A Phase 4 interventional study of FTC/TDF and DMPA and FTC/TDF in Bone Demineralization, Hypoestrogenism and Subclinical Kidney Injury, sponsored by University of Washington. Completed at 1 site in Uganda. Open to female participants aged 16 Years to 25 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2024-06-17.
Sponsored by University of Washington · Phase 4, Interventional, and Diagnostic
The primary objective of this study is to address critical safety questions with concurrent TDF-based PrEP and DMPA use. We hypothesize that young women using TDF-based PrEP and DMPA will have lower bone acquisition and altered bone metabolism. Bone mineral metabolism is in part regulated by the kidney, and we hypothesize that bone effects from concurrent PrEP and DMPA use will be driven by subclinical kidney injury, a known side effect of TDF, as well as DMPA-induced hypoestrogenism. To investigate our hypothesis, we will enroll a prospective cohort of approximately 500 HIV-uninfected women ages 16-25 years in Kampala, Uganda who have substantial HIV risk and are initiating DMPA or barrier method contraception. Over a 24-month period, we will offer TDF-based PrEP. We will use state-of-the-art radiologic, biochemical, and epidemiologic methods to test the hypothesis that concurrent TDF-based PrEP and DMPA use results in compounding adverse effects on bone health.
The proposed research will investigate the hypothesis that TDF-based PrEP and DMPA initiated concurrently by HIV-uninfected women will enhance each other's effects on bone metabolism. The investigators will conduct an open-label prospective study of approximately 500 HIV-uninfected women at substantial risk for HIV-infection who are newly initiating DMPA or using condoms as their only contraceptive in Kampala, Uganda. The investigators will offer PrEP to all of these women and determine the joint effect of PrEP and DMPA on changes in bone mass (Aim 1), bone turnover, subclinical kidney injury, and hypoestrogenism (Aim 2), and conduct mediation analysis to assess the contribution of each pathway to overall losses in bone mass (Aim 3).
At baseline and 24 months, the investigators will measure:
Over a 24-month period, the investigators will follow women quarterly with HIV rapid testing, PrEP adherence counseling and refills, DMPA injections, and provision of other contraceptives as desired. At enrollment and quarterly visits, the investigators will assess physical activity, sexual behavior, and menstrual cycle characteristics. Annually, the investigators will conduct physical exams and anthropometric readings. Sexually transmitted infections will be routinely assessed syndromically, according to national guidelines. Women will be encouraged to consider their HIV risk and fertility desires at every visit and counseled about contraception and PrEP accordingly. Dual energy x-ray absorptiometry (DXA) scans will be performed at baseline and annually thereafter. Blood and urine samples will be obtained quarterly, aliquoted, and archived at minus 80o Celsius.
DXA and TBS assessments:
DXA scans will be conducted at study enrollment (within 1 week of contraceptive initiation), 12, and 24 months after enrollment. DXA is the clinical standard for measuring BMD. It is painless and non-invasive. Women will be exposed to a relatively low level of radiation which is \<1/10 the dose of a standard chest x-ray, and less than a day's exposure to natural radiation. BMD by DXA of the hip and spine is generally considered the most reliable way to classify osteoporosis, assess changes in BMD, and predict fracture risk. The investigators will measure areal BMD of the lumbar spine (L1-4), hip, and wrist, and body composition (total and % fat and lean mass) using a DXA machine. For the TBS analysis, no additional image acquisition is required. TBS will be performed as a re-analysis of the lumbar spine taken as part of the standard DXA procedure with specialized software.
Contraceptive provision:
Women will initiate contraception at the study clinic or a family planning clinic, as they are seeking services. Throughout study follow up, the study will assume responsibility for contraceptive provision, including DMPA injections, and care of all other methods desired by women. The staff at the IDI-Kasangati research clinic have extensive experience with the provision of contraception and contraceptive counseling during previous HIV prevention studies.
PrEP provision and adherence monitoring
Co-formulated emtricitabine FTC/TDF will be provided as PrEP by the study. PrEP counseling and provision will follow WHO guidelines, or Ugandan clinical guidelines when they are available. The investigators will measure adherence using three different methods:
Laboratory processing to measure markers of bone turnover, subclinical kidney injury, and hypoestrogenism.
Using state-of-the-art assay techniques on archival samples, the investigators will measure 1) established markers of bone turnover and bone health, 2) markers of subclinical kidney injury, and 3) markers of hypoestrogenism. Archived samples will be batch-analyzed.
University of Washington is the lead sponsor of 1,433 studies on the registry; 225 are open to participants now.
Of its 158 completed or terminated interventional studies of FDA-regulated products, 136 (86%) have results posted.
Counted across the registry records on this site, refreshed daily.
Inclusion Criteria:
If age 16-17:
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
How quickly the kidneys clear creatinine, a waste product, from the blood. A study may estimate it from a blood test with age, weight and sex (often by the Cockcroft–Gault formula), or measure it using blood and urine collected over a set time. Given in mL/min; higher is better.
Hepatitis B is a virus that infects the liver. These are separate tests: HBsAg positive usually means a current infection (a recent vaccination can briefly cause it too); total anti-HBc (HBcAb) positive means an infection now or in the past; HBV DNA measures how much virus is in the blood.
Some studies accept a past infection if HBV DNA is undetectable, sometimes with antiviral medicine during the study. Check what this study allows.
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HIV
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Creatinine clearance (CrCl)
How quickly the kidneys clear creatinine, a waste product, from the blood. A study may estimate it from a blood test with age, weight and sex (often by the Cockcroft–Gault formula), or measure it using blood and urine collected over a set time. Given in mL/min; higher is better.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hepatitis B tests
Hepatitis B is a virus that infects the liver. These are separate tests: HBsAg positive usually means a current infection (a recent vaccination can briefly cause it too); total anti-HBc (HBcAb) positive means an infection now or in the past; HBV DNA measures how much virus is in the blood.
Some studies accept a past infection if HBV DNA is undetectable, sometimes with antiviral medicine during the study. Check what this study allows.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Corticosteroids (steroids)
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Combination Product: FTC/TDF and DMPA
Drug: DMPA
Drug: FTC/TDF
Other: Neither DMPA nor FTC/TDF
Drug pages: Emtricitabine · Tenofovir · Medroxyprogesterone Acetate
The primary analysis will be separate comparisons of the annualized rates of change in BMD and TBS of the spine and hip between women using PrEP and DMPA concurrently versus women using DMPA only (comparison 1), women using PrEP only (comparison 2), and women using neither (comparison 3). Analyses will account for baseline BMD.
The primary analysis will be separate comparisons of the annualized rates of change in BMD and TBS of the spine and hip between women using PrEP and DMPA concurrently versus women using DMPA only (comparison 1), women using PrEP only (comparison 2), and women using neither (comparison 3). Analyses will account for baseline BMD.
The primary analysis will be separate comparisons of the annualized rates of change in BMD and TBS of the spine and hip between women using PrEP and DMPA concurrently versus women using DMPA only (comparison 1), women using PrEP only (comparison 2), and women using neither (comparison 3). Analyses will account for baseline BMD.
The primary analysis will be separate comparisons of the annualized rates of change in BMD and TBS of the spine and hip between women using PrEP and DMPA concurrently versus women using DMPA only (comparison 1), women using PrEP only (comparison 2), and women using neither (comparison 3). Analyses will account for baseline BMD.
The investigators will assess whether young women using TDF-based PrEP and DMPA concurrently attain lower peak bone mass over a 24-month relative to women using either agent singly or neither agent.
The investigators will use dual energy x-ray absorptiometry (DXA) scans to measure BMD annually at 3 anatomical sites (lumbar spine, total hip, and wrist). Hypothesis: Relative to women using DMPA only (without tenofovir exposure) and women using PrEP only (without DMPA exposure), women concurrently using TDF-based PrEP and DMPA will have lower bone mass.
Time frame: 24 months
The investigators will assess whether young women using TDF-based PrEP and DMPA concurrently have evidence of disrupted microarchitecture, relative to women using either agent singly or neither agent.
The investigators will use dual energy x-ray absorptiometry (DXA) scans to derive the trabecular bone score (TBS), an index of lumbar spine trabecular microarchitecture. Hypothesis: Relative to women using DMPA only (without tenofovir exposure) and women using PrEP only (without DMPA exposure), women concurrently using TDF-based PrEP and DMPA will have more disruptions in bone microarchitecture.
Time frame: 24 months
The investigators will investigate whether young women concurrently using TDF-based PrEP and DMPA experience higher rates of bone turnover.
At baseline and 24 months, the investigators will measure: Markers of bone formation and resorption (e.g. NTX, P1NP, serum intact parathyroid hormone, total and bioavailable 25-OH-vitamin D). Hypothesis: Relative to women using DMPA only and PrEP only, women concurrently using TDF-based PrEP and DMPA will have increased bone turnover markers and PTH.
Time frame: Change from Baseline at 24 months
The investigators will investigate whether young women concurrently using TDF-based PrEP and DMPA experience higher rates of subclinical kidney injury.
At baseline and 24 months, the investigators will measure: Markers of kidney function (phosphate, glucose, creatinine, total protein, albumin). Hypothesis: Relative to women using DMPA only and PrEP only, women concurrently using TDF-based PrEP and DMPA will have more frequent subclinical kidney injury (relative to women without tenofovir exposure)
Time frame: Change from Baseline at 24 months
The investigators will investigate whether young women concurrently using TDF-based PrEP and DMPA experience higher rates of hypoestrogenism.
At baseline and 24 months, the investigators will measure: Markers of estrogen (serum estradiol, sex hormone binding protein, and the occurrence of amenorrhea). Hypothesis: Relative to women using DMPA only and PrEP only, women concurrently using TDF-based PrEP and DMPA will have reduced serum estrogen (relative to women without DMPA exposure).
Time frame: Change from Baseline at 24 months
Using mediation analysis, the investigators will identify the degree to which the pathways through subclinical kidney injury and hypoestrogenism account for changes in bone density among women concurrently using TDF-based PrEP and DMPA
The investigators will conduct mediation analysis to determine the degree to which changes in the pathways through subclinical kidney injury, hypoestrogenism and the combination of these pathways account for changes in bone density. Hypothesis: The pathway through hypoestrogenism will be a stronger link between concurrent TDF-based PrEP and DMPA use and bone density changes.
Time frame: 24 months
Plan to share: No
Ran from May 2018 to primary completion in Dec 2023, 67 months.
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Studies of the drugs tested here: Emtricitabine · Tenofovir · Medroxyprogesterone Acetate
Bone Demineralization, Pathologic