DRIVESHAFT: Darunavir/Ritonavir In HIV-infected Virologically-suppressed Experienced Subjects

• Sponsor: Ruth M. Rothstein CORE Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01423812
• Collaborator: Tibotec Therapeutics, a Division of Ortho Biotech Products, L.P., USA (Industry)
• Enrollment: 60
• Location: 1
• Arms: 2
• Duration (Months): 39
• Patients Per Site Per Month: 1.5

Study Details

Study Description

Brief Summary

Darunavir is a nonpeptidic protease inhibitor with a high genetic barrier to resistance that evolved from a prototype compound synthesized using structure-based design strategies. Once-daily darunavir at 800mg boosted with 100mg of ritonavir is an effective antiretroviral agent indicated for HIV-infected treatment-naïve patients. In treatment-experienced patients, darunavir was initially approved for twice-daily administration boosted with twice-daily ritonavir at 600mg and 100mg, respectively. Recently, once-daily darunavir/ritonavir was approved for use in treatment-experienced adult patients with viremia with no darunavir resistance mutations. In treatment-experienced patients with viral suppression, switching from an antiretroviral taken twice-daily to a once-daily dose is an attractive option to promote greater patient acceptability and adherence, and potentially minimize side effects and toxicities. Because of darunavir/ritonavir's high genetic barrier to resistance and well-established safety profile at a once-daily dose, switching patients with virologic suppression from twice-daily darunavir/ritonavir to once-daily darunavir/ritonavir will likely confer attributes more favorable to patients through a simplified dosing schedule and lower potential for lipid elevation without the loss of virologic control. DRIVESHAFT is a 48-week Phase 4, randomized, open label, comparative study. The study will be conducted in 60 HIV-1 infected, antiretroviral experienced, virologically-suppressed patients on regimens containing darunavir 600mg/ ritonavir 100mg twice-daily and a minimum of two other antiretrovirals, with a history of 0-1 darunavir-associated resistance mutations. Subjects will be randomized 1:1 to switch to darunavir 800mg/ ritonavir 100mg once-daily or continue on their current regimen. Rates of virologic suppression of once-daily darunavir/ritonavir regimens relative to darunavir/ritonavir twice-daily regimens will be compared, and safety, change from baseline fasting lipid parameters, and adherence will be evaluated.

Condition or Disease	Intervention/Treatment	Phase
HIV	Drug: Twice-daily Darunavir and ritonavir; Drug: Once-daily Darunavir and ritonavir	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: DRIVESHAFT : Darunavir/Ritonavir In Virologically-suppressed Experienced Subjects Halving an Antiretroviral by Finetuning Therapy - A Phase IV Randomized, Open-Label Study to Evaluate in HIV-1 Infected , Virologically-suppressed Patients on Regimens With Darunavir 600mg/ Ritonavir 100mg Twice-daily Switching to Darunavir 800mg/ Ritonavir 100mg Once-daily Versus Continuing Darunavir 600mg/ Ritonavir 100mg Twice-daily Containing Regimens
• Study Start Date: Jan 1, 2012
• Actual Primary Completion Date: May 1, 2014
• Actual Study Completion Date: Apr 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Once-daily Darunavir and ritonavir Subjects switched from Darunavir 600mg plus Ritonavir 100mg twice-daily to Darunavir 800mg plus Ritonavir 100mg once-daily	Drug: Once-daily Darunavir and ritonavir; Subjects switched from Darunavir 600mg plus Ritonavir 100mg twice-daily at baseline to Darunavir 800mg plus Ritonavir 100mg once-daily for 48 weeks
Active Comparator: Twice-daily Darunavir and ritonavir Subjects remain on regimens containing Darunavir 600mg plus Ritonavir 100mg twice-daily	Drug: Twice-daily Darunavir and ritonavir; Subjects remain on regimens containing Darunavir 600mg plus Ritonavir 100mg twice-daily

Outcome Measures

Primary Outcome Measures

1. Primary Efficacy Endpoint for Virologic Suppression in HIV-infected Subjects [48 weeks after randomization to study medication]

   Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 48 using a Missing, Switch, or Discontinuation = Failure (MSDF) algorithm as codified by the FDA's "snapshot" algorithm

Secondary Outcome Measures

1. Secondary Efficacy Endpoints [Within 48 weeks after randomization to study medication]

   Proportion of subjects with plasma HIV-1 RNA <50 c/mL and <400 c/mL at Week 24 Proportion of subjects with plasma HIV-1 RNA <400 c/mL at Week 48

2. Safety Assessment [Within 48 weeks of randomization to study medications]

   •Compare the tolerability, safety, and change in lipid parameters(total cholesterol, LDL, HDL, triglycerides) of once-daily versus twice-daily darunavir/ritonavir containing regimens over 48 weeks

3. Immunologic Endpoints [48 weeks after randomization to study medications]

   •Absolute values and changes from baseline in CD4+ and CD8+ over time

4. Assessment of Virologic Failure [Within 48 weeks of randomization to study medications]

   •Assess the development of viral resistance in subjects experiencing virological failure

5. Medication Adherence Assessment [Within 48 weeks of randomization to study medications]

   Characterize adherence to once-daily versus twice-daily darunavir/ritonavir containing regimens using the Modified Medication Adherence Self-Report Inventory (M-MASRI) scale

6. Secondary Efficacy Endpoints [week 24]

   •Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 24

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. ART-experienced, HIV-1 infected subjects ≥18 years of age.

2. A female subject is eligible to enter and participate in the study if she:

3. is of non-childbearing potential defined as either post-menopausal (12 months of spontaneous amenorrhea and ≥45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy, or bilateral oophorectomy or,

4. is of child-bearing potential, with a negative pregnancy test at both Screen and Day 1 and agrees to one of the following methods of contraception to avoid pregnancy:

• Complete abstinence from intercourse from 2 weeks prior to administration of study medications, throughout the study, and for at least 2 weeks after discontinuation of all study medications.

• Double barrier method (male condom/spermicide, male condom/diaphragm, diaphragm/spermicide).

• Approved hormonal contraception may be administered with darunavir/ritonavir

• Any intrauterine device (IUD) with published data showing that the expected failure rate is <1% per year

• Any other method with published data showing that the expected failure rate is <1% per year.

Any contraception method must be used consistently and in accordance with the approved product label. All subjects participating in the study should be counseled on safer sexual practices including the use of effective barrier methods (e.g. male condom/spermicide).

1. CD4 >50 cells/mm3

2. HIV-1 RNA concentrations at undetectable levels (according to local assay being used) for at least 12 weeks on stable current regimen

3. Current regimen includes darunavir/ritonavir 600/100 mg twice-daily plus a minimum of two other antiretrovirals

4. Negative serum pregnancy test at screening visit

Exclusion Criteria:

Subjects meeting any of the following criteria must not be enrolled in the study:

1. Known hypersensitivity reaction to agents being utilized in the study

2. 1 cumulative darunavir associated mutations (V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V, or L89V) detected from any previous genotype or a VircoTYPE HIV-1 darunavir fold-change >10.0 on any previous virtual phenotype

3. Pregnant or breast feeding woman

4. Liver dysfunction with Child-Pugh class C disease or decompensated cirrhosis

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ruth M. Rothstein CORE Center	Chicago	Illinois	United States	60612

Sponsors and Collaborators

• Ruth M. Rothstein CORE Center
• Tibotec Therapeutics, a Division of Ortho Biotech Products, L.P., USA

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• published results

Publications

• 1. De Meyer S, et al. Antiviral activity of TMC 114, a potent next generation protease inhibitor against more than 4000 recent recombinant clinical isolates exhibiting a wide range of protease inhibitor resistance profile. Antiviral Ther 2003;8:3S19. 2. De Meyer S, et al. In vitro selection experiments demonstrate an increased genetic barrier to resistance development to TMC 114 as compared with currently licensed protease inhibitors. Antiviral Ther 2002;7(Suppl 1):S5. 3. De Meyer SD, et al. Phenotypic and genotypic determinants of resistance to TMC 114: pooled analysis of POWER 1,2, and 3. Antiviral Ther 2006;11:S83. 4. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. December 1,2009;1-161. Available at http://www.aidsinfo.nih.gov/ContentFiles/Adultand AdolescentGL.pdf. Accessed September 15, 2010. 5. Clotet B, et al. Efficacy and Safety of Darunavir/ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: A Pooled Subgroup Analysis of Data from Two Randomized Trials. The Lancet 2007;369:1169-78. 6. Cahn PK, et al. Efficacy and Safety at 48 Weeks of Once-daily vs Twice-daily DRV.r in Treatment-experienced HIV-1-positive Patients with No DRV Resistance-associated Mutations: The ODIN Trial. Abstract 57. 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. 7. Moltó J, et al. Treatment simplification to once daily darunavir/ritonavir guided by the darunavir inhibitory quotient in heavily pretreated HIV-infected patients. Antivir Ther. 2010;15(2):219-25. 8. Paterson DL, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med 2000;133:21-30.

• Responsible Party: Gregory Huhn, Attending Physician, Ruth M. Rothstein CORE Center
• ClinicalTrials.gov Identifier: NCT01423812
• Other Study ID Numbers: TMC114HIV4063
• First Posted: Aug 26, 2011
• Last Update Posted: Feb 7, 2018
• Last Verified: Jan 1, 2018

• Keywords provided by Gregory Huhn, Attending Physician, Ruth M. Rothstein CORE Center: HIV; treatment-experienced; protease inhibitor; adherence; lipids
• Additional relevant MeSH terms: Ritonavir; Darunavir

Study Results

Participant Flow

Arm/Group Title	Once-daily Darunavir/Ritonavir	Twice-daily Darunavir/Ritonavir
Arm/Group Description	Subjects switched from Darunavir 600mg plus Ritonavir 100mg twice-daily to Darunavir 800mg plus Ritonavir 100mg once-daily Once-daily Darunavir/ritonavir: Subjects switched from Darunavir 600mg plus Ritonavir 100mg twice-daily at baseline to Darunavir 800mg plus Ritonavir 100mg once-daily for 48 weeks	Subjects remain on regimens containing Darunavir 600mg plus Ritonavir 100mg twice-daily Twice-daily Darunavir/ritonavir: Subjects remain on regimens containing Darunavir 600mg plus Ritonavir 100mg twice-daily
Period Title: Overall Study
STARTED	30	30
COMPLETED	27	26
NOT COMPLETED	3	4

Baseline Characteristics

Arm/Group Title	Once-daily Darunavir/Ritonavir	Twice-daily Darunavir/Ritonavir	Total
Arm/Group Description	Subjects switched from Darunavir 600mg plus Ritonavir 100mg twice-daily to Darunavir 800mg plus Ritonavir 100mg once-daily Once-daily Darunavir/ritonavir: Subjects switched from Darunavir 600mg plus Ritonavir 100mg twice-daily at baseline to Darunavir 800mg plus Ritonavir 100mg once-daily for 48 weeks	Subjects remain on regimens containing Darunavir 600mg plus Ritonavir 100mg twice-daily Twice-daily Darunavir/ritonavir: Subjects remain on regimens containing Darunavir 600mg plus Ritonavir 100mg twice-daily	Total of all reporting groups
Overall Participants	30	30	60
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	30 100%	29 96.7%	59 98.3%
>=65 years	0 0%	1 3.3%	1 1.7%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	48	49	48
Sex: Female, Male (Count of Participants)
Female	6 20%	5 16.7%	11 18.3%
Male	24 80%	25 83.3%	49 81.7%
Region of Enrollment (participants) [Number]
United States	30 100%	30 100%	60 100%

Outcome Measures

1. Primary Outcome

Title	Primary Efficacy Endpoint for Virologic Suppression in HIV-infected Subjects
Description	Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 48 using a Missing, Switch, or Discontinuation = Failure (MSDF) algorithm as codified by the FDA's "snapshot" algorithm
Time Frame	48 weeks after randomization to study medication

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Once-daily Darunavir/Ritonavir	Twice-daily Darunavir/Ritonavir
Arm/Group Description	Subjects switched from Darunavir 600mg plus Ritonavir 100mg twice-daily to Darunavir 800mg plus Ritonavir 100mg once-daily Once-daily Darunavir/ritonavir: Subjects switched from Darunavir 600mg plus Ritonavir 100mg twice-daily at baseline to Darunavir 800mg plus Ritonavir 100mg once-daily for 48 weeks	Subjects remain on regimens containing Darunavir 600mg plus Ritonavir 100mg twice-daily Twice-daily Darunavir/ritonavir: Subjects remain on regimens containing Darunavir 600mg plus Ritonavir 100mg twice-daily
Measure Participants	30	30
Number [participants]	27 90%	25 83.3%

2. Secondary Outcome

Title	Secondary Efficacy Endpoints
Description	Proportion of subjects with plasma HIV-1 RNA <50 c/mL and <400 c/mL at Week 24 Proportion of subjects with plasma HIV-1 RNA <400 c/mL at Week 48
Time Frame	Within 48 weeks after randomization to study medication

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Safety Assessment
Description	•Compare the tolerability, safety, and change in lipid parameters(total cholesterol, LDL, HDL, triglycerides) of once-daily versus twice-daily darunavir/ritonavir containing regimens over 48 weeks
Time Frame	Within 48 weeks of randomization to study medications

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Immunologic Endpoints
Description	•Absolute values and changes from baseline in CD4+ and CD8+ over time
Time Frame	48 weeks after randomization to study medications

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Assessment of Virologic Failure
Description	•Assess the development of viral resistance in subjects experiencing virological failure
Time Frame	Within 48 weeks of randomization to study medications

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Medication Adherence Assessment
Description	Characterize adherence to once-daily versus twice-daily darunavir/ritonavir containing regimens using the Modified Medication Adherence Self-Report Inventory (M-MASRI) scale
Time Frame	Within 48 weeks of randomization to study medications

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Secondary Efficacy Endpoints
Description	•Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 24
Time Frame	week 24

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Once-daily Darunavir and Ritonavir	Twice-daily Darunavir and Ritonavir
Arm/Group Description	Subjects switched from Darunavir 600mg plus Ritonavir 100mg twice-daily to Darunavir 800mg plus Ritonavir 100mg once-daily Once-daily Darunavir and ritonavir: Subjects switched from Darunavir 600mg plus Ritonavir 100mg twice-daily at baseline to Darunavir 800mg plus Ritonavir 100mg once-daily for 48 weeks	Subjects remain on regimens containing Darunavir 600mg plus Ritonavir 100mg twice-daily Twice-daily Darunavir and ritonavir: Subjects remain on regimens containing Darunavir 600mg plus Ritonavir 100mg twice-daily
Measure Participants	30	30
Count of Participants [Participants]	29 96.7%	25 83.3%

Adverse Events

Time Frame	48 weeks during the trial, and 30 days after participant completion of the trial
Arm/Group Title	Once-daily Darunavir/Ritonavir		Twice-daily Darunavir/Ritonavir
Arm/Group Description	Subjects switched from Darunavir 600mg plus Ritonavir 100mg twice-daily to Darunavir 800mg plus Ritonavir 100mg once-daily Once-daily Darunavir/ritonavir: Subjects switched from Darunavir 600mg plus Ritonavir 100mg twice-daily at baseline to Darunavir 800mg plus Ritonavir 100mg once-daily for 48 weeks		Subjects remain on regimens containing Darunavir 600mg plus Ritonavir 100mg twice-daily Twice-daily Darunavir/ritonavir: Subjects remain on regimens containing Darunavir 600mg plus Ritonavir 100mg twice-daily
All Cause Mortality
	Once-daily Darunavir/Ritonavir		Twice-daily Darunavir/Ritonavir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Once-daily Darunavir/Ritonavir		Twice-daily Darunavir/Ritonavir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		0/30 (0%)
Other (Not Including Serious) Adverse Events
	Once-daily Darunavir/Ritonavir		Twice-daily Darunavir/Ritonavir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		0/30 (0%)

Limitations/Caveats

The sample size was not adequately powered to evaluate non-inferiority, which might be clinically relevant. As a single-center study, identifying an appropriate number of eligible patients to determine non-inferiority was not feasible.

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.