Drug Interaction Potential Between Dolutegravir and Simeprevir in HIV/HCV Seronegative Volunteers

• Sponsor: University of Colorado, Denver (Other)
• Overall Status: Completed
• CT.gov ID: NCT02404805
• Collaborator: (none)
• Enrollment: 25
• Location: 1
• Arms: 6
• Duration (Months): 8
• Patients Per Site Per Month: 3.1

Study Details

Study Description

Brief Summary

The investigator believes simeprevir concentrations are unchanged when administered in combination with dolutegravir relative to administration alone. The investigator believes dolutegravir concentrations are unchanged when administered in combination with simeprevir. Additionally, the investigator believes simeprevir and dolutegravir are safe when administered alone and in combination.

Condition or Disease	Intervention/Treatment	Phase
HIV; Hepatitis C	Drug: dolutegravir; Drug: simeprevir	N/A

Detailed Description

To investigate the potential for drug interactions between simeprevir and dolutegravir, participants will receive each drug alone and the drugs in combination for 7 days. The pharmacokinetics of simeprevir and dolutegravir when given in combination vs. alone will be compared.

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Drug Interaction Potential Between Dolutegravir and Simeprevir in HIV/Hepatitis C Virus (HCV) Seronegative Volunteers
• Study Start Date: Feb 1, 2016
• Actual Primary Completion Date: Oct 1, 2016
• Actual Study Completion Date: Oct 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sequence 1a Sequence 1,2,3: simeprevir only, then dolutegravir only, then both simeprevir and dolutegravir.	Drug: dolutegravir; dolutegravir tablets 50mg, once daily x 7 days.; Drug: simeprevir; simeprevir tablets 150mg, once daily x 7 days.
Experimental: Sequence 1b Sequence 1,3,2: simeprevir only, then both simeprevir and dolutegravir, then dolutegravir only.	Drug: dolutegravir; dolutegravir tablets 50mg, once daily x 7 days.; Drug: simeprevir; simeprevir tablets 150mg, once daily x 7 days.
Experimental: Sequence 2a Sequence 2,1,3: dolutegravir only, then simeprevir only, then both simeprevir and dolutegravir.	Drug: dolutegravir; dolutegravir tablets 50mg, once daily x 7 days.; Drug: simeprevir; simeprevir tablets 150mg, once daily x 7 days.
Experimental: Sequence 2b Sequence 2,3,1: dolutegravir only, then both simeprevir and dolutegravir, then simeprevir only.	Drug: dolutegravir; dolutegravir tablets 50mg, once daily x 7 days.; Drug: simeprevir; simeprevir tablets 150mg, once daily x 7 days.
Experimental: Sequence 3a Sequence 3,1,2: both simeprevir and dolutegravir, then simeprevir only, then dolutegravir only.	Drug: dolutegravir; dolutegravir tablets 50mg, once daily x 7 days.; Drug: simeprevir; simeprevir tablets 150mg, once daily x 7 days.
Experimental: Sequence 3b Sequence 3,2,1: Both simeprevir and dolutegravir, then dolutegravir only, then simeprevir only.	Drug: dolutegravir; dolutegravir tablets 50mg, once daily x 7 days.; Drug: simeprevir; simeprevir tablets 150mg, once daily x 7 days.

Outcome Measures

Primary Outcome Measures

1. Simeprevir AUC Pharmacokinetics [Pre-dose and, 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose on day 7]

   Determine simeprevir area-under-the concentration time curve (AUC) when administered alone and when being co-administered with Dolutegravier.

2. Dolutegravir AUC Pharmacokinetics [Pre-dose and, 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose on day 7]

   Determine Dolutegravir area-under-the concentration time curve (AUC) when administered alone and when co-administered with simeprevir.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Men and women ages 18-60 years

• Absence of HIV-1 and HCV antibodies at screening,

• Ability and willingness to give written informed consent before the first trial-related activity.

Exclusion Criteria:

• Pregnancy

• Breastfeeding

• Active alcohol or drug abuse that, in the opinion of the investigators, would interfere with adherence to study requirements

• Participation in any investigational drug study within 30 days prior to study entry

• Currently active or chronic gastrointestinal, cardiovascular, neurologic, psychiatric, metabolic, renal, hepatic, respiratory, inflammatory, or infectious disease or malignancy requiring pharmacologic treatment, and/or if in the opinion of the investigator, would affect study participation, safety, or integrity of results

• Use of concomitant medication, including investigational, prescription, and over-the-counter products and dietary supplements with the following exceptions: aspirin, acetaminophen, ibuprofen, hormonal oral contraceptives

• Concomitant medications other than those listed above must have been discontinued at least 14 days before study entry

• Currently active dermatitis or urticaria or diagnosis of eczema or psoriasis,

• History of significant drug allergy (i.e., anaphylaxis and/or angioedema)

• Subjects with the following laboratory abnormalities at screening as defined by the 2004 Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events ("DAIDS grading table") and in accordance with the normal ranges of the trial clinical laboratory: serum creatinine grade 1 or greater (≥ 1.1 x upper limit of laboratory normal range (ULN)); hemoglobin grade 1 or greater (≤ 10.9 g/dL); platelet count grade 1 or greater (≤ 124.999 x 109/L); absolute neutrophil count grade 1 or greater (≤ 1.3 x 109/L); aspartate aminotransferase (AST) or alanine aminotransferase (ALT) grade 1 or greater (≥ 1.25 x ULN); total bilirubin grade 1 or greater (≥ 1.1 x ULN), any other laboratory abnormality of grade 2 or above.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado Anschutz Medical Campus	Aurora	Colorado	United States	80045

Sponsors and Collaborators

• University of Colorado, Denver

Investigators

• Principal Investigator: Jennifer J Kiser, PharmD, University of Colorado, Denver

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT02404805
• Other Study ID Numbers: 15-0106; 152252
• First Posted: Apr 1, 2015
• Last Update Posted: Mar 17, 2021
• Last Verified: Feb 1, 2021

• Keywords provided by University of Colorado, Denver: dolutegravir; simeprevir; HIV; HCV
• Additional relevant MeSH terms: Hepatitis C; Hepatitis; Dolutegravir; Simeprevir

Study Results

Participant Flow

Arm/Group Title	Sequence 1a	Sequence 1b	Sequence 2a	Sequence 2b	Sequence 3a	Sequence 3b
Arm/Group Description	Sequence 1,2,3: simeprevir only, then dolutegravir only, then both simeprevir and dolutegravir. dolutegravir: dolutegravir tablets 50mg, once daily x 7 days. simeprevir: simeprevir tablets 150mg, once daily x 7 days.	Sequence 1,3,2: simeprevir only, then both simeprevir and dolutegravir, then dolutegravir only. dolutegravir: dolutegravir tablets 50mg, once daily x 7 days. simeprevir: simeprevir tablets 150mg, once daily x 7 days.	Sequence 2,1,3: dolutegravir only, then simeprevir only, then both simeprevir and dolutegravir. dolutegravir: dolutegravir tablets 50mg, once daily x 7 days. simeprevir: simeprevir tablets 150mg, once daily x 7 days.	Sequence 2,3,1: dolutegravir only, then both simeprevir and dolutegravir, then simeprevir only. dolutegravir: dolutegravir tablets 50mg, once daily x 7 days. simeprevir: simeprevir tablets 150mg, once daily x 7 days.	Sequence 3,1,2: both simeprevir and dolutegravir, then simeprevir only, then dolutegravir only. dolutegravir: dolutegravir tablets 50mg, once daily x 7 days. simeprevir: simeprevir tablets 150mg, once daily x 7 days.	Sequence 3,2,1: Both simeprevir and dolutegravir, then dolutegravir only, then simeprevir only. dolutegravir: dolutegravir tablets 50mg, once daily x 7 days. simeprevir: simeprevir tablets 150mg, once daily x 7 days.
Period Title: Overall Study
STARTED	5	3	5	5	3	4
COMPLETED	4	3	5	5	3	4
NOT COMPLETED	1	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Sequence 1a	Sequence 1b	Sequence 2a	Sequence 2b	Sequence 3a	Sequence 3b	Total
Arm/Group Description	Sequence 1,2,3: simeprevir only, then dolutegravir only, then both simeprevir and dolutegravir. dolutegravir: dolutegravir tablets 50mg, once daily x 7 days. simeprevir: simeprevir tablets 150mg, once daily x 7 days.	Sequence 1,3,2: simeprevir only, then both simeprevir and dolutegravir, then dolutegravir only. dolutegravir: dolutegravir tablets 50mg, once daily x 7 days. simeprevir: simeprevir tablets 150mg, once daily x 7 days.	Sequence 2,1,3: dolutegravir only, then simeprevir only, then both simeprevir and dolutegravir. dolutegravir: dolutegravir tablets 50mg, once daily x 7 days. simeprevir: simeprevir tablets 150mg, once daily x 7 days.	Sequence 2,3,1: dolutegravir only, then both simeprevir and dolutegravir, then simeprevir only. dolutegravir: dolutegravir tablets 50mg, once daily x 7 days. simeprevir: simeprevir tablets 150mg, once daily x 7 days.	Sequence 3,1,2: both simeprevir and dolutegravir, then simeprevir only, then dolutegravir only. dolutegravir: dolutegravir tablets 50mg, once daily x 7 days. simeprevir: simeprevir tablets 150mg, once daily x 7 days.	Sequence 3,2,1: Both simeprevir and dolutegravir, then dolutegravir only, then simeprevir only. dolutegravir: dolutegravir tablets 50mg, once daily x 7 days. simeprevir: simeprevir tablets 150mg, once daily x 7 days.	Total of all reporting groups
Overall Participants	5	3	5	5	3	4	25
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	5 100%	3 100%	5 100%	5 100%	3 100%	4 100%	25 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	30.8	34.3	36.4	35.6	35.7	33.8	34.3
Sex: Female, Male (Count of Participants)
Female	3 60%	3 100%	3 60%	3 60%	2 66.7%	2 50%	16 64%
Male	2 40%	0 0%	2 40%	2 40%	1 33.3%	2 50%	9 36%
Race/Ethnicity, Customized (Count of Participants)
CAUCASIAN	5 100%	3 100%	4 80%	4 80%	2 66.7%	4 100%	22 88%
HISPANIC	0 0%	0 0%	1 20%	1 20%	1 33.3%	0 0%	3 12%
Region of Enrollment (participants) [Number]
United States	5 100%	3 100%	5 100%	5 100%	3 100%	4 100%	25 100%

Outcome Measures

1. Primary Outcome

Title	Simeprevir AUC Pharmacokinetics
Description	Determine simeprevir area-under-the concentration time curve (AUC) when administered alone and when being co-administered with Dolutegravier.
Time Frame	Pre-dose and, 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose on day 7

Outcome Measure Data

Analysis Population Description

Only arms that included Simeprevir administration are included.

Arm/Group Title	Simeprevir Administered Alone	Simeprevir and Dolutegravier Co-administered
Arm/Group Description	simeprevir: simeprevir tablets 150mg, once daily x 7 days.	Dolutegravir and simeprevir together: dolutegravir tablets 50mg, once daily and simeprevir tablets 150mg, once daily x 7 days.
Measure Participants	24	24
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	30946 (80)	30333 (82)

2. Primary Outcome

Title	Dolutegravir AUC Pharmacokinetics
Description	Determine Dolutegravir area-under-the concentration time curve (AUC) when administered alone and when co-administered with simeprevir.
Time Frame	Pre-dose and, 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose on day 7

Outcome Measure Data

Analysis Population Description

Only arms that included Dolutegravir administration are included.

Arm/Group Title	Dolutegravir Administered Alone	Simeprevir and Dolutegravier Co-administered
Arm/Group Description	dolutegravir: dolutegravir tablets 50mg, once daily x 7 days.	Dolutegravir and simeprevir co-administered: dolutegravir tablets 50mg, once daily and simeprevir tablets 150mg, once daily x 7 da
Measure Participants	24	24
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	68186 (30)	78433 (24)

Adverse Events

Time Frame	Time of consenting to study exit (Phone follow up 7 days after final intensive PK visit, max 3 months)
Adverse Event Reporting Description	AEs were graded per the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0, November, 2014. Available: http://rsc.tech-res.com/safetyandpharmacovigilance/.
Arm/Group Title	Simeprevir Only		Dolutegravir Only		Dolutegravir and Simeprevir Co-administered:
Arm/Group Description	Simeprevir tablets 150mg, once daily x 7 days.		Dolutegravir tablets 50mg, once daily x 7 days.		Dolutegravir and simeprevir co-administered: dolutegravir tablets 50mg, once daily, and simeprevir tablets 150mg, once daily, x 7 days
All Cause Mortality
	Simeprevir Only		Dolutegravir Only		Dolutegravir and Simeprevir Co-administered:
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/24 (0%)		0/24 (0%)
Serious Adverse Events
	Simeprevir Only		Dolutegravir Only		Dolutegravir and Simeprevir Co-administered:
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/24 (0%)		0/24 (0%)
Other (Not Including Serious) Adverse Events
	Simeprevir Only		Dolutegravir Only		Dolutegravir and Simeprevir Co-administered:
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/25 (16%)		7/24 (29.2%)		10/24 (41.7%)
Gastrointestinal disorders
Gastrointestinal issues (stomach pain, gas, vomiting, nausea, diarrhea)	2/25 (8%)	2	4/24 (16.7%)	4	3/24 (12.5%)	3
General disorders
Fatigue	0/25 (0%)	0	0/24 (0%)	0	2/24 (8.3%)	2
Abnormal Labs	1/25 (4%)	1	5/24 (20.8%)	7	7/24 (29.2%)	7
Nervous system disorders
Headache	2/25 (8%)	2	3/24 (12.5%)	3	3/24 (12.5%)	3
Skin and subcutaneous tissue disorders
Photosensitivity	0/25 (0%)	0	0/24 (0%)	0	2/24 (8.3%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.