RALDAR: Dual Therapy With Raltegravir and Darunavir/Ritonavir in HIV Infected Patients.

• Sponsor: Hospital Clinic of Barcelona (Other)
• Overall Status: Completed
• CT.gov ID: NCT01258374
• Collaborator: (none)
• Enrollment: 15
• Location: 1
• Duration (Months): 19
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

While 3-drug regimens remain standard of care, concerns exist regarding the safety of multi-drug regimens taken for a lifetime. Problems with nucleoside analogue therapy prompted successful trials with ritonavir (RTV) boosted PI monotherapy, however long term safety and efficacy of such regimens remains unknown. Clinical trials have shown Raltegravir (RAL) to have potent activity when patients have few active background drugs; it has a superior lipid profile compared with EFV and LPV/RTV. Darunavir/r (DRV) is a potent, well tolerated PI with few GI side effects and lipid disturbances and with a high genetic barrier. The investigators hypothesized that RAL/DRV would be a well tolerated and effective regimen for those patients who are failing nucleoside reverse transcriptase inhibitors based regimens, due to poor tolerability or resistance. The investigators also would like to explore the plasma pharmacokinetics of Raltegravir combined with Darunavir in a sub-group of 12 HIV-infected patients.

Condition or Disease	Intervention/Treatment	Phase
Integrase Inhibitors, HIV; HIV PROTEASE INHIB	Drug: Raltegravir; Drug: Darunavir

Detailed Description

Hypothesis

• NRTI-sparing regimens are attractive options to avoid NRTI-associated toxicity and to provide a full active regimen in patients with some extent of NRTI resistance.

• Raltegravir (RAL) and Darunavir (DRV) are potent "third drugs" and they provide a synergistic inhibition of 2 different steps in HIV replication.

• DRV has a high genetic barrier, and could be an excellent accompanying drug for Raltegravir, providing a potent, safe and well tolerated dual therapy to patients who are failing NNRTI based treatments.

Objectives:

• To describe the safety, tolerability and efficacy of the combination of Raltegravir and Darunavir after 24 weeks of follow up in HIV infected patients failing a NRTI based regimen.

• To describe plasma pharmacokinetics of Raltegravir when combined with Darunavir 800mg QD in HIV-infected patients.

Study Design

• Study Type: Observational
• Actual Enrollment: 15 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Dual Therapy With Raltegravir 400 mg BID and Darunavir/Ritonavir 800/100 mg QD in HIV Infected Patients Failing to Nucleoside Reverse Transcriptase Inhibitors Based Regimens
• Study Start Date: May 1, 2010
• Actual Primary Completion Date: May 1, 2011
• Actual Study Completion Date: Dec 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Single arm with dual therapy Dual therapy RAL 400 mg bid + DRV/r 800/100 mg QD	Drug: Raltegravir; Raltegravir, 400 mg bid; Other Names: Isentress ; Drug: Darunavir; Darunavir, 800 mg QD + ritonavir 100 mg QD; Other Names: Prezista, Norvir.

Outcome Measures

Primary Outcome Measures

1. Geometric Mean of C-Trough, of Raltegravir (RAL) at a Dose of 400 mg Twice a Day Plus Darunavir/Ritonavir (DRV/RTV) at a Dose of 800/100 mg Once a Day in HIV-1-infected Patients Were Mesured After 15 Days of Therapy. [After at least 15 days on therapy, patients were admitted for a 24-hour PK study. The moorning dose of RAL adn DRV/r was administered in the clinic with. Blood samples were drawn immediatly before breakfast and 0.5, 1,2,3,4,6,8,12 and 24 hours afterward.]

   Geometric mean of C-Trough, of raltegravir (RAL) at a dose of 400 mg twice a day plus darunavir/ritonavir (DRV/RTV) at a dose of 800/100 mg once a day in HIV-1-infected patients were mesured after 15 days of therapy.The treating physician chose an NRTI-sparing regimen because of toxicity or resistance mutations to NRTIs, which included DRV/RTV 800/100 mg once daily plus RAL 400 mg twice daily. All patients were RAL and DRV naive and had no evidence of protease inhibitor mutations.

2. Geometric Mean of AUC, of Raltegravir (RAL) at a Dose of 400 mg Twice a Day Plus Darunavir/Ritonavir (DRV/RTV) at a Dose of 800/100 mg Once a Day in HIV-1-infected Patients Were Mesured After 15 Days of Therapy. [After at least 15 days on therapy, patients were admitted for a 24-hour PK study. The moorning dose of RAL adn DRV/r was administered in the clinic with. Blood samples were drawn immediatly before breakfast and 0.5, 1,2,3,4,6,8,12 and 24 hours afterward.]

   Geometric mean of AUC0 of raltegravir (RAL) at a dose of 400 mg twice a day plus darunavir/ritonavir (DRV/RTV) at a dose of 800/100 mg once a day in HIV-1-infected patients were mesured after 15 days of therapy. The treating physician chose an NRTI-Geometric mean of C-Trough, of raltegravir (RAL) at a dose of 400 mg twice a day plus darunavir/ritonavir (DRV/RTV) at a dose of 800/100 mg once a day in HIV-1-infected patients were mesured after 15 days of therapy.sparing regimen because of toxicity or resistance mutations to NRTIs, which included DRV/RTV 800/100 mg once daily plus RAL 400 mg twice daily. All patients were RAL and DRV naive and had no evidence of protease inhibitor mutations.

3. Geometric Mean of C-max, of Raltegravir (RAL) at a Dose of 400 mg Twice a Day Plus Darunavir/Ritonavir (DRV/RTV) at a Dose of 800/100 mg Once a Day in HIV-1-infected Patients Were Mesured After 15 Days of Therapy. [After at least 15 days on therapy, patients were admitted for a 24-hour PK study. The moorning dose of RAL adn DRV/r was administered in the clinic with. Blood samples were drawn immediatly before breakfast and 0.5, 1,2,3,4,6,8,12 and 24 hours afterward.]

   Geometric mean of C-max of raltegravir (RAL) at a dose of 400 mg twice a day plus darunavir/ritonavir (DRV/RTV) at a dose of 800/100 mg once a day in HIV-1-infected patients were mesured after 15 days of therapy. The treating physician chose an NRTI-Geometric mean of C-max, of raltegravir (RAL) at a dose of 400 mg twice a day plus darunavir/ritonavir (DRV/RTV) at a dose of 800/100 mg once a day in HIV-1-infected patients were mesured after 15 days of therapy.sparing regimen because of toxicity or resistance mutations to NRTIs, which included DRV/RTV 800/100 mg once daily plus RAL 400 mg twice daily. All patients were RAL and DRV naive and had no evidence of protease inhibitor mutations.

4. Geometric Mean of t1/2, of Raltegravir (RAL) at a Dose of 400 mg Twice a Day Plus Darunavir/Ritonavir (DRV/RTV) at a Dose of 800/100 mg Once a Day in HIV-1-infected Patients Were Mesured After 15 Days of Therapy [After at least 15 days on therapy, patients were admitted for a 24-hour PK study. The moorning dose of RAL adn DRV/r was administered in the clinic with. Blood samples were drawn immediatly before breakfast and 0.5, 1,2,3,4,6,8,12 and 24 hours afterward.]

   Geometric mean of t1/2 of raltegravir (RAL) at a dose of 400 mg twice a day plus darunavir/ritonavir (DRV/RTV) at a dose of 800/100 mg once a day in HIV-1-infected patients were mesured after 15 days of therapy. The treating physician chose an NRTI-Geometric mean of t1/2, of raltegravir (RAL) at a dose of 400 mg twice a day plus darunavir/ritonavir (DRV/RTV) at a dose of 800/100 mg once a day in HIV-1-infected patients were mesured after 15 days of therapy.sparing regimen because of toxicity or resistance mutations to NRTIs, which included DRV/RTV 800/100 mg once daily plus RAL 400 mg twice daily. All patients were RAL and DRV naive and had no evidence of protease inhibitor mutations.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Documented HIV infection

• Naïve to Raltegravir.

• CD4 cell count above 200 cell/mm3.

• No history of failure to PI containing regimens.

• No evidence of PI mutations (IAS-mutation list) by genotype test.

• Failing to a NRTI based regimen.

• The treating physician decides a NRTI sparing regimen which includes DRV/r 800/100 mg QD plus Raltegravir 400 mg BID.

• Signed informed consent form

• In opinion of the investigator, the patient should be considered clinically stable and could follow regular visits as scheduled per protocol.

Exclusion Criteria:

• Patients receiving drugs considered contraindicated to Raltegravir and DRV/r. Contraindicated drugs are: rifampin, fenitoin, phenobarbital in the case of raltegravir. Pravastatin, astemizole, sildenafil, are contraindicated in combination with DRV/r.

• Pregnancy

• Documented PI mutations

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital Clinic	Barcelona		Spain	08036

Sponsors and Collaborators

• Hospital Clinic of Barcelona

Investigators

• Principal Investigator: Josep Mallolas, MD, PhD, Hospital Clinic of Barcelona

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Josep Mallolas Masferrer, MD, PhD, Hospital Clinic of Barcelona
• ClinicalTrials.gov Identifier: NCT01258374
• Other Study ID Numbers: RALDAR-HCB
• First Posted: Dec 13, 2010
• Last Update Posted: Sep 27, 2019
• Last Verified: Aug 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Josep Mallolas Masferrer, MD, PhD, Hospital Clinic of Barcelona: Pharmacokinetics, raltegravir, darunavir, NRTI sparing regimen
• Additional relevant MeSH terms: Raltegravir Potassium; Darunavir

Study Results

Participant Flow

Pre-assignment Detail	The treating physician chose an NRTI-sparing regimen because of toxicity or resistance mutations to NRTIs, which included DRV/RTV 800/100 mg once daily plus RAL 400 mg twice daily. 15 patients were screenend and all of them were included and finish the study

Arm/Group Title	Single Arm With Dual Therapy
Arm/Group Description	Dual therapy RAL 400 mg bid + DRV/r 800/100 mg QD Raltegravir: Raltegravir, 400 mg bid Darunavir: Darunavir, 800 mg QD + ritonavir 100 mg QD
Period Title: Overall Study
STARTED	15
COMPLETED	15
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Single Arm With Dual Therapy
Arm/Group Description	Dual therapy RAL 400 mg bid + DRV/r 800/100 mg QD Raltegravir: Raltegravir, 400 mg bid Darunavir: Darunavir, 800 mg QD + ritonavir 100 mg QD
Overall Participants	15
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	44
Sex: Female, Male (Count of Participants)
Female	2 13.3%
Male	13 86.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	11 73.3%
More than one race	0 0%
Unknown or Not Reported	4 26.7%
Region of Enrollment (participants) [Number]
Spain	15 100%

Outcome Measures

1. Primary Outcome

Title	Geometric Mean of C-Trough, of Raltegravir (RAL) at a Dose of 400 mg Twice a Day Plus Darunavir/Ritonavir (DRV/RTV) at a Dose of 800/100 mg Once a Day in HIV-1-infected Patients Were Mesured After 15 Days of Therapy.
Description	Geometric mean of C-Trough, of raltegravir (RAL) at a dose of 400 mg twice a day plus darunavir/ritonavir (DRV/RTV) at a dose of 800/100 mg once a day in HIV-1-infected patients were mesured after 15 days of therapy.The treating physician chose an NRTI-sparing regimen because of toxicity or resistance mutations to NRTIs, which included DRV/RTV 800/100 mg once daily plus RAL 400 mg twice daily. All patients were RAL and DRV naive and had no evidence of protease inhibitor mutations.
Time Frame	After at least 15 days on therapy, patients were admitted for a 24-hour PK study. The moorning dose of RAL adn DRV/r was administered in the clinic with. Blood samples were drawn immediatly before breakfast and 0.5, 1,2,3,4,6,8,12 and 24 hours afterward.

Outcome Measure Data

Analysis Population Description

HIV-1-infected patients, receiving a NRTI-based regimen, naive to RAL, with no evidence of PI mutations by genotype test, and signed informed consent forms. 15 patients ere screened and enrolled

Arm/Group Title	Single Arm With Dual Therapy
Arm/Group Description	Fifteen patients were screened and enrolled, and all of them completed the study procedures. The treating physician chose an NRTI-sparing regimen because of toxicity or resistance mutations to NRTIs, which included DRV/RTV 800/100 mg once daily plus RAL 400 mg twice daily. Inclusion criteria were HIV-1-infected patients, receiving a NRTI-based regimen, naive to RAL, with no evidence of PI mutations by genotype test, and signed informed consent forms. All doses of RAL were administered in the morning and evening, orally with food (light meal). Patients were admitted to the hospital in the morning on day 15 and stayed for 12 hours after the last administration of RAL. The morning dose of RAL and DRV/ RTV was administered in the clinic with a light breakfast (200 mL of whole milk and a ham and cheese sandwich), and blood samples were drawn immediately before breakfast and 0.5 1, 2, 3, 4, 6, 8, 12, and 24 hours afterward
Measure Participants	15
C trough Darunavir	1330
C trough Raltegravir	40
C trough Ritonavir	90

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Single Arm With Dual Therapy
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments	The PK paramaters reported as geometric means, were calculated using noncompartmental modelinf techniques (WinNolin; Pharsight Corporation, Mountain View, CA)
	Method	Noncompartmental modeling techniques
	Comments
Other Statistical Analysis		The pharmacokinetic parameters calculated for DRV, RTV and RAL were trough plasma concentration (C trough), defined as the concentration at 24 or 12 h after observed dose, the maximum observed plasma concentration (C max), the area under the plasma concentration-time curve from 0 to 24 H (AUC 0-24) or 0 to 12 h (AUC 0-12) and the elimination half-life (t1/2). AUC and t1/2 were calculated using non using noncompartmental modeling techniques (WinNolin; Pharsight Corporation, Mountain View, CA). All of these PK parameters are reported as geometric means.

2. Primary Outcome

Title	Geometric Mean of AUC, of Raltegravir (RAL) at a Dose of 400 mg Twice a Day Plus Darunavir/Ritonavir (DRV/RTV) at a Dose of 800/100 mg Once a Day in HIV-1-infected Patients Were Mesured After 15 Days of Therapy.
Description	Geometric mean of AUC0 of raltegravir (RAL) at a dose of 400 mg twice a day plus darunavir/ritonavir (DRV/RTV) at a dose of 800/100 mg once a day in HIV-1-infected patients were mesured after 15 days of therapy. The treating physician chose an NRTI-Geometric mean of C-Trough, of raltegravir (RAL) at a dose of 400 mg twice a day plus darunavir/ritonavir (DRV/RTV) at a dose of 800/100 mg once a day in HIV-1-infected patients were mesured after 15 days of therapy.sparing regimen because of toxicity or resistance mutations to NRTIs, which included DRV/RTV 800/100 mg once daily plus RAL 400 mg twice daily. All patients were RAL and DRV naive and had no evidence of protease inhibitor mutations.
Time Frame	After at least 15 days on therapy, patients were admitted for a 24-hour PK study. The moorning dose of RAL adn DRV/r was administered in the clinic with. Blood samples were drawn immediatly before breakfast and 0.5, 1,2,3,4,6,8,12 and 24 hours afterward.

Outcome Measure Data

Analysis Population Description

HIV-1-infected patients, receiving a NRTI-based regimen, naive to RAL, with no evidence of PI mutations by genotype test, and signed informed consent forms. 15 patients ere screened and enrolled

Arm/Group Title	Single Arm With Dual Therapy
Arm/Group Description	Dual therapy RAL 400 mg bid + DRV/r 800/100 mg QD Raltegravir: Raltegravir, 400 mg bid Darunavir: Darunavir, 800 mg QD + ritonavir 100 mg QD
Measure Participants	15
AUC Raltegravir	3050
AUC Darunavir	68,730
AUC Ritonavir	5470

3. Primary Outcome

Title	Geometric Mean of C-max, of Raltegravir (RAL) at a Dose of 400 mg Twice a Day Plus Darunavir/Ritonavir (DRV/RTV) at a Dose of 800/100 mg Once a Day in HIV-1-infected Patients Were Mesured After 15 Days of Therapy.
Description	Geometric mean of C-max of raltegravir (RAL) at a dose of 400 mg twice a day plus darunavir/ritonavir (DRV/RTV) at a dose of 800/100 mg once a day in HIV-1-infected patients were mesured after 15 days of therapy. The treating physician chose an NRTI-Geometric mean of C-max, of raltegravir (RAL) at a dose of 400 mg twice a day plus darunavir/ritonavir (DRV/RTV) at a dose of 800/100 mg once a day in HIV-1-infected patients were mesured after 15 days of therapy.sparing regimen because of toxicity or resistance mutations to NRTIs, which included DRV/RTV 800/100 mg once daily plus RAL 400 mg twice daily. All patients were RAL and DRV naive and had no evidence of protease inhibitor mutations.
Time Frame	After at least 15 days on therapy, patients were admitted for a 24-hour PK study. The moorning dose of RAL adn DRV/r was administered in the clinic with. Blood samples were drawn immediatly before breakfast and 0.5, 1,2,3,4,6,8,12 and 24 hours afterward.

Outcome Measure Data

Analysis Population Description

HIV-1-infected patients, receiving a NRTI-based regimen, naive to RAL, with no evidence of PI mutations by genotype test, and signed informed consent forms. 15 patients ere screened and enrolled

Arm/Group Title	Single Arm With Dual Therapy
Arm/Group Description	Dual therapy RAL 400 mg bid + DRV/r 800/100 mg QD Raltegravir: Raltegravir, 400 mg bid Darunavir: Darunavir, 800 mg QD + ritonavir 100 mg QD
Measure Participants	15
Cmax Darunavir	7630
Cmax Raltegravir	970
Cmax Ritonavir	490

4. Primary Outcome

Title	Geometric Mean of t1/2, of Raltegravir (RAL) at a Dose of 400 mg Twice a Day Plus Darunavir/Ritonavir (DRV/RTV) at a Dose of 800/100 mg Once a Day in HIV-1-infected Patients Were Mesured After 15 Days of Therapy
Description	Geometric mean of t1/2 of raltegravir (RAL) at a dose of 400 mg twice a day plus darunavir/ritonavir (DRV/RTV) at a dose of 800/100 mg once a day in HIV-1-infected patients were mesured after 15 days of therapy. The treating physician chose an NRTI-Geometric mean of t1/2, of raltegravir (RAL) at a dose of 400 mg twice a day plus darunavir/ritonavir (DRV/RTV) at a dose of 800/100 mg once a day in HIV-1-infected patients were mesured after 15 days of therapy.sparing regimen because of toxicity or resistance mutations to NRTIs, which included DRV/RTV 800/100 mg once daily plus RAL 400 mg twice daily. All patients were RAL and DRV naive and had no evidence of protease inhibitor mutations.
Time Frame	After at least 15 days on therapy, patients were admitted for a 24-hour PK study. The moorning dose of RAL adn DRV/r was administered in the clinic with. Blood samples were drawn immediatly before breakfast and 0.5, 1,2,3,4,6,8,12 and 24 hours afterward.

Outcome Measure Data

Analysis Population Description

HIV-1-infected patients, receiving a NRTI-based regimen, naive to RAL, with no evidence of PI mutations by genotype test, and signed informed consent forms. 15 patients ere screened and enrolled

Arm/Group Title	Single Arm With Dual Therapy
Arm/Group Description	Dual therapy RAL 400 mg bid + DRV/r 800/100 mg QD Raltegravir: Raltegravir, 400 mg bid Darunavir: Darunavir, 800 mg QD + ritonavir 100 mg QD
Measure Participants	15
t1/2 Darunavir	10.91
t1/2 Raltegravir	2.68
t1/2 Ritonavir	9.48

Adverse Events

Time Frame	24 weeks
Arm/Group Title	Single Arm With Dual Therapy
Arm/Group Description	Dual therapy RAL 400 mg bid + DRV/r 800/100 mg QD Raltegravir: Raltegravir, 400 mg bid Darunavir: Darunavir, 800 mg QD + ritonavir 100 mg QD
All Cause Mortality
	Single Arm With Dual Therapy
	Affected / at Risk (%)	# Events
Total	0/15 (0%)
Serious Adverse Events
	Single Arm With Dual Therapy
	Affected / at Risk (%)	# Events
Total	0/15 (0%)
Other (Not Including Serious) Adverse Events
	Single Arm With Dual Therapy
	Affected / at Risk (%)	# Events
Total	0/15 (0%)

Limitations/Caveats

The main limitation of our study is that it is a single-arm PK study and, thus, the effect of the introduction or withdrawal of one drug over the other cannot be compared.

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.