Time to Protection and Adherence Requirements of Raltegravir With or Without Lamivudine in Protection From HIV Infection

NCT03205566 | Completed Phase 4 Results

• 1 other identifier: 202316
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 1

Brief Summary

This study evaluates whether a 7-day course of Raltegravir 400mg bd or Raltegravir 400mg/lamivudine 150mg bd can prevent HIV from infecting genital tissue and will relate the level of drug in the blood to the level of drug in genital tissue and to the ability to of HIV to infect genital tissue. As well as determining whether these regimes can provide ex vivo protection against HIV, this study will also determine speed to provision of protection and a 48 hour PK/PD decay profile of Raltegravir following drug cessation after attaining steady state concentrations. The results will also inform all future HIV pre-exposure prophylaxis studies of Raltegravir and form the basis for large scale clinical trials without the need for tissue sampling. To date, efficacy studies assessing PrEP regimens have utilized HIV-acquisition endpoints with the consequence being such studies are required to be large in subject number in order to power observations. In addition the study will provide for the first time data on HIV protection rather than just Raltegravir drug levels in tissue, and allow assessment of the possibility of Raltegravir being used as an intermittent dosing regimen in PrEP.

Conditions

Hiv

Outcome Measures

Primary Outcomes (1)

• The Level of Raltegravir Alone or Raltegravir /Lamivudine Required in the Plasma, Vagina and Rectum for 100% ex Vivo Protection From HIV

  The level of Raltegravir alone or Raltegravir /lamivudine required in the plasma, vagina and rectum for 100% ex vivo protection from HIV . High viral dose challenge: ex vivo challenge of tissue with 104 TCID50/mL HIV-1BaL Low viral dose challenge: ex vivo challenge of tissue with 102 TCID50/mL HIV-1BaL

  Through Study completion, an average of 55 days

Secondary Outcomes (3)

• The Time From First Dose of Drug to Maximum Mucosal ex Vivo Protection From HIV.

  Up to 7 days from first dose

• Number of Adverse Events Based on PE, Blood Test and Event Reporting on Raltegravir Based PrEP, in HIV Negative Individuals

  Through Study completion, an average of 55 days

• The Time to Cessation of Mucosal ex Vivo Protection From HIV After Stopping ART at Steady State.

  5 days post last dose

Study Arms (2)

Arm A Raltegravir, then Raltegravir/Lamivudine

ACTIVE COMPARATOR

7 days Raltegravir 400mg bd followed by minimum 4 weeks wash out and then 7 days Raltegravir 400mg/lamivudine 150mg (oral tablets) bd.

Drug: Raltegravir 400Mg Tab; Drug: Lamivudine 150Mg Tablet

Arm B Raltegravir/Lamivudine, then Raltegravir

ACTIVE COMPARATOR

Raltegravir 400mg + Lamivudine 150mg tablet, taken twice a day for 7days followed by a minimum of 4 weeks wash out and then 7 days Raltegravir 400mg bd.

Drug: Raltegravir 400Mg Tab; Drug: Lamivudine 150Mg Tablet

Interventions

Raltegravir 400Mg Tab DRUG

bd for 7 days

Also known as: Isentress

Arm A Raltegravir, then Raltegravir/Lamivudine; Arm B Raltegravir/Lamivudine, then Raltegravir

Lamivudine 150Mg Tablet DRUG

\+ Raltegravir 400Mg tablet bd for 7 days

Also known as: Epivir

Arm A Raltegravir, then Raltegravir/Lamivudine; Arm B Raltegravir/Lamivudine, then Raltegravir

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• The ability to understand and sign a written informed consent form prior to participation in any screening procedures and must be willing to comply with all trial requirements.
• Male or non-pregnant, non-lactating females
• Age between 18 to 60 years, inclusive.
• Body Mass Index (BMI) of 16 to 35 kg/m2, inclusive.
• Negative antibody/antigen combined test for HIV.
• Absence of any significant health problems (in the opinion of the investigator) on the basis of the screening procedures; including medical history, physical examination, vital signs.
• Women participating in sexual intercourse that could result in pregnancy -must use an adequate form of contraception throughout the study and for two weeks after the study. This includes intrauterine device, condoms, anatomical sterility in self or partner. Oral hormonal methods and implant contraceptives are allowed but only in combination with the additional protection of a barrier method.
• Female participants may not use any vaginal products or objects or have vaginal sex for 48 hours before and after the collection of vaginal fluid and vaginal biopsies. This list includes tampons, female condoms, cotton wool, rags, diaphragms, cervical caps (or any other vaginal barrier method),douches, lubricants, vibrators/dildos, and drying agents.
• Males participating in sexual intercourse that could result in pregnancy must use condoms during the duration of the study.
• Men and women cannot use anal products or objects including but not exclusive to douches, lubricants and vibrators/dildos, butt plugs or urethral sounds or have receptive anal intercourse for 48 hours before and after the collection of rectal biopsies.
• Willing to abstain from multivitamins and antacids for the study duration.

You may not qualify if:

• Any significant acute or chronic medical illness.
• Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs or clinical laboratory determinations.
• Positive blood screen for syphilis, hepatitis B (HBs Ag) and/or C antibodies.
• Positive blood screen for HIV antibodies.
• Positive screen for sexually transmitted infections at screening visit
• High-risk behaviour for HIV infection which is defined as having one of the following within three months before trial day 0 (first dose): had unprotected vaginal or anal sex with a known HIV infected person or a casual partner. engaged in sex work for money or drugs. acquired a bacterial sexually transmitted disease in the past 3 months. having a known HIV positive partner either currently or in the previous six months Females who are pregnant or breast-feeding.
• Clinically significant laboratory abnormalities (according to normal range as defined by central laboratory).
• Participation in a clinical trial of an Investigational product within 1 month of planned baseline enrolment in this study.
• Ingestion of H2 receptor antagonists or proton pump inhibitor drugs in the preceding 14 days
• Current of planned use of anti-epileptics

Sponsors & Collaborators

• Guy's and St Thomas' NHS Foundation Trust: lead

Study Sites (1)

Harrison Wing, Guy's Hospital

London, SE1 9RT, United Kingdom

Location

Related Publications (6)

• Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, Goicochea P, Casapia M, Guanira-Carranza JV, Ramirez-Cardich ME, Montoya-Herrera O, Fernandez T, Veloso VG, Buchbinder SP, Chariyalertsak S, Schechter M, Bekker LG, Mayer KH, Kallas EG, Amico KR, Mulligan K, Bushman LR, Hance RJ, Ganoza C, Defechereux P, Postle B, Wang F, McConnell JJ, Zheng JH, Lee J, Rooney JF, Jaffe HS, Martinez AI, Burns DN, Glidden DV; iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010 Dec 30;363(27):2587-99. doi: 10.1056/NEJMoa1011205. Epub 2010 Nov 23.

  PMID: 21091279 BACKGROUND

• Garcia-Lerma JG, Otten RA, Qari SH, Jackson E, Cong ME, Masciotra S, Luo W, Kim C, Adams DR, Monsour M, Lipscomb J, Johnson JA, Delinsky D, Schinazi RF, Janssen R, Folks TM, Heneine W. Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir. PLoS Med. 2008 Feb;5(2):e28. doi: 10.1371/journal.pmed.0050028.

  PMID: 18254653 BACKGROUND

• Herrera C, Cranage M, McGowan I, Anton P, Shattock RJ. Colorectal microbicide design: triple combinations of reverse transcriptase inhibitors are optimal against HIV-1 in tissue explants. AIDS. 2011 Oct 23;25(16):1971-9. doi: 10.1097/QAD.0b013e32834b3629.

  PMID: 21811139 BACKGROUND

• Anton PA, Saunders T, Elliott J, Khanukhova E, Dennis R, Adler A, Cortina G, Tanner K, Boscardin J, Cumberland WG, Zhou Y, Ventuneac A, Carballo-Dieguez A, Rabe L, McCormick T, Gabelnick H, Mauck C, McGowan I. First phase 1 double-blind, placebo-controlled, randomized rectal microbicide trial using UC781 gel with a novel index of ex vivo efficacy. PLoS One. 2011;6(9):e23243. doi: 10.1371/journal.pone.0023243. Epub 2011 Sep 28.

  PMID: 21969851 BACKGROUND

• O'Quigley J, Zohar S. Experimental designs for phase I and phase I/II dose-finding studies. Br J Cancer. 2006 Mar 13;94(5):609-13. doi: 10.1038/sj.bjc.6602969.

  PMID: 16434987 BACKGROUND

• Herrera C, Lwanga J, Lee M, Mantori S, Amara A, Else L, Penchala SD, Egan D, Challenger E, Dickinson L, Boffito M, Shattock R, Khoo S, Fox J. Pharmacokinetic/pharmacodynamic investigation of raltegravir with or without lamivudine in the context of HIV-1 pre-exposure prophylaxis (PrEP). J Antimicrob Chemother. 2021 Jul 15;76(8):2129-2136. doi: 10.1093/jac/dkab136.

  PMID: 33993302 DERIVED

MeSH Terms

Conditions

Acquired Immunodeficiency Syndrome

Interventions

Raltegravir Potassium; Lamivudine; Tablets

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pyrrolidinones; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Zalcitabine; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Dideoxynucleosides; Dosage Forms; Pharmaceutical Preparations

Results Point of Contact

• Title: Dr Julie Fox
• Organization: Guy's & St. Thomas' NHS Foundation Trust

julie.fox@gstt.nhs.uk

020 7188 7188

Study Officials

• Julie Fox

  Guy's and St Thomas' NHS Foundation Trust

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 8, 2017
• First Posted: July 2, 2017
• Study Start: September 19, 2017
• Primary Completion: September 24, 2018
• Study Completion: September 24, 2018
• Last Updated: March 16, 2021
• Results First Posted: February 21, 2021

Record last verified: 2021-02

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)