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

NCT01423812 | Completed Phase 4 Results DMC

• 1 other identifier: TMC114HIV4063
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

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.

Conditions

HIV

Keywords

HIV; treatment-experienced; protease inhibitor; adherence; lipids

Outcome Measures

Primary Outcomes (1)

• Primary Efficacy Endpoint for Virologic Suppression in HIV-infected Subjects

  Proportion of subjects with plasma HIV-1 RNA \<40 c/mL at Week 48 using a Missing, Switch, or Discontinuation = Failure (MSDF) algorithm as codified by the FDA's "snapshot" algorithm

  48 weeks after randomization to study medication

Secondary Outcomes (6)

• Secondary Efficacy Endpoints

  Within 24 weeks after randomization to study medication

• Change in Total Cholesterol From Baseline to 48 Weeks

  Within 48 weeks of randomization baseline to study medications

• Absolute Value Change in CD4+ From Baseline to Week 48

  48 weeks after randomization baseline to study medications

• Assessment of Virologic Failure

  Within 48 weeks of randomization to study medications

• Number of Participants With Greater Than 95% Adherence at 48 Weeks

  Within 48 weeks of randomization to study medications

Study Arms (2)

Once-daily Darunavir and ritonavir

EXPERIMENTAL

Subjects switched from Darunavir 600mg plus Ritonavir 100mg twice-daily to Darunavir 800mg plus Ritonavir 100mg once-daily

Drug: Once-daily combination Darunavir and ritonavir

Twice-daily Darunavir and ritonavir

ACTIVE COMPARATOR

Subjects remain on regimens containing Darunavir 600mg plus Ritonavir 100mg twice-daily

Drug: Twice-daily combination Darunavir and ritonavir

Interventions

Twice-daily combination Darunavir and ritonavir DRUG

Subjects randomized 1:1 to remain on regimens containing combination Darunavir 600mg plus Ritonavir 100mg twice-daily

Also known as: Prezista and norvir twice-daily

Twice-daily Darunavir and ritonavir

Once-daily combination Darunavir and ritonavir DRUG

Subjects randomized 1:1 to switch to from combination Darunavir 600mg plus Ritonavir 100mg twice-daily at baseline to the experimental combination Darunavir 800mg plus Ritonavir 100mg once-daily for 48 weeks

Also known as: Prezista and norvir once-daily

Once-daily Darunavir and ritonavir

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ART-experienced, HIV-1 infected subjects ≥18 years of age.
• A female subject is eligible to enter and participate in the study if she:
• 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,
• 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).
• CD4 \>50 cells/mm3
• HIV-1 RNA concentrations at undetectable levels (according to local assay being used) for at least 12 weeks on stable current regimen
• Current regimen includes darunavir/ritonavir 600/100 mg twice-daily plus a minimum of two other antiretrovirals
• Negative serum pregnancy test at screening visit

You may not qualify if:

• Subjects meeting any of the following criteria must not be enrolled in the study:
• Known hypersensitivity reaction to agents being utilized in the study
• \>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
• Pregnant or breast feeding woman
• Liver dysfunction with Child-Pugh class C disease or decompensated cirrhosis

Sponsors & Collaborators

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

Study Sites (1)

Ruth M. Rothstein CORE Center

Chicago, Illinois, 60612, United States

Location

Related Publications (2)

• 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 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. 3. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. December 1,2009;1-161. Accessed September 15, 2010. 4. 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 CROI 2010. 5. 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.

  BACKGROUND

• Huhn GD, Sigman A, Livak B. Simplification from twice-daily to once-daily darunavir/ritonavir in a randomized trial among HIV-infected persons with HIV-1 RNA suppression on antiretroviral therapy. Antivir Ther. 2015;20(8):849-54. doi: 10.3851/IMP2962. Epub 2015 Apr 17.

  PMID: 25881614 DERIVED

Related Links

• published results

MeSH Terms

Interventions

Ritonavir; Darunavir

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Sulfonamides; Amides; Carbamates; Acids, Acyclic; Carboxylic Acids; Sulfones; Furans

Limitations and 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.

Results Point of Contact

• Title: Gregory Huhn, MD
• Organization: The Ruth M. Rothstein CORE Center

ghuhn@cookcountyhhs.org

312-572-4575

Study Officials

• GREGORY G HUHN, MD

  The Ruth M. Rothstein CORE Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Attending Physician

Study Record Dates

• First Submitted: August 24, 2011
• First Posted: August 26, 2011
• Study Start: January 1, 2012
• Primary Completion: May 1, 2014
• Study Completion: April 1, 2015
• Last Updated: July 19, 2023
• Results First Posted: February 7, 2018

Record last verified: 2023-06

Locations

US (1)