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

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Hiv	Drug: Raltegravir 400Mg Tab; Drug: Lamivudine 150Mg Tablet	Phase 4

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 Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	36 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Prevention
Official Title:	The Time to Protection and Adherence Requirements of Raltegravir With or Without Lamivudine in Protection From HIV Infection
Estimated Study Start Date :	July 2017
Estimated Primary Completion Date :	December 2017
Estimated Study Completion Date :	June 2018

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: Arm A Raltegravir; Raltegravir 400mg tablet, taken twice a day for 7days.	Drug: Raltegravir 400Mg Tab; bd for 7 days; Other Name: Isentress
Active Comparator: Arm B Raltegravir Lamivudine; Raltegravir 400mg + Lamivudine 150mg tablet, taken twice a day for 7days.	Drug: Raltegravir 400Mg Tab; bd for 7 days; Other Name: Isentress; Drug: Lamivudine 150Mg Tablet; + Raltegravir 400Mg tablet bd for 7 days; Other Name: Epivir

Outcome Measures

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Primary Outcome Measures :

1. The level of Raltegravir alone or Raltegravir /lamivudine required in the plasma, vagina and rectum for 100% ex vivo protection from HIV [ Time Frame: Through Study completion, an average of 55 days ]
   Results from Raltegravir and Raltegravir/lamivudine will be compared at study completion.

Secondary Outcome Measures :

1. The time from first dose of drug to mucosal ex vivo protection from HIV infection [ Time Frame: 15 days post biopsy ]
   Confirmation of time that participant administered Raltegravir 400mg +/-lamivudine. All individuals will receive tissue sampling for ex vivo analysis to ensure biopsies are infectable on challenge assays. Biopsy tissue will be exposed to different concentrations of HIV virus (BAL R5), washed and cultured for 15 days. Cultures wil be fed at days 3, 7, 11 and 15 when culture supernatant will be harvested and frozen prior to addition of fresh media. HIV p24 Ag ELISA measurements will be carried out for detection of antigen in culture supernatants though out the 15 days of culture.
2. The time to cessation of mucosal ex vivo protection from HIV after stopping ART at steady state. [ Time Frame: 3 days post last dose ]
   Confirmation of time that participant administered Raltegravir 400mg +/-lamivudine. All individuals will receive tissue sampling for ex vivo analysis to ensure biopsies are infectable on challenge assays. Biopsy tissue will be exposed to different concentrations of HIV virus (BAL R5), washed and cultured for 15 days. Cultures wil be fed at days 3, 7, 11 and 15 when culture supernatant will be harvested and frozen prior to addition of fresh media. HIV p24 Ag ELISA measurements will be carried out for detection of antigen in culture supernatants though out the 15 days of culture.
3. The safety and tolerability of Raltegravir based PrEP in HIV negative individuals [ Time Frame: Through Study completion, an average of 55 days ]
   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.

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 60 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes

Criteria

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

Contacts and Locations

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Contacts

Contact: Julie Fox	+44 0207 188 6243	julie.fox@kcl.ac.uk

Sponsors and Collaborators

Guy's and St Thomas' NHS Foundation Trust

Investigators

Study Director:	Julie Fox	Guy's and St Thomas' NHS Foundation Trust

More Information

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Additional Information:

FDA 

Publications of Results:

Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, Goicochea P, Casapía M, Guanira-Carranza JV, Ramirez-Cardich ME, Montoya-Herrera O, Fernández T, Veloso VG, Buchbinder SP, Chariyalertsak S, Schechter M, Bekker LG, Mayer KH, Kallás 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.

García-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-Diéguez 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. Review.

Responsible Party:	Guy's and St Thomas' NHS Foundation Trust
ClinicalTrials.gov Identifier:	NCT03205566 History of Changes
Other Study ID Numbers:	202316
First Posted:	July 2, 2017
Last Update Posted:	July 2, 2017
Last Verified:	June 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Studies a U.S. FDA-regulated Drug Product:		No
Studies a U.S. FDA-regulated Device Product:		No

Additional relevant MeSH terms:

HIV Infections; Acquired Immunodeficiency Syndrome; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; Lamivudine	Raltegravir Potassium; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents; Anti-HIV Agents; HIV Integrase Inhibitors; Integrase Inhibitors