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| Name | Class |
|---|---|
| University of Cape Town | OTHER |
| Desmond Tutu HIV Foundation | OTHER |
| Gilead Sciences | INDUSTRY |
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This study will establish benchmarks of TFV-DP concentrations as measures of adherence following daily dosing with Tenofovir Alafenamide (TAF) compared with Tenofovir Disoproxil Fumarate (TDF) during pregnancy and postpartum. Study Investigators will recruit from an ongoing observational cohort study in Cape Town, South Africa, PrEP-PP (recruitment ongoing through July, 2021; NIMH R01MH116771; PI Coates & Myer). Findings form this PK sub-study will be used to inform future PrEP in pregnancy and postpartum studies and develop benchmarks of the relative PK between TDF and TAF.
This study will establish benchmarks of TFV-DP concentrations as measures of adherence following daily dosing with Tenofovir Alafenamide (TAF) compared with Tenofovir Disoproxil Fumarate (TDF) during pregnancy and postpartum. Study Investigators will recruit from an ongoing observational cohort study in Cape Town, South Africa, PrEP-PP (recruitment ongoing through July, 2021; NIMH R01MH116771; PI Coates & Myer). Findings form this PK sub-study will be used to inform future PrEP in pregnancy and postpartum studies and develop benchmarks of the relative PK between TDF and TAF.
Study aims. (1) To establish benchmarks of TFV-DP concentrations as measures of adherence following daily dosing with TAF vs TDF in pregnancy and again in postpartum; (2) To compare the difference of TFV-DP within TDF and TAF for pregnancy vs. postpartum, and to establish adherence benchmarks of levels of TFV in breastmilk in postpartum women and compare with TDF sample.
The study will take place in an urban township in Cape Town (Gugulethu) with high HIV incidence that spans the different socioeconomic, cultural, and ethnic groups in South Africa. We selected this community because of the high HIV prevalence there in pregnant and breastfeeding women, and because of the high number of mothers visiting every month for ANC and labour/delivery.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| TAF arm | Experimental | Fixed dose combination of 200 mg emtricitabine (FTC) and 25 mg tenofovir alafenamide (TAF) delivered under direct observation for 8 weeks during pregnancy and 8 weeks in postpartum period |
|
| TDF arm | Active Comparator | Fixed dose combination of 200 mg emtricitabine (FTC) and 300 mg tenofovir disoproxil fumarate (TDF) delivered under direct observation for 8 weeks during pregnancy and 8 weeks in postpartum period |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tenofovir alafenamide | Drug | Daily DOT fixed dose combination of 200 mg emtricitabine (FTC) and 25 mg tenofovir alafenamide (TAF) |
|
| Measure | Description | Time Frame |
|---|---|---|
| Tenofovir Diphosphate (TFV-DP) Levels in Plasma and Intracellular Levels in Pregnant Women on Daily PrEP | Levels of TFV-DP (geometric mean), comparing the drugs TAF to TDF, observed in pregnancy. Note: Observation of daily PrEP dosing spanned 16 weeks in total, including 8 weeks during pregnancy and 8 weeks in postpartum. Once participants had completed their 8 weeks of in-pregnancy observation, observation of therapy was paused until they entered the postpartum phase. | 8 week period during Pregnancy |
| Tenofovir Diphosphate (TFV-DP) Levels in Plasma and Intracellular Levels in Postpartum Women on Daily PrEP | Levels of TFV-DP (geometric mean), comparing the drugs TAF to TDF, observed in postpartum period. Note: Observation of daily PrEP dosing spanned 16 weeks in total, including 8 weeks during pregnancy and 8 weeks in postpartum. Once participants had completed their 8 weeks of in-pregnancy observation, observation of therapy was paused until they entered the postpartum phase. | 8 week period during Postpartum (up to 1 year from baseline pregnancy visit) |
| Measure | Description | Time Frame |
|---|---|---|
| Tenofovir Diphosphate (TFV-DP) Concentrations in Plasma and Intracellular Levels Comparing Pregnancy Against Postpartum Women | Plasma and intracellular concentrations of tenofovir and plasma TFV-DP in antenatal and postpartum groups intra-individual comparisons. Note: TFV-DP measures were obtained by DBS once a week during periods of observation. Observation of daily PrEP dosing spanned 16 weeks in total, including 8 weeks during pregnancy and 8 weeks in postpartum. Once participants had completed their 8 weeks of in-pregnancy observation, observation of therapy was paused until they entered the postpartum phase. |
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Inclusion Criteria:
Exclusion Criteria:
Individuals not meeting the above criteria or meeting any of the following criteria will be excluded:
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| Name | Affiliation | Role |
|---|---|---|
| Landon Myer, MD | UCT | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Gugulethu Midwife Obstetric Unit | Cape Town | South Africa |
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We received IRB approval to increase the sample size to up to 30 participants per group to account for potential attrition and pregnancy loss (total up to N=60 women).
Between June 2022 and October 2022, the study enrolled participants from a large, urban clinic outside of Cape Town, South Africa. Inclusion criteria required the women to: (1) be aged 18 and older; (2) test HIV-negative; (3) be between 20-30 weeks of gestation; (4) own a smart phone; and (5) to consent to daily video observations of taking a PrEP pill.
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| ID | Title | Description |
|---|---|---|
| FG000 | TAF Arm | Fixed dose combination of 200 mg emtricitabine (FTC) and 25 mg tenofovir alafenamide (TAF) delivered under direct observation for 8 weeks during pregnancy and 8 weeks in postpartum period Tenofovir alafenamide: Daily DOT fixed dose combination of 200 mg emtricitabine (FTC) and 300 mg tenofovir disoproxil fumarate (TDF) |
| FG001 | TDF Arm | Fixed dose combination of 200 mg emtricitabine (FTC) and 300 mg tenofovir disoproxil fumarate (TDF) delivered under direct observation for 8 weeks during pregnancy and 8 weeks in postpartum period Tenofovir Disoproxil Fumarate: Daily DOT fixed dose combination of 200 mg emtricitabine (FTC) and 25 mg tenofovir alafenamide (TAF) |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
While N=60 women initially enrolled, final analysis population was N=39, as 7 individuals withdrew from study and 14 individuals were censored.
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| ID | Title | Description |
|---|---|---|
| BG000 | TAF Arm | Fixed dose combination of 200 mg emtricitabine (FTC) and 25 mg tenofovir alafenamide (TAF) delivered under direct observation for 8 weeks during pregnancy and 8 weeks in postpartum period Tenofovir alafenamide: Daily DOT fixed dose combination of 200 mg emtricitabine (FTC) and 300 mg tenofovir disoproxil fumarate (TDF) |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Tenofovir Diphosphate (TFV-DP) Levels in Plasma and Intracellular Levels in Pregnant Women on Daily PrEP | Levels of TFV-DP (geometric mean), comparing the drugs TAF to TDF, observed in pregnancy. Note: Observation of daily PrEP dosing spanned 16 weeks in total, including 8 weeks during pregnancy and 8 weeks in postpartum. Once participants had completed their 8 weeks of in-pregnancy observation, observation of therapy was paused until they entered the postpartum phase. | Posted | Geometric Mean | 95% Confidence Interval | TFV-DP PBMC (fmol/10^6cells) | 8 week period during Pregnancy |
|
Participants were then observed for 16 weeks* of daily PrEP dosing *This included 8 weeks of observation during pregnancy and 8 weeks in postpartum. Once participants had completed their 8 weeks of in-pregnancy observation, observation of therapy was paused until they entered the postpartum phase. PrEP dosing was not observed or measured during this pause, but participants were supplied with sufficient pills during this time and were encouraged to continue with daily use.
Serious Adverse Events, defined as any untoward occurrence that 1) results in death, 2) is life threatening, 3) requires patient hospitalization, 4) results in a congenital anomaly/ birth defect, 5) results in persistent or significant disability/incapacity, or 6) is a medically significant event or reaction, were recorded among all participants during periods of observation, according to South African Health Products Regulatory Authority (SAHPRA) safety reporting guidelines.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | TAF Arm | Fixed dose combination of 200 mg emtricitabine (FTC) and 25 mg tenofovir alafenamide (TAF) delivered under direct observation for 8 weeks during pregnancy and 8 weeks in postpartum period Tenofovir alafenamide: Daily DOT fixed dose combination of 200 mg emtricitabine (FTC) and 300 mg tenofovir disoproxil fumarate (TDF) |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| C-Section Delivery (Emergency) | Pregnancy, puerperium and perinatal conditions | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dvora Joseph Davey | UCLA | 3107011526 | dvoradavey@ucla.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Oct 12, 2022 | Apr 16, 2024 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D000163 | Acquired Immunodeficiency Syndrome |
| ID | Term |
|---|---|
| D015658 | HIV Infections |
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D007239 | Infections |
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| ID | Term |
|---|---|
| C442442 | tenofovir alafenamide |
| D000068698 | Tenofovir |
| D000069480 | Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination |
| ID | Term |
|---|---|
| D063065 | Organophosphonates |
| D009943 | Organophosphorus Compounds |
| D009930 | Organic Chemicals |
| D000225 | Adenine |
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This phase III study is a randomised control trial (RCT) of up to 60 pregnant women who will be recruited at first antenatal visit (ANC) from the Gugulethu Midwife and Obstetrics Unit.
Participants will be randomized into the TDF vs TAF arm:
TDF Arm: Women will receive a fixed dose combination of 200 mg emtricitabine (FTC) and 300 mg tenofovir disoproxil fumarate (TDF) administered once daily under direct observation for 8 weeks during pregnancy and again for 8 weeks in postpartum period
TAF Arm: Fixed dose combination of 200 mg emtricitabine (FTC) and 25 mg tenofovir alafenamide (TAF) administered once daily under direct observation for 8 weeks during pregnancy and again for 8 weeks in postpartum period Women will provide their own controls, providing pregnant and postpartum samples.
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| Tenofovir Disoproxil Fumarate | Drug | Daily DOT fixed dose combination of 200 mg emtricitabine (FTC) and 300 mg tenofovir disoproxil fumarate (TDF) |
|
|
| Pregnancy (TVF-DP measures via DBS collected weekly, reported 8 weeks after start of pregnancy observation); Postpartum (TVF-DP measures via DBS collected weekly, reported 8 weeks after start of postpartum observation, up to 1 year from baseline). |
| TDF Arm |
Fixed dose combination of 200 mg emtricitabine (FTC) and 300 mg tenofovir disoproxil fumarate (TDF) delivered under direct observation for 8 weeks during pregnancy and 8 weeks in postpartum period Tenofovir Disoproxil Fumarate: Daily DOT fixed dose combination of 200 mg emtricitabine (FTC) and 25 mg tenofovir alafenamide (TAF) |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Age, Customized | Count of Participants | Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| OG001 | TDF Arm | Fixed dose combination of 200 mg emtricitabine (FTC) and 300 mg tenofovir disoproxil fumarate (TDF) delivered under direct observation for 8 weeks during pregnancy and 8 weeks in postpartum period Tenofovir Disoproxil Fumarate: Daily DOT fixed dose combination of 200 mg emtricitabine (FTC) and 300 mg tenofovir disoproxil fumarate (TDF) |
|
|
| Primary | Tenofovir Diphosphate (TFV-DP) Levels in Plasma and Intracellular Levels in Postpartum Women on Daily PrEP | Levels of TFV-DP (geometric mean), comparing the drugs TAF to TDF, observed in postpartum period. Note: Observation of daily PrEP dosing spanned 16 weeks in total, including 8 weeks during pregnancy and 8 weeks in postpartum. Once participants had completed their 8 weeks of in-pregnancy observation, observation of therapy was paused until they entered the postpartum phase. | Posted | Geometric Mean | 95% Confidence Interval | TFV-DP PBMC (fmol/10^6 cells) | 8 week period during Postpartum (up to 1 year from baseline pregnancy visit) |
|
|
|
| Secondary | Tenofovir Diphosphate (TFV-DP) Concentrations in Plasma and Intracellular Levels Comparing Pregnancy Against Postpartum Women | Plasma and intracellular concentrations of tenofovir and plasma TFV-DP in antenatal and postpartum groups intra-individual comparisons. Note: TFV-DP measures were obtained by DBS once a week during periods of observation. Observation of daily PrEP dosing spanned 16 weeks in total, including 8 weeks during pregnancy and 8 weeks in postpartum. Once participants had completed their 8 weeks of in-pregnancy observation, observation of therapy was paused until they entered the postpartum phase. | Posted | Median | Inter-Quartile Range | TDF:fmol/3mm punch; TAF:fmol/3mm punch | Pregnancy (TVF-DP measures via DBS collected weekly, reported 8 weeks after start of pregnancy observation); Postpartum (TVF-DP measures via DBS collected weekly, reported 8 weeks after start of postpartum observation, up to 1 year from baseline). |
|
|
|
| 0 |
| 20 |
| 9 |
| 20 |
| 0 |
| 20 |
| EG001 | TDF Arm | Fixed dose combination of 200 mg emtricitabine (FTC) and 300 mg tenofovir disoproxil fumarate (TDF) delivered under direct observation for 8 weeks during pregnancy and 8 weeks in postpartum period Tenofovir Disoproxil Fumarate: Daily DOT fixed dose combination of 200 mg emtricitabine (FTC) and 25 mg tenofovir alafenamide (TAF) | 0 | 19 | 5 | 19 | 0 | 19 |
| Attempted suicide | Psychiatric disorders | Non-systematic Assessment |
|
| Intimate Partner Violence | Social circumstances | Non-systematic Assessment |
|
| Premature Birth | Pregnancy, puerperium and perinatal conditions | Non-systematic Assessment |
|
| Shigella dysenteriae, Infant | Infections and infestations | Non-systematic Assessment |
|
| Bartholin cyst | Reproductive system and breast disorders | Non-systematic Assessment |
|
| Premature rupture of membranes | Pregnancy, puerperium and perinatal conditions | Non-systematic Assessment |
|
| Fetal tachycardia | Pregnancy, puerperium and perinatal conditions | Non-systematic Assessment |
|
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| D015229 |
| Sexually Transmitted Diseases, Viral |
| D012749 | Sexually Transmitted Diseases |
| D016180 | Lentivirus Infections |
| D012192 | Retroviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D012897 | Slow Virus Diseases |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |
| D011687 |
| Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D000068679 | Emtricitabine |
| D003841 | Deoxycytidine |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D003853 | Deoxyribonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D004338 | Drug Combinations |
| D004364 | Pharmaceutical Preparations |