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Comparison of Virologic and Immunologic Responses to Raltegravir and Dolutegravir in the Gastrointestinal Tract of HIV-Positive Adults

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ClinicalTrials.gov Identifier: NCT02218320
Recruitment Status : Completed
First Posted : August 18, 2014
Results First Posted : October 29, 2018
Last Update Posted : December 25, 2018
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill

Tracking Information
First Submitted Date August 13, 2014
First Posted Date August 18, 2014
Results First Submitted Date February 27, 2017
Results First Posted Date October 29, 2018
Last Update Posted Date December 25, 2018
Study Start Date October 2014
Actual Primary Completion Date October 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: December 4, 2018)
  • Rectal Tissue Concentrations of Ralegravir and Dolutegravir [ Time Frame: 2 to 6 hours post dose ]
  • RNA Concentrations From Gastrointestinal Tissues [ Time Frame: 2 to 6 hours post dose ]
    We measured RNA concentrations in copies/1000cells for both drug groups
  • Percentage of Total CD8+ T-cells With CCR5 Expression [ Time Frame: 2 to 6 hours post dose ]
    Local immunologic markers in gastrointestinal tract tissues
Original Primary Outcome Measures
 (submitted: August 14, 2014)
  • HIV RNA and DNA in three gastrointestinal tract tissues (terminal ileum/ascending colon, splenic flexure, and rectum/sigmoid colon) [ Time Frame: 2 to 6 hours post dose ]
  • Raltegravir/Dolutegravir Drug Exposure in three gastrointestinal tract tissues (terminal ileum/ascending colon, splenic flexure, and rectum/sigmoid colon) [ Time Frame: 2 to 6 hours post dose ]
  • Local immunologic markers in three gastrointestinal tract tissues (terminal ileum/ascending colon, splenic flexure, and rectum/sigmoid colon) [ Time Frame: 2 to 6 hours post dose ]
Change History Complete list of historical versions of study NCT02218320 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures Not Provided
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Comparison of Virologic and Immunologic Responses to Raltegravir and Dolutegravir in the Gastrointestinal Tract of HIV-Positive Adults
Official Title A Phase IV, Open-Label Study to Compare Virologic and Immunologic Responses to Raltegravir and Dolutegravir in the Gastrointestinal Tract of HIV-Positive Men and Women
Brief Summary This is a Phase IV, open label, observational study to compare the gastrointestinal tissue concentrations, inflammatory response, and viral replication of two integrase-inhibitors, raltegravir and dolutegravir, in HIV-infected volunteers who are virologically suppressed in blood plasma. The study will be comprised of 20 HIV-infected volunteers who will be enrolled equally into two groups. Group A will consist of 10 subjects receiving an antiretroviral regimen of tenofovir, emtricitabine, and raltegravir, and Group B will consist of 10 subjects receiving an antiretroviral regimen of tenofovir, emtricitabine, and dolutegravir. Participants will provide small pieces of tissue, or biopsies, which will be taken from three distinct locations of the large intestine during a colonoscopy procedure. These biopsies will be used to measure the amount of raltegravir or dolutegravir, HIV virus, and inflammatory markers present in the gastrointestinal tract.
Detailed Description

Purpose: To compare virologic and immunologic responses to raltegravir and dolutegravir in the gastrointestinal tract of HIV-positive men and women

Participants: Twenty HIV-infected volunteers will be enrolled equally into two groups. Group A will consist of subjects receiving an antiretroviral regimen of raltegravir, tenofovir, and emtricitabine and Group B will consist of subjects receiving an antiretroviral regimen of dolutegravir, tenofovir, and emtricitabine.

Procedures (methods): This is a Phase IV, open label study to compare the gastrointestinal tissue concentrations, cytokine response, and viral replication in gut-associated lymphoid tissue of two integrase-inhibitors in HIV-infected volunteers who are virologically suppressed in blood plasma. Subjects will undergo an observed bowel preparation, followed by a colonoscopy in which tissue will be obtained by a board-certified gastroenterologist from the terminal ileum/ascending colon, splenic flexture, and rectum/sigmoid colon. Blood plasma will be collected immediately prior to collection of tissue samples.

Study Type Observational
Study Design Observational Model: Other
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Not Provided
Sampling Method Non-Probability Sample
Study Population Subjects will be recruited from University of North Carolina Infectious Diseases Clinic.
Condition Human Immunodeficiency Virus
Intervention
  • Drug: Raltegravir
    Other Name: Isentress ®
  • Drug: Dolutegravir
    Other Name: Tivicay ®
  • Procedure: Colonoscopy with biopsy
    This procedure is not standard of care for patients receiving combination antiretroviral therapy (cART), but is necessary to obtain tissue samples.
Study Groups/Cohorts
  • Group A
    Ten HIV-infected adults will be in Group A and take the HIV medication raltegravir in combination with tenofovir and emtricitabine as their provider-prescribed antiretroviral regimen.
    Interventions:
    • Drug: Raltegravir
    • Procedure: Colonoscopy with biopsy
  • Group B
    Ten HIV-infected adults will be in Group B and take the HIV medication dolutegravir in combination with tenofovir and emtricitabine as their provider-prescribed antiretroviral regimen.
    Interventions:
    • Drug: Dolutegravir
    • Procedure: Colonoscopy with biopsy
Publications * Weber MD, Andrews E, Prince HA, Sykes C, Rosen EP, Bay C, Shaheen NJ, Madanick RD, Dellon ES, De Paris K, Nelson JA, Gay CL, Kashuba AD. Virological and immunological responses to raltegravir and dolutegravir in the gut-associated lymphoid tissue of HIV-infected men and women. Antivir Ther. 2018;23(6):495-504. doi: 10.3851/IMP3236.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Completed
Actual Enrollment
 (submitted: August 14, 2014)
20
Original Estimated Enrollment Same as current
Actual Study Completion Date October 2015
Actual Primary Completion Date October 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • Healthy HIV-positive adults aged 18-65, inclusive on the date of screening, with documentation of at least one positive HIV test. Healthy is defined as no clinically relevant abnormalities that would interfere with the interpretation of results, or pose unnecessary risk onto volunteers due to study procedures.
  • Receiving an antiretroviral regimen containing tenofovir+emtricitabine with raltegravir (Group A) or dolutegravir (Group B) for > 3 months, with blood plasma HIV RNA < 50copies/mL for at least 4 weeks, or a 2 log decrease in baseline blood plasma HIV RNA.
  • Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the trial.
  • Documentation of at least 80% adherence to antiretroviral regimen, through clinician or self-report, with no missed doses in the 3 days prior to the inpatient visit.
  • Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.
  • Women of childbearing potential must be utilizing at least one acceptable form of birth control.

Exclusion Criteria:

  • Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, or neurologic disease that would pose unnecessary risk or interfere with study results. Subjects will be excluded for any condition that would increase risk from sedation, endoscopy, or biopsy.
  • Subjects with a history of having a gastrectomy, colostomy, ileostomy, or any other clinically significant procedure altering the gastrointestinal tract, or any condition possibly affecting drug absorption.
  • Subjects with inflammatory bowel diseases (ulcerative colitis or Crohn's disease).
  • Female subjects who are currently pregnant or breastfeeding, or planning to become pregnant during the study period.
  • Subjects who are unwilling to refrain from insertion of medical/recreation devices and products into the rectum, and from receptive anal intercourse, for 72 hours before inpatient study visit and through 7 days after the last biopsy unless instructed otherwise by the investigators.
  • A positive urine drug screen.
  • Untreated rectal sexually transmitted infection at screening.
  • Treatment with an investigational drug within 2 months preceding study enrollment.
  • Participated in a gastrointestinal biopsy study in the 3 months preceding study enrollment.
  • Participants with a history of clotting or bleeding disorders.
  • Participants with a history of abnormal reaction to, or complication from, conscious sedation or anesthesia
  • Subjects who are unwilling or unable to comply with the following dietary restrictions in regard to study procedures, including a clear liquid diet during bowel preparation and a period of NPO (nil per os) prior to the colonoscopy. While confined, the total daily nutritional composition will be 50% carbohydrate, 15% protein, and 35% fat. The daily caloric intake should not exceed 3200kcal.
  • Abnormalities of the colorectal mucosa, or significant colorectal symptom(s), which in the opinion of the clinician represents a contraindication to biopsy (including but not limited to presence of any unresolved injury, infectious or inflammatory condition of the local mucosa, and presence of symptomatic external hemorrhoids).
  • Any other reason or condition that in the judgment of the investigators would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives.
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries United States
Removed Location Countries  
 
Administrative Information
NCT Number NCT02218320
Other Study ID Numbers 14-1647
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement
Plan to Share IPD: No
Responsible Party University of North Carolina, Chapel Hill
Study Sponsor University of North Carolina, Chapel Hill
Collaborators Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Angela DM Kashuba, PharmD University of North Carolina, Chapel Hill
PRS Account University of North Carolina, Chapel Hill
Verification Date April 2017