Clinical Trial Results:
A Single-dose, Open-label, Randomized, Crossover Pivotal Bioequivalence Study in Healthy Participants to Assess the Bioequivalence of Darunavir 600 mg in the Presence of Cobicistat 90 mg When Administered as a Fixed Dose Combination Tablet (Darunavir/Cobicistat) Compared to the Co-administration of the Separate Available Formulations (Darunavir 100 mg/mL Suspension at a Dose of 600 mg and Cobicistat 90 mg tablet), Under Fed Conditions
Summary
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EudraCT number |
2021-003955-40 |
Trial protocol |
BE |
Global end of trial date |
28 Sep 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
07 Oct 2023
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First version publication date |
07 Oct 2023
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
TMC114FD1HTX1004
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT05378906 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Janssen-Cilag International N.V.
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Sponsor organisation address |
Turnhoutseweg 30, Beerse, Belgium, B-2340
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Public contact |
Clinical Registry Group, Janssen-Cilag International N.V., ClinicalTrialsEU@its.jnj.com
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Scientific contact |
Clinical Registry Group, Janssen-Cilag International N.V., ClinicalTrialsEU@its.jnj.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001280-PIP01-12 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
28 Sep 2022
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Sep 2022
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The main objective of this study was to evaluate the single-dose pharmacokinetic (PK) and bioequivalence of darunavir (DRV) 600 milligrams (mg) in the presence of cobicistat (COBI) 90 mg when administered as a fixed dose combination (FDC) tablet dispersed in water (DRV/COBI 600/90 mg) compared to the coadministration of the separate available formulations (DRV 100 milligram per millilitre [mg/mL] suspension at a dose of 600 mg and COBI 1*90 mg tablet), under fed conditions in healthy subjects.
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Protection of trial subjects |
This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
07 Jun 2022
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Belgium: 32
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Worldwide total number of subjects |
32
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EEA total number of subjects |
32
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
32
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||
Pre-assignment
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Screening details |
A total of 32 healthy subjects were randomised and treated (16 subjects in each treatment sequence AB and treatment sequence BA). | ||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Treatment Sequence AB | ||||||||||||||||||||||||
Arm description |
Subjects received a single oral dose of Darunavir (DRV) (600 milligrams [mg]) and Cobicistat (COBI) (90 mg) as one fixed dose combination (FDC) tablet under fed conditions (Treatment A, test) on Day 1 of Period 1 followed by a single oral dose of DRV 600 mg as 100 milligram per millilitre (mg/mL) suspension and COBI 90 mg tablet under fed conditions (Treatment B, reference) on Day 1 of Period 2. Each period was separated by a washout period of at least 7 days. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Darunavir 100 mg/mL suspension
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Investigational medicinal product code |
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Other name |
TMC114
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Pharmaceutical forms |
Oral suspension
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received a single dose of Darunavir 600mg as 100 mg/mL suspension orally as Treatment B on Day 1 as per assigned treatment sequences.
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Investigational medicinal product name |
Cobicistat 90 mg
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Investigational medicinal product code |
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Other name |
JNJ-48763364
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received a single dose of Cobicistat 90 mg tablet orally as a component of Treatment B on Day 1 as per assigned treatment sequences.
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Investigational medicinal product name |
Darunavir 600 mg and Cobicistat 90 mg as one FDC tablet
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Investigational medicinal product code |
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Other name |
TMC114/JNJ-48763364
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received a single dose of Darunavir 600 mg and Cobicistat 90 mg FDC tablet orally as Treatment A on Day 1 as per assigned treatment sequences.
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Arm title
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Treatment Sequence BA | ||||||||||||||||||||||||
Arm description |
Subjects received a single oral dose of DRV 600 mg as 100 mg/mL suspension and COBI 90 mg tablet under fed conditions (Treatment B, reference) on Day 1 of Period 1 followed by a single oral dose of DRV (600 mg) and COBI (90 mg) as one FDC tablet under fed conditions (Treatment A, test) on Day 1 of Period 2. Each period was separated by a washout period of at least 7 days. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Darunavir 100 mg/mL suspension
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Investigational medicinal product code |
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Other name |
TMC114
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Pharmaceutical forms |
Oral suspension
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received a single dose of Darunavir 600mg as 100 mg/mL suspension orally as Treatment B on Day 1 as per assigned treatment sequences.
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Investigational medicinal product name |
Darunavir 600 mg and Cobicistat 90 mg as one FDC tablet
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Investigational medicinal product code |
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Other name |
TMC114/JNJ-48763364
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received a single dose of Darunavir 600 mg and Cobicistat 90 mg FDC tablet orally as Treatment A on Day 1 as per assigned treatment sequences.
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Investigational medicinal product name |
Cobicistat 90 mg
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Investigational medicinal product code |
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Other name |
JNJ-48763364
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received a single dose of Cobicistat 90 mg tablet orally as a component of Treatment B on Day 1 as per assigned treatment sequences.
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Baseline characteristics reporting groups
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Reporting group title |
Treatment Sequence AB
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Reporting group description |
Subjects received a single oral dose of Darunavir (DRV) (600 milligrams [mg]) and Cobicistat (COBI) (90 mg) as one fixed dose combination (FDC) tablet under fed conditions (Treatment A, test) on Day 1 of Period 1 followed by a single oral dose of DRV 600 mg as 100 milligram per millilitre (mg/mL) suspension and COBI 90 mg tablet under fed conditions (Treatment B, reference) on Day 1 of Period 2. Each period was separated by a washout period of at least 7 days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Treatment Sequence BA
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Reporting group description |
Subjects received a single oral dose of DRV 600 mg as 100 mg/mL suspension and COBI 90 mg tablet under fed conditions (Treatment B, reference) on Day 1 of Period 1 followed by a single oral dose of DRV (600 mg) and COBI (90 mg) as one FDC tablet under fed conditions (Treatment A, test) on Day 1 of Period 2. Each period was separated by a washout period of at least 7 days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Treatment Sequence AB
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Reporting group description |
Subjects received a single oral dose of Darunavir (DRV) (600 milligrams [mg]) and Cobicistat (COBI) (90 mg) as one fixed dose combination (FDC) tablet under fed conditions (Treatment A, test) on Day 1 of Period 1 followed by a single oral dose of DRV 600 mg as 100 milligram per millilitre (mg/mL) suspension and COBI 90 mg tablet under fed conditions (Treatment B, reference) on Day 1 of Period 2. Each period was separated by a washout period of at least 7 days. | ||
Reporting group title |
Treatment Sequence BA
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Reporting group description |
Subjects received a single oral dose of DRV 600 mg as 100 mg/mL suspension and COBI 90 mg tablet under fed conditions (Treatment B, reference) on Day 1 of Period 1 followed by a single oral dose of DRV (600 mg) and COBI (90 mg) as one FDC tablet under fed conditions (Treatment A, test) on Day 1 of Period 2. Each period was separated by a washout period of at least 7 days. | ||
Subject analysis set title |
Treatment A
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Subjects received a single oral dose of Darunavir (DRV) (600 milligrams [mg]) and Cobicistat (COBI) (90 mg) as one fixed dose combination (FDC) tablet under fed conditions on Day 1 of each treatment period.
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Subject analysis set title |
Treatment B
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Subjects received a single oral dose of DRV 600 mg as 100 milligram per millilitre (mg/mL) suspension and COBI 90 mg tablet under fed conditions on Day 1 of each treatment period.
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End point title |
Maximum Observed Plasma Concentration (Cmax) of Darunavir (DRV) | ||||||||||||
End point description |
Cmax was defined as the maximum observed plasma concentration of Darunavir. Pharmacokinetic (PK) data analysis set included all subjects who received at least 1 dose of study intervention and who had at least 1 plasma concentration data value/1 PK parameter value after study intervention administration.
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End point type |
Primary
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End point timeframe |
Pre dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, and 72 hours post dose on Day 1
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Statistical analysis title |
Treatment A Versus Treatment B | ||||||||||||
Statistical analysis description |
Log transformed PK parameters were analysed by a linear mixed-effect model that includes treatment, period, and treatment sequence as fixed effects and subject within sequence as a random effect. The results were back-transformed using anti-logarithm.
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Comparison groups |
Treatment A v Treatment B
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Number of subjects included in analysis |
62
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Analysis specification |
Pre-specified
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Analysis type |
equivalence [1] | ||||||||||||
Method |
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Parameter type |
Geometric Mean Ratio | ||||||||||||
Point estimate |
96.85
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
88.94 | ||||||||||||
upper limit |
105.47 | ||||||||||||
Notes [1] - Subjects analysed for statistical analysis in both the treatments (in each Treatment A and Treatment B) as per assigned treatment sequence were 30. Pre-defined bioequivalence limits were 80 to 125%. |
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End point title |
Area Under the Concentration-time Curve From Time Zero to Last Quantifiable Time (AUC[0-last]) of DRV | ||||||||||||
End point description |
AUC(0-last) was area under the analyte concentration-time curve from time zero to the time of the last measurable (non-below quantification limit [non-BQL]) concentration, calculated by linear-linear trapezoidal summation. PK data analysis set included all subjects who received at least 1 dose of study intervention and who had at least 1 plasma concentration data value/1 PK parameter value after study intervention administration.
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End point type |
Primary
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End point timeframe |
Pre dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, and 72 hours post dose on Day 1
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Statistical analysis title |
Treatment A Versus Treatment B | ||||||||||||
Statistical analysis description |
Log transformed PK parameters were analysed by a linear mixed-effect model that includes treatment, period, and treatment sequence as fixed effects and subject within sequence as a random effect. The results were back-transformed using anti-logarithm.
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Comparison groups |
Treatment A v Treatment B
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Number of subjects included in analysis |
62
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Analysis specification |
Pre-specified
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Analysis type |
equivalence [2] | ||||||||||||
Method |
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Parameter type |
Geometric Mean Ratio | ||||||||||||
Point estimate |
98.22
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
92.46 | ||||||||||||
upper limit |
104.33 | ||||||||||||
Notes [2] - Subjects analysed for statistical analysis in both the treatments (in each Treatment A and Treatment B) as per assigned treatment sequence were 30. Pre-defined bioequivalence limits were 80 to 125%. |
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End point title |
Area Under the Concentration-time Curve from Time Zero to Infinite Time (AUC[0-infinity]) of DRV | ||||||||||||
End point description |
The AUC (0-infinity) was the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last) divided by lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant. PK data analysis set included all subjects who received at least 1 dose of study intervention and who had at least 1 plasma concentration data value/1 PK parameter value after study intervention administration. Here, ‘Number of Subjects Analysed’ = subjects evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Pre dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, and 72 hours post dose on Day 1
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Statistical analysis title |
Treatment A Versus Treatment B | ||||||||||||
Statistical analysis description |
Log transformed PK parameters were analysed by a linear mixed-effect model that includes treatment, period, and treatment sequence as fixed effects and subject within sequence as a random effect. The results were back-transformed using anti-logarithm.
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Comparison groups |
Treatment A v Treatment B
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Number of subjects included in analysis |
61
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Analysis specification |
Pre-specified
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Analysis type |
equivalence [3] | ||||||||||||
Method |
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Parameter type |
Geometric Mean Ratio | ||||||||||||
Point estimate |
98.6
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
92.66 | ||||||||||||
upper limit |
104.91 | ||||||||||||
Notes [3] - Subjects analysed for statistical analysis in both the treatments (in each Treatment A and Treatment B) as per assigned treatment sequence were 29. Pre-defined bioequivalence limits were 80 to 125%. |
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End point title |
Maximum Observed Plasma Concentration (Cmax) of Cobicistat (COBI) | ||||||||||||
End point description |
Cmax was defined as the maximum observed plasma concentration of cobicistat. PK data analysis set included all subjects who received at least 1 dose of study intervention and who had at least 1 plasma concentration data value/1 PK parameter value after study intervention administration.
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End point type |
Secondary
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End point timeframe |
Pre dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, and 72 hours post dose on Day 1
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Statistical analysis title |
Treatment A Versus Treatment B | ||||||||||||
Statistical analysis description |
Log transformed PK parameters were analysed by a linear mixed-effect model that includes treatment, period, and treatment sequence as fixed effects and subject within sequence as a random effect. The results were back-transformed using anti-logarithm.
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Comparison groups |
Treatment A v Treatment B
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Number of subjects included in analysis |
62
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Analysis specification |
Pre-specified
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Analysis type |
equivalence [4] | ||||||||||||
Method |
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Parameter type |
Geometric Mean Ratio | ||||||||||||
Point estimate |
74.18
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
66.68 | ||||||||||||
upper limit |
82.53 | ||||||||||||
Notes [4] - Subjects analysed for statistical analysis in both the treatments (in each Treatment A and Treatment B) as per assigned treatment sequence were 30. Pre-defined bioequivalence limits were 80 to 125%. |
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End point title |
Area Under the Concentration-time Curve From Time Zero to Last Quantifiable Time (AUC[0-last]) of COBI | ||||||||||||
End point description |
AUC(0-last) was area under the analyte concentration-time curve from time zero to the time of the last measurable (non-BQL) concentration, calculated by linear-linear trapezoidal summation. PK data analysis set included all subjects who received at least 1 dose of study intervention and who had at least 1 plasma concentration data value/1 PK parameter value after study intervention administration.
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End point type |
Secondary
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End point timeframe |
Pre dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, and 72 hours post dose on Day 1
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Statistical analysis title |
Treatment A Versus Treatment B | ||||||||||||
Statistical analysis description |
Log transformed PK parameters were analysed by a linear mixed-effect model that includes treatment, period, and treatment sequence as fixed effects and subject within sequence as a random effect. The results were back-transformed using anti-logarithm.
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Comparison groups |
Treatment A v Treatment B
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Number of subjects included in analysis |
62
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Analysis specification |
Pre-specified
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Analysis type |
equivalence [5] | ||||||||||||
Method |
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Parameter type |
Geometric Mean Ratio | ||||||||||||
Point estimate |
85.23
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
77.72 | ||||||||||||
upper limit |
93.47 | ||||||||||||
Notes [5] - Subjects analysed for statistical analysis in both the treatments (in each Treatment A and Treatment B) as per assigned treatment sequence were 30. Pre-defined bioequivalence limits were 80 to 125%. |
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End point title |
Area Under the Concentration-time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of COBI | ||||||||||||
End point description |
The AUC (0-infinity) was the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant. PK data analysis set included all subjects who received at least 1 dose of study intervention and who had at least 1 plasma concentration data value/1 PK parameter value after study intervention administration. Here, ‘Number of Subjects Analysed’ = subjects evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Pre dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, and 72 hours post dose on Day 1
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Statistical analysis title |
Treatment A Versus Treatment B | ||||||||||||
Statistical analysis description |
Log transformed PK parameters were analysed by a linear mixed-effect model that includes treatment, period, and treatment sequence as fixed effects and subject within sequence as a random effect. The results were back-transformed using anti-logarithm.
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Comparison groups |
Treatment A v Treatment B
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Number of subjects included in analysis |
60
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Analysis specification |
Pre-specified
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Analysis type |
equivalence [6] | ||||||||||||
Method |
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Parameter type |
Geometric Mean Ratio | ||||||||||||
Point estimate |
84.68
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Confidence interval |
|||||||||||||
level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
77.05 | ||||||||||||
upper limit |
93.08 | ||||||||||||
Notes [6] - Subjects analysed for statistical analysis in both the treatments (in each Treatment A and Treatment B) as per assigned treatment sequence were 28. Pre-defined bioequivalence limits were 80 to 125%. |
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End point title |
Number of Subjects With Serious Adverse Events (SAEs) | |||||||||
End point description |
An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. SAE was any untoward medical occurrence that at any dose resulted in death, was life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a suspected transmission of any infectious agent via a medicinal product. Safety analysis set included all subjects who received at least one dose of study intervention.
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End point type |
Secondary
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End point timeframe |
From screening up to end of study (up to 7 weeks)
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No statistical analyses for this end point |
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End point title |
Number of Subjects With Clinically Significant Abnormalities in Physical Examinations | |||||||||
End point description |
Clinically significant abnormalities in physical examinations was reported in this endpoint. Physical examination included skin examination, height and body weight measurement. Safety analysis set included all subjects who received at least 1 dose of study intervention.
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End point type |
Secondary
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End point timeframe |
From screening up to end of study (up to 7 weeks)
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No statistical analyses for this end point |
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End point title |
Number of Subjects With Clinically Significant Abnormalities in Vital Sign | |||||||||
End point description |
Abnormal vital parameters included pulse rate: abnormally low- less than or equal to (<=45) beats per minute (bpm), abnormally high- greater than or equal to (>=) 120 bpm; Systolic Blood Pressure (SBP): abnormally low <=90 millimeter of mercury (mmHg), Grade 1 (mild): >140 mmHg to <160 mmHg, Grade 2 (moderate): >=160 mmHg to <180 mmHg, Grade 3 (severe): >=180 mmHg; Diastolic BP: abnormally low <=50 mmHg, Grade 1 (mild): >90 mmHg to <100 mmHg, Grade 2 (moderate): >=100 mmHg to <110 mmHg, Grade 3 (severe): >=110 mmHg. Safety analysis set included all subjects who received at least one dose of study intervention.
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End point type |
Secondary
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End point timeframe |
From screening up to end of study (up to 7 weeks)
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No statistical analyses for this end point |
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End point title |
Number of Subjects With Clinically Significant Abnormalities in Clinical Laboratory Tests | |||||||||
End point description |
Safety laboratory assessments included clinical chemistry, hematology, coagulation, urinalysis, and other screening tests. Abnormality was determined at the investigator's discretion. Safety analysis set included all subjects who received at least 1 dose of study intervention.
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End point type |
Secondary
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End point timeframe |
From screening up to end of study (up to 7 weeks)
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
From screening up to end of study (up to 7 weeks)
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Assessment type |
Non-systematic | |||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||
Dictionary version |
25.0
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Reporting groups
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Reporting group title |
Treatment A
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Reporting group description |
Subjects received a single oral dose of Darunavir (DRV) (600 milligrams [mg]) and Cobicistat (COBI) (90 mg) as one fixed dose combination (FDC) tablet under fed conditions on Day 1 of each treatment period. | |||||||||||||||||||||
Reporting group title |
Treatment B
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Reporting group description |
Subjects received a single oral dose of DRV 600 mg as 100 milligram per millilitre (mg/mL) suspension and COBI 90 mg tablet under fed conditions on Day 1 of each treatment period. | |||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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22 Feb 2022 |
The original protocol dated 08 December 2021 was amended once (22 February 2022) to correct an inconsistency between the Schedule of Activities and Section 8.1.3 (Electrocardiograms) of the protocol. The requirement for an electrocardiogram (ECG) assessment on Day -1 was removed from the Schedule of Activities as ECG was only required during screening. A more detailed instruction regarding the allowed intake of paracetamol/acetaminophen was added. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |