Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202209528604242 Date of Approval: 22/09/2022
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title The Women TAF-FTC Benchmark Study.
Official scientific title Safety and Pharmacokinetics of TAF-FTC Pre-Exposure Prophylaxis in Kenyan Cisgender women- of TDF-FTC Pre-exposure Prophylaxis in Kenyan Cisgender women.
Brief summary describing the background and objectives of the trial PROTOCOL ABSTRACT/SUMMARY Pre-exposure prophylaxis (PrEP) using co-formulated emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) is a potent HIV prevention method for men and cisgender women., with its Efficacy is highly dependent on adherence. Pivotal studies that combined clinical epidemiology and pharmacology defined thresholds for PrEP protection in men who have sex with men (MSM) that have been key to PrEP promotion and development of new PrEP agents. For African cisgender women at risk for HIV, a priority group due to disproportionately high incident HIV infections, variable adherence in PrEP clinical trials and limited pharmacokinetics data have resulted in lack of clarity about levels of PrEP use required for HIV protection. A new form of tenofovir, tenofovir alafenamide fumarate, co-formulated with emtricitabine (TAF-FTC) or Descovy® has recently been approved by the U.S. Food and Drug Administration for PrEP use in men. However, Descovy® is not indicated in at risk cisgender women because its the safety and effectiveness in this population has not been evaluated. Studies are now planned or ongoing in African cisgender women to evaluate TAF-FTC for PrEP. Tenofovir-diphosphate (TFV-DP) in dried blood spots was critical for interpreting Descovy® study outcomes in the DISCOVER trial, and will again be essential for the planned studies to evaluate the effectiveness of Descovy® for PrEP in women. Thus, clear knowledge of African women-specific adherence-concentration benchmark for TAF-FTC relationship is essential to define success of these studies. To date, no study has evaluated safety and directly observed expected TAF-FTC PrEP concentrations in African cisgender women with varying frequency of PrEP adherence. TAF efficiently achieves higher concentrations within lymphoid cells while attaining lower TFV concentration in plasma compared to TDF. This creates potential advantages of TAF for PrEP, as the higher TFV-DP in lymphoid cells may confer high activity, whereas the lower plasma TFV concentrations may improve markers of bone and renal changes compared with TDF. Although, the clinical significance of these marker changes is unknown, it is thought that TAF may exhibit improved long-term safety compared with TDF. We will conduct an open-label, randomized, three-arm, directly observed dosing pharmacokinetics study of TAF-FTC PrEP in African cisgender women. The primary objectives are: 1) To assess the safety of TAF-FTC PrEP in cisgender women. 2) To define the cisgender women-specific expected blood concentrations and dose-proportionality for TFV-DP in DBS and PBMCs using directly observed TAF-FTC therapy at 2, 4, 7 doses per week. 3) To establish a model to predict adherence rate to TAF-FTC by level of TFV-DP in DBS for cisgender women. HIV-uninfected non-pregnant cisgender women will be randomly assigned to 1 of 3 dosing frequencies of directly observed therapy (DOT) TAF-FTC PrEP: 2, 4, or 7 doses/week, to help differentiate represent poor, and modest, and from perfect adherence, respectively. The study will enrol up to 54, 18-30 years old HIV uninfected cisgender women at low risk of HIV at Thika site in Kenya. The proposed study will be the first to define TAF-PrEP adherence-blood concentration thresholds for African cisgender women, a priority population for HIV prevention. The findings will guide accurate interpretation of safety, adherence, and efficacy of planned or ongoing HIV prevention trials in African women.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) TAF FTC
Disease(s) or condition(s) being studied Infections and Infestations
Sub-Disease(s) or condition(s) being studied HIV/AIDS
Purpose of the trial Prevention
Anticipated trial start date 01/06/2022
Actual trial start date
Anticipated date of last follow up 26/10/2022
Actual Last follow-up date
Anticipated target sample size (number of participants) 54
Actual target sample size (number of participants)
Recruitment status Not yet recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Parallel: different groups receive different interventions at same time during study Randomised Simple randomization using a randomization table created by a computer software program Allocation was determined by the holder of the sequence who is situated off site Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Control Group Pre exposure prophylaxes PrEP HIV-uninfected non-pregnant cisgender women will be randomly assigned 1:1:1 to 1 of 3 dosing frequencies of DOT TAF-FTC PrEP: 2, 4, or 7 doses/week to help differentiate poor and modest adherence from perfect adherence. We will measure Drug concentrations in blood, cervico-vaginal fluid, and tissue will be measured during the study. The frequency of adverse events will be described. The study product is Descovy® formulated as tenofovir alafenamide (TAF) 25 mg/ emtricitabine 200 mg(FTC). Group #1: “7 doses per week or Perfect Adherence arm”— cisgender women will receive a single tablet of co-formulated 25 mg TAF/ 200mg FTC once daily (7 doses per week). 18 weeks This is an open-label, randomized, three-arm, directly observed therapy, pharmacokinetic study of TAFFTC PrEP among low-risk HIV-uninfected non-pregnant cisgender women. HIV-uninfected non-pregnant cisgender women at low risk for HIV will be randomly assigned to 1of 3 dosing frequencies of directly observed (DOT) TAF-FTC PrEP. 18 Dose Comparison
Experimental Group Pre Exposure Prophylaxis Group #2: “4 doses per week or Moderate Adherence arm” — cisgender women will receive a single tablet of co-formulated 25 mg TAF/ 200mg FTC tablet on Monday, Tuesday, Thursday, Friday. 18 weeks This is an open-label, randomized, three-arm, directly observed therapy, pharmacokinetic study of TAFFTC PrEP among low-risk HIV-uninfected non-pregnant cisgender women. HIV-uninfected non-pregnant cisgender women at low risk for HIV will be randomly assigned to 1of 3 dosing frequencies of directly observed (DOT) TAF-FTC PrEP. 18
Experimental Group Pre Exposure Prophylaxis Group #3: “2 doses per week or Poor Adherence arm” — cisgender women will receive a single tablet of co-formulated 25 mg TAF/ 200mg FTC tablet on Monday and Tuesday 18 week This is an open-label, randomized, three-arm, directly observed therapy, pharmacokinetic study of TAFFTC PrEP among low-risk HIV-uninfected non-pregnant cisgender women. HIV-uninfected non-pregnant cisgender women at low risk for HIV will be randomly assigned to 1of 3 dosing frequencies of directly observed (DOT) TAF-FTC PrEP. 18
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
For all cisgender women - Age ≥18 and ≤30 years old. - Willing to undergo urine pregnancy tests. - Has understood the information provided and has provided written informed consent before any study-related procedures are performed.. - HIV uninfected based on negative HIV rapid tests, according to Kenyan national algorithm. - Normal renal function (estimated glomerular filtration rate >60 mL/min). - Hepatitis B surface antigen Ag negative.. - No active, clinically significant medical or psychiatric conditions that, in the opinion of the investigators, would interfere with study participation . - Lack of severe anemia (Hemoglobin >10 g/dL). - Willing to use DOT and come to clinic frequently for DOT PrEP for at least 10 weeks. - Willing to have home visits for follow up. - Has access to an active smartphone to allow off-site observation of dosing if unable to come to the clinic, or, as determined by the study staff, the participant resides in a close enough location to the clinic to permit a home visit if unable to come to the clinic. That isi.e., potential participants without a smartphone may be enrolled in the study if investigator determines that the participant resides within reasonable distance from the clinic that would permit home visit ID the participant misses their visit for a home visit in the case of a missed clinic visit. - Intention to stay within the study site’s catchment area for at least 10 weeks. Women TAF-FTC Benchmark Study. - Resides or works in catchment area with high speed internet coverage to permit video streaming. - Not pregnant or breast feeding. - Willing to use effective contraception during the study period. - At low risk for HIV. In Kenya, national guidelines define substantial risk for HIV and recommend PrEP be an option for individuals reporting: partner of HIV-infected person not on ART or on ART for <6 months, >1 partner of unknown status, transactional sex, recent STI, recurrent PEP use, For all cisgender women – Inability to give informed consent – Positive screening HIV+ as determined by standard rapid serologic assays or suspected acute HIV infection in the opinion of the clinician. (Eexample signs and symptoms of acute HIV infection include combinations of fever, headache, fatigue, arthralgia, vomiting, myalgia, diarrhea, pharyngitis, rash, night sweats, and cervical or inguinal adenopathy cervical or inguinal.) – Positive HBV surface antigen test at screening. – Calculated creatinine clearance <60 ml/min. – Any laboratory value or uncontrolled medical conditions that, in the opinion of the investigators, would interfere with the study conditions such as, heart disease and/or cancer. – Prohibited concomitant medications are: investigational agents (within 30 days of enrollment), aminoglycosides, ganciclovir/valganciclovir, chronic high-dose acyclovir/valacyclovir (>800mg acyclovir or >500mg valacyclovir for >7 days), cyclosporine, amphotericin B, foscarnet, and cidofovir, and products with same or similar active ingredients as the study medications including TAF®, TRUVADA®, ATRIPLA®, COMPLERA®, EMTRIVA®, VIREAD®; or drugs containing lamivudine or adefovir, which are close analogs of FTC and tenofovir, respectively. – Current or past use of PrEP (pre-exposure prophylaxis). – Not willing to have home visits. – Pregnantcy or plan to become pregnant in the next 6 months or unwillingness to use birth control . – Currently breastfeeding. – High risk of HIV infection (for example: sexually active with an HIV infected partner; engages in condomless intercourse with HIV-infected partners or partner of unknown status during the study; females who exchanges sex for money, shelter, or gifts; active injection drug use or during the last 12 months; newly diagnosed sexually transmitted infections in last 6 months. Adult: 19 Year-44 Year 18 Year(s) 30 Year(s) Female
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 21/01/2022 KEMRI Scientific Ethics Review Unit
Ethics Committee Address
Street address City Postal code Country
Mbagathi way Nairobi 00100 Kenya
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Primary outcomes Primary outcome 1: The goal is to describe the frequency of adverse events, including emergent HIV infection during the study period. We will conduct a descriptive analysis for meeting PrEP157 eligibility among participants. The distribution of demographics and graded adverse events will characteristics by overall and study arms and proportions will compared between study arms using chi-square statistics. Primary outcome 2: The goal is to quantify the effect of dose on steady state TFV-DP in DBS and PBMC based on an incomplete block design. Css (drug concentration at steady state) will likely require a normalizing log transform, such that geometric means and CIs will be reported. Dose proportionality will be assessed using the power model (on the natural log scale) ln(Yijk) = µ + Si + Pj + log(Dk) + ijk (Eqn. 1).37 Where Yijk is the response, Css, for the kth dose (k=2, 4, 7 doses/week), jth period (j=1,2), ith subject(i=1,…45); µ is the overall mean, Si is a random subject effect, Pj is the period effect and ijk is random error. Dose proportionality dictates that = for dose-dependent parameters and we will assume dose proportionality if the 90% CI is contained within the limits (0.8, 1.25). The SAS mixed procedure will be utilized for model (Eqn 1), again assuming a random subject effect. Although we do not anticipate a period effect, our design allows us to test this effect. For the primary analysis, we assume no effect of ‘non-daily dosing’ regimens; although this will be examined in a secondary analysis. If dose proportionality is not shown, we will examine proportionality separately for each of the ‘‘non-daily dosing’ dosing regimens. If dose proportionality is still not demonstrated when adherence regimens are examined separately, we will consider dose as a categorical predictor. Primary outcome 3: The goal is to identify TFV-DP cut points associated with adherence levels. For the primary analyses, we will attempt to discriminate adherence for 2, 4 and 7 dosing based upon TFV-DP. As above, we will combine the “non-daily dosing’” regimens. Linear mixed models with random intercepts, 25th percentiles, and receiver operating characteristics curves will be used to generate predicted concentration thresholds for varying dosing frequency (ranging from 1 to 7 doses/week) for each matrix analyte pair. Analyses will be adjusted for age, contraception use, study arm, BMI, eGFR, and haematocrit 18 weeks
Secondary Outcome 1. Examine models to predict non-daily adherence based on TFV/FTC and FTC-TP/TFV-DP in DBS. We will first consider a saturated model allowing a separate mean for each dose/adherence group. The results will then be compared to a reduced model with a class variable indicating non-daily dosing groups” or 100% dosing (that is, the effect of “non-daily dosing” adherence does not differ by dose groups). Drug concentration predictors of “non-daily dosing” will focus on TFV-DP in relationship to other drug moieties such as FTC-TP and FTC and TFV. For instance, the ratio of TFV-DP to FTC-TP may be used as a predictor of “2” versus “4 dosing per week. A proportional odds logistic approach which allows for an ordinal outcome and extensions which control for correlations between repeated measurements on a subject will be utilized in SAS or R statistical software. In addition, we will employ PK models (see Aim-1) to simulate TFV-DP to FTC-TP ratios for other dose regimens and estimate cut points for predicting non-daily dosing patterns. 2. Examine relationships among drug concentrations in plasma, RBC, DBS, and PBMC.We will use mixed and non-linear mixed effects models to determine if concentrations in various matrices are related. 3. Evaluate the influence of demographics, and biological on drug concentrations. Kruskal-Wallis parametric test will be used to compare demographics and key study variables (e.g., age, pregnancy, HCT, contraception use, study arm, BMI, and eGFR). Non-linear mixed effects models also will be used to probe covariate effects on PK. Secondary analyses are considered hypothesis generating and will not correct for multiple comparisons. 4. Compare drug concentrations in DBS from finger stick versus transferring blood from blood tubes. Since these are paired DBS samples, we will compute the ratio of TFV-DP in the two samples and a mixed model on the natural log of the ratio will be utilized to determine if CI is within 0.8 and 1.25, indicating equivalence. 18 weeks
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
KEMRI PHRD THIKA Thika Super highway Thika 01000 Kenya
FUNDING SOURCES
Name of source Street address City Postal code Country
Gilead Sciences 333 Lakeside Drive Foster City, CA 94404. 333 Lakeside City 00001. Wallis and Futuna Islands
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor University of Washington 1st Ave NE Seattle, Seattle 98195 United States of America University
COLLABORATORS
Name Street address City Postal code Country
Dr Kenneth Mugwanya 1st Ave NE Seattle, Seattle 00001. United States of America
Gilead Sciences ida business park Carrigtwohill T45 DP77 Ireland
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Nelly Mugo rwamba@uw.edu 254067222256 Thika Super Highway
City Postal code Country Position/Affiliation
Thika 01000 Kenya Senior Principal Clinical Research Scientist KEMRI
Role Name Email Phone Street address
Scientific Enquiries Kenneth Mugwanya mugwanya@uw.edu 2065204520 NE Campus Parkway
City Postal code Country Position/Affiliation
Seattle 98195 United States of America Assistant Professor University of Washington
Role Name Email Phone Street address
Public Enquiries Matilda Saina sainamatilda@pipsthika.org +254736464299 OAU Road
City Postal code Country Position/Affiliation
Thika Section 9 Kenya Study Physician KEMRI CCR PHRD
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes The Principal Investigators commit to share this data once the study is completed and published Study Protocol IPD will be shared after study completion and results published. After data analyses, the PIs will seek to publish the study results in publicly accessible sites and journals. The PIs are ready and willing to circulate the published data to individuals who may reach out to them, individually.
URL Results Available Results Summary Result Posting Date First Journal Publication Date
No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
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