and COBI 150 mg, under fed conditions in healthy participants. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants must satisfy the following criteria to be enrolled in the study:
1. Must be male or female (according to their reproductive organs and functions assigned by chromosomal complement).
2. Must be 18 to 55 years of age, inclusive.
3. Must have a body mass index (BMI; weight [kg]/height^2 [m]^2) between 18.5 and 30.0 kg/m^2 (inclusive), and body weight not less than 50.0 kg.
4. Must be healthy on the basis of physical examination, medical history, vital signs, and 12-lead ECG performed at screening (results must be available on Day -1). If there are abnormalities, participants may be included only if the investigator judges the abnormalities or the deviations from normal to be not clinically significant. This determination must be recorded in the participant's source documents and initialed by the investigator.
5. Must be healthy on the basis of clinical laboratory tests performed at screening (results must be available on Day -1). If the results of the serum chemistry panel, hematology, or urinalysis are outside the normal reference ranges, the participant may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant. This determination must be recorded in the participant's source documents and initialed by the investigator.
6. Must sign an ICF indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study, before any study-related procedures take place.
7. Non-postmenopausal women must have a negative highly sensitive serum β-human chorionic gonadotropin (β-hCG) 4 days or less before dosing of the first treatment period.
8. Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for participants participating in clinical studies.
Before randomization, a woman must be either:
• Not of childbearing potential defined as:
a. premenarchal
A premenarchal state is one in which menarche has not yet occurred.
b. postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high-follicle-stimulating hormone (FSH) level (>40.0 IU/L or mIU/mL) in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to establish menopausal status. If there is a question about menopausal status in women on hormone-replacement therapy (HRT), the woman will be required to use one of the non-estrogen-containing hormonal highly effective contraceptive methods if she wishes to continue HRT during the study.
c. permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal occlusion/ligation procedures, and bilateral oophorectomy.
• Of childbearing potential and
d. be not heterosexually active, or have a vasectomized partner for the duration of the study and for at least 90 days after receiving the last dose of study drug, OR
e. practicing a highly effective method of contraception before entry and agree to continue to use a highly effective method of contraception throughout the study, and for at least 90 days after receiving the last dose of study drug. Women with tubal ligation are required to use one additional contraceptive method.
Note: Estrogen-based hormonal contraception may not be reliable when taking the study drug, therefore, to be eligible for this study, women of childbearing potential should either:
1) Use a double-barrier method (ie, male condom + either diaphragm or cervical cap), OR
2) Use non-estrogen hormonal-based contraceptives in combination with a barrier contraceptive (ie, male condom, diaphragm or cervical cap, or female condom), OR
3) Use an intrauterine device in combination with a barrier contraceptive (ie male condom, diaphragm or cervical cap, or female condom).
Note: If the childbearing potential changes after start of the study or the risk of pregnancy changes (eg, a woman who is not heterosexually active becomes active), a woman must begin a highly effective method of contraception.
9. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for at least 90 days after receiving the last dose of study drug.
10. During the study and for a minimum of at least 90 days after receiving the last dose of study drug, a male participant:
• Must wear a condom when engaging in any activity that allows for passage of ejaculate to another person (male participants should also be advised of the benefit for a female partner to use a highly effective method of contraception as condom may break or leak);
• Must agree not to donate sperm for the purpose of reproduction.
Refer the protocol for all the inclusion criteria.
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| E.4 | Principal exclusion criteria |
Any potential participants who meet any of the following criteria will be excluded from participating in the study:
1. Has a history of or current clinically significant medical illness including (but not limited to) cardiac arrhythmias or other cardiac disease, hematologic disease, coagulation disorders (including any abnormal bleeding or blood dyscrasias), lipid abnormalities, significant pulmonary disease (including bronchospastic respiratory disease), diabetes mellitus, hepatic or renal insufficiency, gastrointestinal disease (such as significant diarrhea, gastric stasis, or constipation that in the investigator’s opinion could influence drug absorption or bioavailability), thyroid disease, neurologic or psychiatric disease, infection, or any other illness that the investigator considers should exclude the participant or that could interfere with the interpretation of the study results.
2. Has one or more of the following laboratory abnormalities at screening or at Day -1 (grading as defined by the Division of acquired immunodeficiency syndrome [DAIDS] Table for Grading the Severity of Adult and Pediatric Adverse Events):
• Serum creatinine Grade 1 or greater (≥1.1 x upper limit of laboratory normal range [ULN]) or estimated GFR (using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula) <90 mL/min/1.73 m^2
• Lipase Grade 1 or greater (≥1.1 x ULN), and/or total amylase Grade 2 or greater (≥1.5 x ULN).
• Hemoglobin (Hb) Grade 1 or greater (female: ≤6.5 mmol/L or ≤10.4 g/dL and male: ≤6.8 mmol/L or ≤10.9 g/dL).
• Platelet count Grade 1 or greater (<125.000 x 10^9/L).
• Absolute neutrophil count Grade 1 or greater (≤1.0 x 10^9/L).
• Aspartate aminotransferase or ALT Grade 1 or greater (≥1.25 x ULN).
• Total bilirubin Grade 2 or greater (≥1.6 x ULN).
Note: Participants with documented Gilbert’s syndrome could have total bilirubin up to 5 x ULN.
• For proteinuria (spot urine) ≥2+.
• Microscopic hematuria (≥6 red blood cells [RBCs]/ high power field [hpf]); if a female participant is menstruating at the time of screening, a urine retest is to be performed after the menstrual period.
• Any other laboratory abnormality of grade 2 or greater. For low-density lipoprotein (LDL) cholesterol values corresponding to DAIDS grade 2 or greater, participants will not to be excluded as long as the value is not higher than ULN of the local lab.
3. Clinically significant abnormalities during physical examination, vital signs, or 12-lead ECG at screening or at admission to the study site as deemed appropriate by the investigator.
4. With a clinically significant skin disease such as, but not limited to, dermatitis, eczema, drug rash, psoriasis, food allergy, or urticaria.
5. Has a history of malignancy within 5 years before screening (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy, which is considered cured with minimal risk of recurrence).
6. Has taken any disallowed therapies before the planned first dose of study drug.
7. Has a history of drug or alcohol abuse according to Diagnostic and Statistical Manual of Mental Disorders (5th edition) (DSM-V) criteria within 1 year before screening or positive test result(s) for alcohol and/or drugs of abuse (such as hallucinogens, barbiturates, opiates, opioids, cocaine, cannabinoids, amphetamines, and benzodiazepines) at screening.
8. With a history of clinically significant drug allergy such as, but not limited to, sulfonamides and penicillins, or drug allergy diagnosed in previous studies with experimental drugs.
9. Has known allergies, hypersensitivity, or intolerance to DRV and/or COBI, or any of their excipients.
10. Has donated blood or plasma within 2 months before the first administration of study drug or intention to donate blood or blood products during the study.
11. Has received an investigational drug or used an investigational medical device within 60 days before the first administration of the study drug.
12. Is a woman who is pregnant, breast-feeding, or planning to become pregnant during the study or within 90 days after the last dose of study drug, or a woman of childbearing potential who is unwilling to use acceptable methods of contraception.
13. Is a man who plans to father a child while enrolled in the study or within 90 days after the last dose of study drug, or who is unwilling to use acceptable methods of contraception.
Refer the protocol for all the exclusion criteria.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. PK and relative bioavailability
a. Cmax: The maximum observed plasma analyte concentration
b. tmax: The actual sampling time to reach the maximum observed plasma analyte concentration.
c. AUClast: Area under the analyte concentration-time curve (AUC) from time 0 to the time of the last measurable (non-below quantification limit [non-BQL]) concentration, calculated by linear-linear trapezoidal summation.
d. AUC∞: AUC from time 0 to infinite time, calculated as AUClast + Clast/λz, , where Clast is the last observed measurable (non-BQL) concentration; extrapolations of more than 20.00% of the total 5. 5. AUC are reported as approximations.
e. Clast: The last observed measurable (non-BQL) plasma analyte concentration.
f. tlast: The actual sampling time of the last measurable (non-BQL) analyte concentration.
g. λz: Apparent terminal elimination rate constant, determined by linear regression using the terminal log-linear phase of the log-transformed concentration vs time curve.
h. t1/2: The apparent terminal elimination half-life, calculated as t1/2 = 0.693 / λz |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1a. to h: Day 1 (D1) (-2 hour [h], 0.5h, 1h, 1.5h, 2h to 6h, 8h, 12h, 18h), D2 (24h, 36h), D3 (48h), D4 (72h) of each treatment period and end of study (EOS) |
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| E.5.2 | Secondary end point(s) |
1. PK and relative bioavailability
a. Cmax: The maximum observed plasma analyte concentration
b. tmax: The actual sampling time to reach the maximum observed plasma analyte concentration.
c. AUClast: Area under the analyte concentration-time curve (AUC) from time 0 to the time of the last measurable (non-below quantification limit [non-BQL]) concentration, calculated by linear-linear trapezoidal summation.
d. AUC∞: AUC from time 0 to infinite time, calculated as AUClast + Clast/λz, , where Clast is the last observed measurable (non-BQL) concentration; extrapolations of more than 20.00% of the total 5. 5. AUC are reported as approximations.
e. Clast: The last observed measurable (non-BQL) plasma analyte concentration.
f. tlast: The actual sampling time of the last measurable (non-BQL) analyte concentration.
g. λz: Apparent terminal elimination rate constant, determined by linear regression using the terminal log-linear phase of the log-transformed concentration vs time curve.
h. t1/2: The apparent terminal elimination half-life, calculated as t1/2 = 0.693 / λz
2. Safety and tolerability
a. AEs
b. Clinical laboratory tests (Hematology, chemistry, coagulation and urinalysis test)
c. Electrocardiogram
d. Vital signs
e. Physical examination |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1a. to h: D1 (-2h, 0.5h, 1h, 1.5h, 2h to 6h, 8h, 12h, 18h), D2 (24h, 36h), D3 (48h), D4 (72h)] of each treatment period and EOS
2a. Through out the study
b. Screening, D-1, D2 (24h), D4 (72h) of each treatment period and EOS
c. Screening
d. and e: Screening, D-1, D4 (72h) of each treatment period and EOS
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | Yes |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | Yes |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Single-dose, 2-treatment, 2-sequence, 2-period crossover, single-center study |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 12 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 12 |
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