The Raltegravir and Ribavirin Pharmacokinetics (PK) Study

• Sponsor: Imperial College London (Other)
• Overall Status: Completed
• CT.gov ID: NCT00982553
• Collaborator: (none)
• Enrollment: 14
• Location: 1
• Arms: 3
• Duration (Months): 3
• Patients Per Site Per Month: 4.7

Study Details

Study Description

Brief Summary

The purpose of this study is to look at levels of both a new anti-HIV drug called raltegravir and an existing anti-hepatitis C drug called ribavirin to see if they affect the blood levels of each other when given separately and together. This is a phase I, open-label, prospective, three phase, pharmacokinetic study.

Condition or Disease	Intervention/Treatment	Phase
HIV Infections	Drug: Ribavirin; Drug: Raltegravir	Phase 1

Detailed Description

Phase I (study day 1 - 14):

• 14 healthy volunteers with a documented negative HIV-1 antibody test during screening procedures will be enrolled.

• On day 1, fasted subjects will be administered ribavirin 800 mg without food (witnessed dosing). This will be followed be a 12 hour detailed pharmacokinetic assessment; blood sampling drawn at 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8 and 12 hours.

• This will be followed by a wash-out period.

• As steady state pharmacokinetics of ribavirin are not reached for several weeks, single dosing pharmacokinetics will be assessed in this study

Phase II (study days 15 - 19):

• On day 15, subjects will commence raltegravir 400 mg twice daily. Subjects will attend for safety visits and witnessed dosing during this phase.

• Day 19 - after 4 days of dosing when steady state pharmacokinetics has been reached, subjects will attend for a 12 hour detailed pharmacokinetic visit where following witnessed administration of raltegravir 400 mg without food, blood sampling will be drawn at 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post dose for the assessment of raltegravir plasma exposure.

Phase III (study day 20):

• Subjects will be administered raltegravir 400 mg and ribavirin 800 mg without food. This will be followed by a 12 hour detailed pharmacokinetic assessment with blood sampling drawn at 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, and 12 hours.

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Prospective, Open-label, Three Phase Pharmacokinetic Study, to Assess the Pharmacokinetic Profile and Safety of Raltegravir 400 mg Twice Daily and Ribavirin 800 mg Once Daily, When Dosed Separately and Together in Healthy Volunteers
• Study Start Date: Sep 1, 2009
• Actual Primary Completion Date: Nov 1, 2009
• Actual Study Completion Date: Dec 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1_ribavirin Treatment with Single dose ribavirin (800 mg) administered on day 1	Drug: Ribavirin; 800mg once daily; Other Names: Copegus
Experimental: Phase2_raltegravir Treatment with Raltegravir (400 mg twice daily) administered from days 15-19	Drug: Raltegravir; 400mg twice daily
Experimental: Phase3_ribavirin+raltegravir Treatment with Ribavirin (800 mg) and Raltegravir (400 mg) administered day 20	Drug: Ribavirin; 800mg once daily; Other Names: Copegus ; Drug: Raltegravir; 400mg twice daily

Outcome Measures

Primary Outcome Measures

1. Ribavirin Maximum Plasma Concentration [Day 20]

   Pharmacokinetic analyses of blood samples

2. Raltegravir Maximum Plasma Concentration [Day 20]

3. Ribavirin Minimum Plasma Concentration [Day 20]

   Ribavirin minimum plasma concentration by pharmacokinetic analyses

4. Raltegravir Minimum Plasma Concentrations [Day 20]

   Raltegravir minimum plasma concentrations by pharmacokinetic analyses

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• The ability to understand and sign a written informed consent form, prior to participation in any screening procedures and must be willing to comply with all study requirements.

• Male or non-pregnant, non-lactating female.

• Between 18 to 60 years, inclusive.

• Subjects in good health upon medical history, physical exam, and laboratory testing and body mass index below 32.

• Female subjects who are heterosexually active and of childbearing potential (i.e., not surgically sterile or at least two years post menopausal) must practice contraception as follows from screening through completion of the study including 180 days following last dose of study drug:

• barrier contraceptives (condom, diaphragm with spermicide)

• oral combined contraceptive pill, implant or injectable hormonal contraceptive PLUS a barrier contraceptive

• Intrauterine device (IUD) or intrauterine system (IUS) PLUS a barrier contraceptive (or a partner who has been vasectomized for at least six months).

• Female subjects of childbearing potential must have a negative urine pregnancy test.

• Male subjects who are heterosexually active must use two forms of barrier contraception (e.g., condom with spermicide) during heterosexual intercourse, from screening through completion of the study including 180 days following last dose of study drug.

• Have no serologic evidence of HIV infection.

• Have no serologic evidence of active hepatitis B virus infection evidenced by negative hepatitis B surface antigen and no serologic evidence of hepatitis C virus infection through antibody testing.

• Have screening laboratory results (haematology, chemistry) that fall within the normal range of the central laboratory's reference ranges unless the results have been determined by the Investigator to have no clinical significance.

Exclusion Criteria:

• Any serious or active medical or psychiatric illness which, in the opinion of the Investigator, would interfere with subject treatment, assessment, or compliance with the protocol. This would include any active clinically significant renal, cardiac, hepatic, pulmonary, vascular, metabolic (thyroid disorders, adrenal disease), immunodeficiency disorders, active infection, or malignancy.

• Have a body mass index (BMI) greater than 32

• Previous participation in an investigational trial involving administration of any investigational compound within 1 month prior to the study screening.

• Clinically relevant alcohol or drug use (positive screening drug screen) or history of alcohol or drug use considered by the Investigator to be sufficient to hinder compliance with treatment, follow-up procedures or evaluation of adverse events. Smoking is permitted, but tobacco intake should remain consistent throughout the study.

• Any medication taken listed in Prior and Concomitant Medication section including over-the-counter medications and herbal products within 21 days of commencing study drug dosing with the exception of vitamins and/or paracetamol and/or hormonal contraceptives including the combined oral contraceptive pill, Depo-Provera and the Mirena intrauterine system. When a concomitant medication is necessary, this will be reviewed by the Investigator and if not contraindicated, may be continued at the same dose and frequency during the study period.

• History of drug sensitivity or drug allergy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Imperial College Healthcare NHS Trust	London		United Kingdom	W2 1NY

Sponsors and Collaborators

• Imperial College London

Investigators

• Principal Investigator: Alan Winston, MB BH, Imperial College London

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Imperial College London
• ClinicalTrials.gov Identifier: NCT00982553
• Other Study ID Numbers: 2009-010005-36; 2009-010005-36
• First Posted: Sep 23, 2009
• Last Update Posted: Oct 11, 2019
• Last Verified: Sep 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Imperial College London: Healthy Volunteers
• Additional relevant MeSH terms: HIV Infections; Ribavirin; Raltegravir Potassium

Study Results

Participant Flow

Recruitment Details	Recruitment was between 24/09/2009 and 29/10/2009. 14 subjects were enrolled. The study took place at a specialist research unit at an National Health Service (NHS) hospital.
Pre-assignment Detail	Subjects were healthy volunteers. There was a 21 day washout for any prescribed and 7 days for over the counter medication before enrolment. The subjects were permitted to take paracetamol during the study but all others were excluded for the duration of the trial.

Arm/Group Title	All Subjects
Arm/Group Description	All subjects received the same study therapy as follows: Day 1 Ribavirin single dose 800 mg oral followed by intensive PK monitoring. Day 2 - 14 washout phase Day 15 - 18 raltegravir 400 mg twice daily followed by by intensive PK monitoring on day 18. Day 19 raltegravir 400 mg plus ribavirin 800 mg by intensive PK monitoring.
Period Title: Phase1
STARTED	14
COMPLETED	14
NOT COMPLETED	0
Period Title: Phase1
STARTED	14
COMPLETED	14
NOT COMPLETED	0
Period Title: Phase1
STARTED	14
COMPLETED	14
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	All Subjects
Arm/Group Description	All subjects received the same study therapy as follows: Day 1 Ribavirin single dose 800 mg oral followed by intensive PK monitoring. Day 2 - 14 washout phase Day 15 - 18 raltegravir 400 mg twice daily followed by by intensive PK monitoring on day 18. Day 19 raltegravir 400 mg plus ribavirin 800 mg by intensive PK monitoring.
Overall Participants	14
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	14 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	35 (10)
Sex: Female, Male (Count of Participants)
Female	4 28.6%
Male	10 71.4%
Region of Enrollment (participants) [Number]
United Kingdom	14 100%

Outcome Measures

1. Primary Outcome

Title	Ribavirin Maximum Plasma Concentration
Description	Pharmacokinetic analyses of blood samples
Time Frame	Day 20

Outcome Measure Data

Analysis Population Description

Per protocol

Arm/Group Title	Phase1_ribavirin	Phase3_ribovarin and Raltegravir
Arm/Group Description	Single dose ribavirin 800mg administered on day 1	Single dose ribavirin 800mg and raltegravir 400mg at day 20
Measure Participants	14	14
Geometric Mean (95% Confidence Interval) [ng/mL]	630.09	496.71

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase1_ribavirin, Phase3_ribovarin and Raltegravir
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratios
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 95%; 0.62 to 1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Raltegravir Maximum Plasma Concentration
Time Frame	Day 20

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase2_Raltegravir	Phase3_ribovarin and Raltegravir
Arm/Group Description	Raltegravir 400 mg twice daily on day 15-19	On day 20 single dose of both ribavirin and raltegravir administered together
Measure Participants	14	14
Geometric Mean (95% Confidence Interval) [ng/mL]	2227.41	2591.19

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase1_ribavirin, Phase3_ribovarin and Raltegravir
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratios
	Estimated Value	1.16
	Confidence Interval	(2-Sided) 95%; 0.73 to 1.86
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Ribavirin Minimum Plasma Concentration
Description	Ribavirin minimum plasma concentration by pharmacokinetic analyses
Time Frame	Day 20

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase1_Ribavirin	Phase3_ribovarin and Raltegravir
Arm/Group Description	Single dose ribavirin 800mg administered on day 1	Onn day 20 single dose of both ribavirin and raltegravir administered together
Measure Participants	14	14
Geometric Mean (95% Confidence Interval) [ng/mL]	184.71	186.98

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase1_ribavirin, Phase3_ribovarin and Raltegravir
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratios
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; 0.87 to 1.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Raltegravir Minimum Plasma Concentrations
Description	Raltegravir minimum plasma concentrations by pharmacokinetic analyses
Time Frame	Day 20

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase2_Raltegravir	Phase3_ribovarin and Raltegravir
Arm/Group Description	Raltegravir 400 mg twice daily on day 15-19	On day 20 single dose of both ribavirin and raltegravir administered together
Measure Participants	14	14
Geometric Mean (95% Confidence Interval) [ng/mL]	83.97	68.91

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase1_ribavirin, Phase3_ribovarin and Raltegravir
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratios
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.36 to 1.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Arm/Group Title	All Subjects
Arm/Group Description	All subjects received the same study therapy as follows: Day 1 Ribavirin single dose 800 mg oral followed by intensive PK monitoring. Day 2 - 14 washout phase Day 15 - 18 raltegravir 400 mg twice daily followed by by intensive PK monitoring on day 18. Day 19 raltegravir 400 mg plus ribavirin 800 mg by intensive PK monitoring.
All Cause Mortality
	All Subjects
	Affected / at Risk (%)	# Events
Total	0/14 (0%)
Serious Adverse Events
	All Subjects
	Affected / at Risk (%)	# Events
Total	0/14 (0%)
Other (Not Including Serious) Adverse Events
	All Subjects
	Affected / at Risk (%)	# Events
Total	0/14 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.