| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Healthy Volunteers; Human immunodeficiency virus type 1 (HIV-1) |
|
| E.1.1.1 | Medical condition in easily understood language |
HIV is a virus that causes HIV infection and over time can lead to
acquired immunodeficiency syndrome (AIDS). AIDS is a condition which
causes progressive failure of the immune system. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068341 |
| E.1.2 | Term | HIV-1 infection |
| E.1.2 | System Organ Class | 100000004862 |
|
| 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 |
| To evaluate the single-dose PK and pivotal bioequivalence of 3 compounds DRV 675 mg, FTC 200 mg, and TAF 10 mg in the presence of COBI 150 mg when administered as an FDC (D/C/F/TAF) compared to the co-administration as the separate commercial formulations (DRV 1×600 mg and 1×75 mg tablet and F/TAF 1×200 mg/10 mg tablet and COBI 1×150 mg tablet), under fed conditions, in healthy adult participants. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the single-dose PK and relative bioavailability of COBI 150 mg in the presence of DRV 675 mg, FTC 200 mg, and TAF 10 mg when administered as an FDC (D/C/F/TAF) compared to co-administration as the separate commercial formulations (COBI 1×150 mg tablet in the presence of DRV 1×600 mg and 1×75 mg tablet and F/TAF 1×200 mg/10 mg tablet), under fed conditions, in healthy adult participants.
To evaluate the short-term safety and tolerability of co-administration of DRV 675 mg, COBI 150 mg, FTC 200 mg, and TAF 10 mg, under fed conditions, in healthy adult participants. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Must be a man or woman between 18 and 55 years of age, extremes included, at screening.
2. Must have a body mass index (BMI; weight [kg]/height2 [m]2) between 18.5 and 30.0 kg/m2 (extremes included), and a body weight of not less than 50 kg at screening.
3. 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.
4. Must be healthy on the basis of physical examination, medical history, vital signs, and ECG performed at screening (results must be available on Day -1). If there are abnormalities (other than those listed in inclusion criterion 10 [for blood pressure]), 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.
5. Participant must be healthy on the basis of clinical laboratory test 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 (other than those listed in exclusion criterion 2), 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. A woman (of childbearing potential) must have a negative highly sensitive serum betahuman chorionic gonadotropin (-hCG) pregnancy test, 4 days or less before dosing of the first treatment period.
7. Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for participant participating in clinical studies.
Before randomization, a female participant must be either:
a. Not of childbearing potential defined as:
-premenarchal
A premenarchal state is one in which menarche has not yet occurred
-postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level (>33.4 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, however in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 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.
-permanently sterile
Permanent sterilization methods include hysterectomy, bilateral
salpingectomy, bilateral tubal occlusion/ligation procedures, and
bilateral oophorectomy.
b. Of childbearing potential and
-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
-practicing a highly effective method of birth control (as specified below) 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: Estrogenbased hormonal contraception may not be reliable when taking the study drug, therefore, to be eligible for this study, woman of childbearing potential should either:
- Use a double barrier method (ie, male condom + either diaphragm or cervical cap), OR
- Use non-estrogen hormonal based contraceptives in combination with a barrier contraceptive (ie, male condom, diaphragm or cervical cap, or female condom), OR
- Use an intrauterine device in combination with a barrier contraceptive (ie male condom, diaphragm or cervical cap, or female condom).
8. 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.
9. 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 participant 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.
10. Must have a blood pressure (supine after at least 5 minutes rest) between 90 and 140 mmHg systolic, inclusive, and between 45 and 90 mmHg diastolic, inclusive, at screening.
11. Must be willing and able to adhere to the prohibitions and restrictions specified in this protocol (see Section 4.4) |
|
| E.4 | Principal exclusion criteria |
1. Has history 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 (eg, estimated creatinine clearance below <90 mL/min at screening), 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. Had one or more of the following laboratory abnormalities at screening as defined by the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events and in accordance with the normal ranges of the clinical laboratory:
-Serum creatinine Grade 1 or greater (≥1.1 x upper limit of laboratory normal range [ULN]) or creatinine clearance (using the CKD-EPI
formula) <90 mL/min.
-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: ≤7.2 mmol/L and Male: ≤8.3 mmol/L).
-Platelet count Grade 1 or greater (<124.999 x 109/L).
-Absolute neutrophil count Grade 1 or greater (≤1.0 x 109/L).
-Aspartate aminotransferase (AST) or alanine aminotransferase (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 (≥5 red blood cells [RBC]/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.
Note: Retesting of abnormal lab values that could lead to exclusion will be allowed once. Retesting will take place during an unscheduled visit in the screening phase.
3. Clinically significant abnormalities during physical examination, vital signs, or 12-lead electrocardiogram (ECG) at screening or at admission to the study center as deemed appropriate by the investigator.
4. With any history of clinically significant skin disease such as, but not limited to, dermatitis, eczema, drug rash, psoriasis, food allergy, or urticaria.
5. Has taken any disallowed therapies as noted in Section 5.5 before the planned first intake of study drug.
6. 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, methadone,
benzodiazepines, methamphetamine, tetrahydrocannabinol, phencyclidine, and tricyclic antidepressants) either at screening or on Day -1 of each treatment period.
7. 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.
8. Has known allergies, hypersensitivity, or intolerance to DRV, COBI, FTC, and/or TAF, or any of their excipients.
9. Has known allergy to heparin or history of heparin induced thrombocytopenia.
10. Has donated blood or plasma within 2 months preceding the first intake 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 intake of study drug.
12. Is a woman who is pregnant, or breast-feeding, or planning to become pregnant during this study or within 90 days after the last intake of study drug, or a woman of childbearing potential who is unwilling to use acceptable methods of contraception as outlined in Section 4.2.
13. Is a man who plans to father a child while enrolled in this study or within 90 days after the last intake of study drug, or who is unwilling to use acceptable methods of contraception as outlined in Section 4.2.
14. Has a history of hepatitis A antibody immunoglobulin M (IgM), hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV) positive, or other clinically active liver disease, or tests positive for hepatitis A antibody IgM, HBsAg or anti-HCV at screening.
Further criteria apply. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The assessment of specified PK parameters for DRV, COBI, FTC, and TAF for each treatment period: Cmax, tmax, AUClast, AUC∞, Clast, tlast, λz, and t1/2.
Other PK parameters may be estimated as appropriate for exploration of the data.
For the PK parameters, definitions and methods of calculation are:
-Cmax maximum observed analyte concentration;
-tmax the actual sampling time to reach the maximum observed analyte concentration;
-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;
-AUC∞ AUC from time 0 to infinity, calculated as AUClast + Clast/λz, where Clast is the last observed measurable (non-BQL) concentration; extrapolations of more than 20.00% of the total AUC are reported as approximations;
-Clast last observed measurable (non-below quantification limit [BQL]) analyte concentration;
-tlast the actual sampling time of the last measurable (non-BQL) analyte concentration
-λz apparent terminal elimination rate constant, determined by linear regression using the terminal log-linear phase of the log-transformed concentration vs. time curve;
-t1/2 apparent terminal elimination half-life, defined as 0.693/λz. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The study will include the following evaluations of safety and
tolerability:
-Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally acceptable representative) for the duration of the study;
-Blood samples for serum biochemistry, blood coagulation (Screening only), and hematology and a random urine sample for urinalysis will be collected. The investigator must review the laboratory report, document this review, and record any clinically relevant changes occurring during the study in the adverse event section of the CRF;
-Electrocardiogram (ECG);
-Vital signs;
-Physical examinations including height, body weight, and skin examination;
-Alcohol Urine Test;
Specific Toxicities: for participants reporting rash, acute allergic reactions, AST/ALT elevations, clinical hepatitis, renal complications, nausea, or diarrhea.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| bioavailability and tolerability |
|
| 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 | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 |
|
| 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
|
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned days | 22 |
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