Time to Protection and Adherence Requirements of Raltegravir With or Without Lamivudine in Protection From HIV Infection (R-PrEP)

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

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.

Study Overview

• Status: Completed
• Conditions: Hiv
• Intervention / Treatment: Drug: Raltegravir 400Mg Tab; Drug: Lamivudine 150Mg Tablet

Detailed Description

This is a multi-site, open-label, randomised, pharmacokinetic (PK) and pharmacodynamic (PD) trial whereby 36 individuals (18 women and 18 men) will be randomised according to gender 1:1:1:1:1:1 to one of 6 arms (A 1 A 2 A 3 B 1 B 2 B 3). The result being 3 women and 3 men will be in each arm. The letter dictates the ART regimen order and the number dictates the time points that tissue sampling will occur on and off ART. Two ART regimes will be investigated and all individuals will receive both regimes separated by a one month wash out.

Arm A (A 1 A 2 A 3): will start with 7 days Raltegravir 400mg bd and then have a one month wash out before then starting 7 days Raltegravir 400mg /lamivudine 150mg bd.

Arm B (B 1 B 2 B 3): will start with 7 days Raltegravir 400mg /lamivudine 150mg bd and then have a one month wash out before then starting 7 days Raltegravir 400mg bd. This will remove sequential selection bias. All individuals will receive tissue sampling at baseline for ex vivo analysis to ensure biopsies are infectable on challenge assays. Sampling from women will avoid menstruation and if possible focus on the luteal phase of the menstrual cycle. Individuals will receive another set of tissue sampling during and after ART in phase 1, have a 4 week wash out period and then have another set of sampling during and after ART in phase 2. Individuals will therefore have 5 sets of sampling during the trial.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 4

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, SE1 9RT
    • Harrison Wing, Guy's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 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.
2. Male or non-pregnant, non-lactating females
3. Age between 18 to 60 years, inclusive.
4. Body Mass Index (BMI) of 16 to 35 kg/m2, inclusive.
5. Negative antibody/antigen combined test for HIV.
6. 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.
7. 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.
8. 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.
9. Males participating in sexual intercourse that could result in pregnancy must use condoms during the duration of the study.
10. 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.
11. Willing to abstain from multivitamins and antacids for the study duration.

Exclusion Criteria:

1. Any significant acute or chronic medical illness.
2. Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs or clinical laboratory determinations.
3. Positive blood screen for syphilis, hepatitis B (HBs Ag) and/or C antibodies.
4. Positive blood screen for HIV antibodies.
5. Positive screen for sexually transmitted infections at screening visit
6. 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.
7. Clinically significant laboratory abnormalities (according to normal range as defined by central laboratory).
8. Participation in a clinical trial of an Investigational product within 1 month of planned baseline enrolment in this study.
9. Ingestion of H2 receptor antagonists or proton pump inhibitor drugs in the preceding 14 days
10. Current of planned use of anti-epileptics

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A Raltegravir, then Raltegravir/Lamivudine; 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; bd for 7 days; Other Names: Isentress; Drug: Lamivudine 150Mg Tablet; + Raltegravir 400Mg tablet bd for 7 days; Other Names: Epivir
Active Comparator: Arm B Raltegravir/Lamivudine, then Raltegravir; 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; bd for 7 days; Other Names: Isentress; Drug: Lamivudine 150Mg Tablet; + Raltegravir 400Mg tablet bd for 7 days; Other Names: Epivir

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Time From First Dose of Drug to Maximum Mucosal ex Vivo Protection From HIV.	Time in days from first receipt of antiretroviral (Raltegravir 400mg +/-lamivudine) until maximal ex vivo protection (against high or low titre of HIV-1BaL) was observed.	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	Subject safety and tolerability will be determined by physical examination, blood tests and adverse event reporting. FBC, U&E and LFTs will be carried out at baseline and thereafter as symptom directed. Adverse event review. If significant adverse events have been reported, these will be clinically followed in accordance to the instruction of the study physician.	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.	Time in days from stopping antiretroviral (Raltegravir 400mg +/-lamivudine) until ex vivo protection (against high or low viral titre of HIV-1BaL) was no longer observed.	5 days post last dose

Collaborators and Investigators

• Sponsor: Guy's and St Thomas' NHS Foundation Trust
• Investigators: Study Director: Julie Fox, Guy's and St Thomas' NHS Foundation Trust

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 19, 2017
• Primary Completion (Actual): September 24, 2018
• Study Completion (Actual): September 24, 2018

Study Registration Dates

• First Submitted: June 8, 2017
• First Submitted That Met QC Criteria: June 29, 2017
• First Posted (Actual): July 2, 2017

Study Record Updates

• Last Update Posted (Actual): March 16, 2021
• Last Update Submitted That Met QC Criteria: February 22, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Raltegravir Potassium; Lamivudine
• Other Study ID Numbers: 202316

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No