Enfuvirtide/Current Protease Inhibitor Switch to PREZISTA (Darunavir)/Ritonavir + TMC125 in HIV Patients With Enfuvirtide Side Effects.

• Sponsor: Tibotec, Inc (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00460746
• Collaborator: Tibotec Therapeutics, a Division of Ortho Biotech Products, L.P., USA (Industry)
• Enrollment: 10
• Location: 1
• Arm: 1
• Duration (Months): 17.1
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The purpose of this study is to examine the safety, tolerability, and effectiveness of darunavir/ritonavir combined with TMC125 when current protease inhibitor(s), Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI(s)) and enfuvirtide are replaced by darunavir/ritonavir and TMC125 in HIV positive patients who can no longer tolerate enfuvirtide and are experiencing viral suppression. Other antiviral drugs in the regimen are to remain unchanged.

Condition or Disease	Intervention/Treatment	Phase
HIV	Drug: TMC125, Darunavir; Ritonavir	Phase 3

Detailed Description

This is a multi-center, open-label (doctors and patients know which drug is being given), Phase IIIb clinical trial to evaluate the effectiveness, safety and tolerability of the combination of PREZISTA (darunavir)/ritonavir and TMC125 when substituted for enfuvirtide, current protease inhibitor(s) and Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI(s)) in antiretroviral resistant patients with viral suppression but who are intolerant of enfuvirtide. This study will be conducted in the U.S. at up to 5 sites where 40 patients will receive PREZISTA (darunavir) /ritonavir twice daily (600/100mg) and TMC125 (200 mg) twice daily over a 48-week treatment period.

The study will consist of a total of 11 patient visits. At the screening visit (Week -1 to -6) blood will be collected from patients to determine eligibility. Once all data are available to determine the eligibility of the patient, the baseline visit will be scheduled and trial treatment initiated at this visit. The Baseline Visit (Day 1) will be followed by a 48-week treatment period. The patient will be evaluated at Weeks 2, 4, 8, 12, 16, 24, 36, and 48. Patients will be asked to return for a 2-week follow up visit at Week 50.

Treatment will include PREZISTA (darunavir) /ritonavir and TMC125 plus continued nucleosides. The patient must continue all existing nucleosides in their background regimen for the duration of the study.

During the treatment period, the patient will be seen at regular visits during which the investigator will assess the patient's medical condition, any Adverse Events and study drug compliance. Laboratory evaluations for efficacy and safety will be done at regular visits. Study patients will receive oral (by mouth) PREZISTA (darunavir) 600 mg and 100 mg of ritonavir twice a day in combination with TMC125 200mg orally twice a day for 48 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open Label Phase 3b, 48 wk Pilot Study of the Antiviral Efficacy and Tolerability of Combination of PREZISTA/r and TMC125 When Substituted for Enfuvirtide, Current Protease Inhibitor(s) and NNRTI(s) in Antiretroviral Resistant Patients With Viral Suppression But Who Are Intolerant of Enfuvirtide.
• Study Start Date: May 1, 2007
• Actual Primary Completion Date: Oct 1, 2008
• Actual Study Completion Date: Oct 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 001 TMC125, Darunavir; RitonavirTMC125-200mg two times a day for 48 weeks; Darunavir -200mg two times a day for 48 weeks; Ritonavir-100mg two times a day for 48 weeks;	Drug: TMC125, Darunavir; Ritonavir; TMC125-200mg two times a day for 48 weeks; Darunavir -200mg two times a day for 48 weeks; Ritonavir-100mg two times a day for 48 weeks;

Outcome Measures

Primary Outcome Measures

1. Proportion of Patients Who Maintain Plasma HIV Viral Load Measurements < 400 Copies/ml at 2, 4, 8, 12, 16, 24, 36 and 48 Weeks After Switching to DRV/r and ETR, Missing Equals Failure. [48 weeks]

Secondary Outcome Measures

1. Proportion of Patients Who Have Viral Load Measurements <50 Copies/ml at 2, 4, 8, 12, 16, 24, 36 and 48 Weeks After Switching to DRV/r and ETR, Missing Equals Failure. [48 weeks]

2. CD4+ Cell Count (x 10^6 Cell/L): Baseline and Median Changes From Baseline at 4, 8, 12, 16, 24, 36 and 48 Weeks. [Week 48]

3. CD4+ Cell Count (x 10^6 Cell/L): Baseline and Mean Changes From Baseline at 4, 8, 12, 16, 24,36 and 48 Weeks. [Week 48]

4. Median Change From Baseline in Triglycerides at Week 48. [Week 48]

5. Median Change From Baseline in Total Cholesterol at Week 48. [Week 48]

6. Median Change From Baseline in LDL Cholesterol at Week 48. [Week 48]

7. Median Change From Baseline in HDL Cholesterol. [Week 48]

8. Median Change From Baseline in Total Cholesterol (TC) / High Denisty Lipoprotein (HDL) Ratio at Week 48. [Week 48]

9. Median Change From Baseline in Glucose at Week 48. [Week 48]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Documented HIV-1 positive

• History of drug resistance or antiretroviral failure while receiving each of three drug classes: Nucleoside Reverse Transcriptase Inhibitors (NRTIs), Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) and (protease inhibitors) PIs

• On a PI containing regimen with enfuvirtide with HIV viral load (VL) < 400 copies/mL for 6 months or longer

• Continuously using the same PI regimen for 4 months prior to Screening

• Decline to continue enfuvirtide or their physician recommends discontinuation due to injection site reactions that persist despite optimal technique and training with available methods of administration or loss of sites for injection due to tissue nodules and hardening.

Exclusion Criteria:

• No use of any drug contraindicated in the current US package insert for PREZISTA (darunavir) or in the investigators brochure for TMC125

• No prior or current therapy with PREZISTA (darunavir) or TMC125

• No prior genotypic results demonstrating 3 or more darunavir resistance-associated mutations associated with diminished response to darunavir (V11I, V32I, L33F, I47V, I50V, I54L, I54M, G73S, L76V, I84V or L89V). Patients with > 3 darunavir resistance-associated mutations with available darunavir phenotypes, may be enrolled if the resistance phenotype demonstrates: Fold Change (FC) <10 to darunavir by PhenoSense GT (Monogram Biosciences) or FC <10 to darunavir by Antivirogram (Virco, BVBA) or FC <3.4 to darunavir by vircoTYPE (Virco BVBA)

• AST or ALT >5 times ULN

• Calculated CrCl < 30 ml/min.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Los Angeles	California	United States

Sponsors and Collaborators

• Tibotec, Inc
• Tibotec Therapeutics, a Division of Ortho Biotech Products, L.P., USA

Investigators

• Study Director: Tibotec, Inc. Clinical Trial, Tibotec, Inc

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Tibotec, Inc
• ClinicalTrials.gov Identifier: NCT00460746
• Other Study ID Numbers: CR011866; TMC114HIV3009
• First Posted: Apr 16, 2007
• Last Update Posted: Jul 31, 2013
• Last Verified: Jul 1, 2013

• Keywords provided by Tibotec, Inc: HIV; AIDS; Immunodeficiency Virus, Human; PREZISTA; darunavir; TMC114; TMC125; Protease Inhibitor; Non-Nucleoside Reverse Transcriptase Inhibitor; enfuvirtide; Treatment Experienced
• Additional relevant MeSH terms: Ritonavir; Darunavir; Etravirine

Study Results

Participant Flow

Arm/Group Title	Darunavir(TMC114)/Eravirine(TMC125)
Arm/Group Description	Darunavir/ritonavir (DRV/r) combined with Etravirine ([ETR] also known as TMC125) when current protease inhibitor(s) (PIs), non-nucleoside reverse transriptase inhibitor(s) (NNRTIs), and enfuviritide (ENF) were replaced by DRV/r and ETR in subjects with intolerance to ENF.
Period Title: Overall Study
STARTED	10
COMPLETED	8
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Darunavir(TMC114)/Eravirine(TMC125)
Arm/Group Description	Darunavir/ritonavir (DRV/r) combined with Etravirine ([ETR] also known as TMC125) when current protease inhibitor(s) (PIs), non-nucleoside reverse transriptase inhibitor(s) (NNRTIs), and enfuviritide (ENF) were replaced by DRV/r and ETR in subjects with intolerance to ENF.
Overall Participants	10
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	48
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	10 100%
Race/Ethnicity, Customized (participants) [Number]
White	6 60%
Hispanic	4 40%
Viral Load <50 copies/mL (participants) [Number]
Number [participants]	10 100%
CD4 count (cells/mm^3) [Median (Full Range) ]
Median (Full Range) [cells/mm^3]	301

Outcome Measures

1. Primary Outcome

Title	Proportion of Patients Who Maintain Plasma HIV Viral Load Measurements < 400 Copies/ml at 2, 4, 8, 12, 16, 24, 36 and 48 Weeks After Switching to DRV/r and ETR, Missing Equals Failure.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

ITT population. One subject (001) who discontinued due to adverse events had a VL < 50 copies/mL at Week 4. Another subject (013) who was lost to follow-up had VL <50 copies/mL through Week 36.

Arm/Group Title	Darunavir(TMC114)/Eravirine(TMC125)
Arm/Group Description	Darunavir/ritonavir (DRV/r) combined with Etravirine ([ETR] also known as TMC125) when current protease inhibitor(s) (PIs), non-nucleoside reverse transriptase inhibitor(s) (NNRTIs), and enfuviritide (ENF) were replaced by DRV/r and ETR in subjects with intolerance to ENF.
Measure Participants	10
Baseline (Day 1)	100 1000%
Week 2	100 1000%
Week 4	100 1000%
Week 8	90 900%
Week 12	80 800%
Week 16	90 900%
Week 24	90 900%
Week 36	90 900%
Week 48	80 800%
Post-Treatment Follow Up	90 900%

2. Secondary Outcome

Title	Proportion of Patients Who Have Viral Load Measurements <50 Copies/ml at 2, 4, 8, 12, 16, 24, 36 and 48 Weeks After Switching to DRV/r and ETR, Missing Equals Failure.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

ITT population. One subject (001) who discontinued due to adverse events had a VL < 50 copies/mL at Week 4. Another subject (013) who was lost to follow-up had VL <50 copies/mL through Week 36.

Arm/Group Title	Darunavir(TMC114)/Eravirine(TMC125)
Arm/Group Description	Darunavir/ritonavir (DRV/r) combined with Etravirine ([ETR] also known as TMC125) when current protease inhibitor(s) (PIs), non-nucleoside reverse transriptase inhibitor(s) (NNRTIs), and enfuviritide (ENF) were replaced by DRV/r and ETR in subjects with intolerance to ENF.
Measure Participants	10
Baseline (Day 1)	100 1000%
Week 2	90 900%
Week 4	90 900%
Week 8	90 900%
Week 12	80 800%
Week 16	90 900%
Week 24	90 900%
Week 36	90 900%
Week 48	80 800%
Post-Treatment Follow Up	90 900%

3. Secondary Outcome

Title	CD4+ Cell Count (x 10^6 Cell/L): Baseline and Median Changes From Baseline at 4, 8, 12, 16, 24, 36 and 48 Weeks.
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

Intent To Treat (ITT), last observation carried forward (LOCF).

Arm/Group Title	Darunavir(TMC114)/Eravirine(TMC125)
Arm/Group Description	Darunavir/ritonavir (DRV/r) combined with Etravirine ([ETR] also known as TMC125) when current protease inhibitor(s) (PIs), non-nucleoside reverse transriptase inhibitor(s) (NNRTIs), and enfuviritide (ENF) were replaced by DRV/r and ETR in subjects with intolerance to ENF.
Measure Participants	10
Baseline (Day 1)	301.0
Week 4 Change from Baseline	-12.0
Week 8 Change from Baseline	-32.0
Week 12 Change from Baseline	-17.0
Week 16 Change from Baseline	-7.0
Week 24 Change from Baseline	19.0
Week 36 Change from Baseline	38.0
Week 48 Change from Baseline	63.5

4. Secondary Outcome

Title	CD4+ Cell Count (x 10^6 Cell/L): Baseline and Mean Changes From Baseline at 4, 8, 12, 16, 24,36 and 48 Weeks.
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

ITT , LOCF.

Arm/Group Title	Darunavir(TMC114)/Eravirine(TMC125)
Arm/Group Description	Darunavir/ritonavir (DRV/r) combined with Etravirine ([ETR] also known as TMC125) when current protease inhibitor(s) (PIs), non-nucleoside reverse transriptase inhibitor(s) (NNRTIs), and enfuviritide (ENF) were replaced by DRV/r and ETR in subjects with intolerance to ENF.
Measure Participants	10
Baseline (Day 1)	338.3 (135.91)
Week 4 Change from Baseline	2.3 (31.22)
Week 8 Change from Baseline	-25.0 (72.04)
Week 12 Change from Baseline	-18.9 (44.25)
Week 16 Change from Baseline	0.5 (53.58)
Week 24 Change from Baseline	24.5 (34.00)
Week 36 Change from Baseline	22.7 (58.84)
Week 48 Change from Baseline	47.3 (48.03)

5. Secondary Outcome

Title	Median Change From Baseline in Triglycerides at Week 48.
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

ITT , LOCF.

Arm/Group Title	Darunavir(TMC114)/Eravirine(TMC125)
Arm/Group Description	Darunavir/ritonavir (DRV/r) combined with Etravirine ([ETR] also known as TMC125) when current protease inhibitor(s) (PIs), non-nucleoside reverse transriptase inhibitor(s) (NNRTIs), and enfuviritide (ENF) were replaced by DRV/r and ETR in subjects with intolerance to ENF.
Measure Participants	10
Baseline (Day 1)	229.0
Week 48 Change from Baseline	-24.5

6. Secondary Outcome

Title	Median Change From Baseline in Total Cholesterol at Week 48.
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

ITT , LOCF.

Arm/Group Title	Darunavir(TMC114)/Eravirine(TMC125)
Arm/Group Description	Darunavir/ritonavir (DRV/r) combined with Etravirine ([ETR] also known as TMC125) when current protease inhibitor(s) (PIs), non-nucleoside reverse transriptase inhibitor(s) (NNRTIs), and enfuviritide (ENF) were replaced by DRV/r and ETR in subjects with intolerance to ENF.
Measure Participants	10
Baseline (Day 1)	189.0
Week 48 Change from Baseline	-27.5

7. Secondary Outcome

Title	Median Change From Baseline in LDL Cholesterol at Week 48.
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

ITT , LOCF.

Arm/Group Title	Darunavir(TMC114)/Eravirine(TMC125)
Arm/Group Description	Darunavir/ritonavir (DRV/r) combined with Etravirine ([ETR] also known as TMC125) when current protease inhibitor(s) (PIs), non-nucleoside reverse transriptase inhibitor(s) (NNRTIs), and enfuviritide (ENF) were replaced by DRV/r and ETR in subjects with intolerance to ENF.
Measure Participants	10
Baseline (Day 1)	100.0
Week 48 Change from Baseline	-9.0

8. Secondary Outcome

Title	Median Change From Baseline in HDL Cholesterol.
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

ITT , LOCF.

Arm/Group Title	Darunavir(TMC114)/Eravirine(TMC125)
Arm/Group Description	Darunavir/ritonavir (DRV/r) combined with Etravirine ([ETR] also known as TMC125) when current protease inhibitor(s) (PIs), non-nucleoside reverse transriptase inhibitor(s) (NNRTIs), and enfuviritide (ENF) were replaced by DRV/r and ETR in subjects with intolerance to ENF.
Measure Participants	10
Baseline (Day 1)	47.5
Week 48 Change from Baseline	-2.5

9. Secondary Outcome

Title	Median Change From Baseline in Total Cholesterol (TC) / High Denisty Lipoprotein (HDL) Ratio at Week 48.
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

ITT , LOCF.

Arm/Group Title	Darunavir(TMC114)/Eravirine(TMC125)
Arm/Group Description	Darunavir/ritonavir (DRV/r) combined with Etravirine ([ETR] also known as TMC125) when current protease inhibitor(s) (PIs), non-nucleoside reverse transriptase inhibitor(s) (NNRTIs), and enfuviritide (ENF) were replaced by DRV/r and ETR in subjects with intolerance to ENF.
Measure Participants	10
Baseline (Day 1)	4.7
Week 48 Change from Baseline	-0.3

10. Secondary Outcome

Title	Median Change From Baseline in Glucose at Week 48.
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

ITT , LOCF.

Arm/Group Title	Darunavir(TMC114)/Eravirine(TMC125)
Arm/Group Description	Darunavir/ritonavir (DRV/r) combined with Etravirine ([ETR] also known as TMC125) when current protease inhibitor(s) (PIs), non-nucleoside reverse transriptase inhibitor(s) (NNRTIs), and enfuviritide (ENF) were replaced by DRV/r and ETR in subjects with intolerance to ENF.
Measure Participants	10
Baseline (Day 1)	92.5
Week 48 Change from Baseline	1.0

Adverse Events

Arm/Group Title	Darunavir(TMC114)/Eravirine(TMC125)
Arm/Group Description	Darunavir/ritonavir (DRV/r) combined with Etravirine ([ETR] also known as TMC125) when current protease inhibitor(s) (PIs), non-nucleoside reverse transriptase inhibitor(s) (NNRTIs), and enfuviritide (ENF) were replaced by DRV/r and ETR in subjects with intolerance to ENF.
All Cause Mortality
	Darunavir(TMC114)/Eravirine(TMC125)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Darunavir(TMC114)/Eravirine(TMC125)
	Affected / at Risk (%)	# Events
Total	1/10 (10%)
Hepatobiliary disorders
Cholecystitis acute	1/10 (10%)	1
Other (Not Including Serious) Adverse Events
	Darunavir(TMC114)/Eravirine(TMC125)
	Affected / at Risk (%)	# Events
Total	10/10 (100%)
Gastrointestinal disorders
Constipation	1/10 (10%)	1
Diarrhea	3/10 (30%)	3
Dry mouth	1/10 (10%)	1
Nausea	1/10 (10%)	1
General disorders
Abdominal pain upper	1/10 (10%)	1
Fatigue	4/10 (40%)	4
Pain	1/10 (10%)	1
Infections and infestations
Diverticulitis	1/10 (10%)	1
Metabolism and nutrition disorders
Decreased appetite	1/10 (10%)	1
Hypercholesterolaemia	1/10 (10%)	1
Nervous system disorders
Amnesia	1/10 (10%)	1
Disturbance in attention	1/10 (10%)	1
Dizziness	1/10 (10%)	1
Headache	3/10 (30%)	3
Somnolence	1/10 (10%)	1
Psychiatric disorders
Depression	2/10 (20%)	2
Insomnia	2/10 (20%)	2
Skin and subcutaneous tissue disorders
Dermatitis	1/10 (10%)	1
Rash	3/10 (30%)	3
Vascular disorders
Heart rate increase	1/10 (10%)	1
Hypertension	2/10 (20%)	2

Limitations/Caveats

Conclusions on efficacy and safety are limited as the target enrollment of 40 subjects was not reached due to a shortage of eligible subjects.

More Information

Certain Agreements

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

If TTCA does not publish within 12 months after study conclusion or after TTCA confirms there will be no multicenter publication, Institution may publish their results from their site individually, provided TTCA has 60 day review for confidentiality and additional 60 day delay for patent application.