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

Primary Purpose

Hiv

Status

Completed

Phase

Phase 4

Locations

United Kingdom

Study Type

Interventional

Intervention

Raltegravir 400Mg Tab

Lamivudine 150Mg Tablet

About this trial

This is an interventional prevention trial for Hiv

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

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.

Exclusion Criteria:

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

Sites / Locations

Harrison Wing, Guy's Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

Arm A Raltegravir, then Raltegravir/Lamivudine

Arm B Raltegravir/Lamivudine, then Raltegravir

Arm Description

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

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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.

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.

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.

Full Information

NCT ID

NCT03205566

First Posted

June 8, 2017

Last Updated

February 22, 2021

Sponsor

Guy's and St Thomas' NHS Foundation Trust

1. Study Identification

Unique Protocol Identification Number

NCT03205566

Brief Title

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

Acronym

R-PrEP

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

February 2021

Overall Recruitment Status

Completed

Study Start Date

September 19, 2017 (Actual)

Primary Completion Date

September 24, 2018 (Actual)

Study Completion Date

September 24, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Guy's and St Thomas' NHS Foundation Trust

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hiv

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 4

Interventional Study Model

Crossover Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

38 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm A Raltegravir, then Raltegravir/Lamivudine

Arm Type

Active Comparator

Arm Description

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

Arm Title

Arm B Raltegravir/Lamivudine, then Raltegravir

Arm Type

Active Comparator

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

Raltegravir 400Mg Tab

Other Intervention Name(s)

Isentress

Intervention Description

bd for 7 days

Intervention Type

Drug

Intervention Name(s)

Lamivudine 150Mg Tablet

Other Intervention Name(s)

Epivir

Intervention Description

+ Raltegravir 400Mg tablet bd for 7 days

Primary Outcome Measure Information:

Title

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

Description

Time Frame

Through Study completion, an average of 55 days

Secondary Outcome Measure Information:

Title

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

Description

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.

Time Frame

Up to 7 days from first dose

Title

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

Description

Time Frame

Through Study completion, an average of 55 days

Title

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

Description

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.

Time Frame

5 days post last dose

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

60 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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. Exclusion Criteria: 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Julie Fox

Organizational Affiliation

Guy's and St Thomas' NHS Foundation Trust

Official's Role

Study Director

Facility Information:

Facility Name

Harrison Wing, Guy's Hospital

City

London

ZIP/Postal Code

SE1 9RT

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

21091279

Citation

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.

Results Reference

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PubMed Identifier

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Citation

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PubMed Identifier

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Citation

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PubMed Identifier

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Citation

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Results Reference

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

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