Study Drug Adherence Research Articles

Patients’ experiences of clinical trial participation involving a product remotely assessing study drug adherence

BackgroundThe participation of patients in clinical trials is crucial for the development of healthcare. There are several challenges in the recruitment of trial participants with acute medical conditions. The registry-based randomized DAPA-MI clinical trial recruited patients during hospitalization for myocardial infarction and provided study drugs in bottles with smart caps that used wireless technology to transmit monitoring data. This interview study aimed to investigate patients’ experience of participation in a clinical trial and their attitude to the new bottle cap technology. MethodsA subset of patients participating in the DAPA-MI trial were recruited from four hospitals in Sweden. Semi-structured interviews were conducted and analysed using manifest content analysis. ResultsVideo interviews were performed including 21 patients (four women and 17 men). The median age was 59 years (range 44–80). Four categories of patients' experiences were identified. A willingness to contribute consisted of patients’ positive attitudes to participation and to be a part of development and research. The perception of information emphasized the value of the oral information as well as the importance of time for reflection. Be in a vulnerable condition highlighted the impaired ability to perceive and remember in the acute medical condition. Adaptation to a new technology described the overall positive experiences of the smart bottle cap to evaluate adherence. ConclusionsPatients’ experiences of trial participation were in general positive but some challenges in the acute setting of a myocardial infarction were revealed. The smart bottle cap was well accepted, despite some handling difficulties.

DETECT‐AD (Digital Evaluations and Technologies Enabling Clinical Translation for Alzheimer’s Disease): A simulated anti‐amyloid clinical trial using digital biomarkers as primary outcome measures

AbstractBackgroundEarly detection and precise monitoring of cognitive and functional decline in persons with Alzheimer’s Disease (AD) in clinical trials is a high priority. Unfortunately, early detection and monitoring of the subtle and slow changes of disease with conventional cognitive testing and self‐report questionnaires has been fraught with poor sensitivity and lack ecological validity. Digital biomarkers using ambient sensing technologies may afford a more effective approach to conducting trials. Remaining to be established is the ability of this approach to fundamentally improve early AD treatment response readout in a formal clinical trial setting. A simulated clinical trial (DETECT‐AD: ClinicalTrials.gov, NCT05385913) is being conducted to determine how well continuously assessed, home‐based digital biomarkers may detect clinically meaningful changes in individuals with changing amyloid (Aß) burdens in pre‐symptomatic AD.MethodClinically prodromal AD patients with estimable rates of AD progression based on Aß Florbetapir‐PET status are enrolled divided n = 50:n = 50 into Aß “positive” (higher amyloid burden) patients who predictably progress (as if they were receiving placebo) and Aß “negative” patients progressing more slowly (representing the treatment group). A study‐provided multivitamin mimics RCT conditions and study drug adherence behavior. Baseline standard clinical and biomarker measures are obtained along with digital biomarkers (DB) captured with passive and active sensors (actigraphy, bed mats, IR sensing, e‐pillbox, computing/phone device use, weekly online reporting/cognitive assessment). Primary outcome is the change in a composite DB composed of measures in 4 domains: mobility, cognition, sleep, and socialization. Secondary measures are the relationship of DB to fluid biomarkers (plasma ptau181/217, amyloid, NfL) and MRI/PET measures.ResultTo date (01/16/2023), 46/100 have been enrolled with mean(SD): follow‐up = 27.0(7.9) weeks (no dropout); age = 78(6.6); 63% women; MoCA = 25.5(2.3); PET SUVR = 1.09(0.20), range: 0.850‐2.07. Exemplary baseline digital biomarker metrics are presented in the Table. Preliminary data shows an inverse Aß‐SUVR correlation with mean steps/day (r = ‐.41, p = .012) and a positive correlation of MoCA with computer use (r = .61; p = .036).ConclusionHome‐based continuous capture of multi‐domain DBs is feasible in a clinical trial setting and may yield early meaningful indicators of clinically relevant changes in older adults with pre‐AD dementia. Further evidence will evolve as sample sizes and longitudinal follow‐up increases.

DETECT‐AD (Digital Evaluations and Technologies Enabling Clinical Translation for Alzheimer’s Disease): A simulated anti‐amyloid clinical trial using digital biomarkers as primary outcome measures

AbstractBackgroundEarly detection and precise monitoring of cognitive and functional decline in persons with Alzheimer’s Disease (AD) in clinical trials is a high priority. Unfortunately, early detection and monitoring of the subtle and slow changes of disease with conventional cognitive testing and self‐report questionnaires has been fraught with poor sensitivity and lack ecological validity. Digital biomarkers using ambient sensing technologies may afford a more effective approach to conducting trials. Remaining to be established is the ability of this approach to fundamentally improve early AD treatment response readout in a formal clinical trial setting. A simulated clinical trial (DETECT‐AD: ClinicalTrials.gov, NCT05385913) is being conducted to determine how well continuously assessed, home‐based digital biomarkers may detect clinically meaningful changes in individuals with changing amyloid (Aβ) burdens in pre‐symptomatic AD.MethodClinically prodromal AD patients with estimable rates of AD progression based on Aβ Florbetapir‐PET status are enrolled divided n = 50:n = 50 into Aβ “positive” (higher amyloid burden) patients who predictably progress (as if they were receiving placebo) and Aβ “negative” patients progressing more slowly (representing the treatment group). A study‐provided multivitamin mimics RCT conditions and study drug adherence behavior. Baseline standard clinical and biomarker measures are obtained along with digital biomarkers (DB) captured with passive and active sensors (actigraphy, bed mats, IR sensing, e‐pillbox, computing/phone device use, weekly online reporting/cognitive assessment). Primary outcome is the change in a composite DB composed of measures in 4 domains: mobility, cognition, sleep, and socialization. Secondary measures are the relationship of DB to fluid biomarkers (plasma ptau181/217, amyloid, NfL) and MRI/PET measures.ResultTo date (01/16/2023), 46/100 have been enrolled with mean(SD): follow‐up = 27.0(7.9) weeks (no dropout); age = 78(6.6); 63% women; MoCA = 25.5(2.3); PET SUVR = 1.09(0.20), range: 0.850‐2.07. Exemplary baseline digital biomarker metrics are presented in the Table. Preliminary data shows an inverse Aβ‐SUVR correlation with mean steps/day (r = ‐.41, p = .012) and a positive correlation of MoCA with computer use (r = .61; p = .036).ConclusionHome‐based continuous capture of multi‐domain DBs is feasible in a clinical trial setting and may yield early meaningful indicators of clinically relevant changes in older adults with pre‐AD dementia. Further evidence will evolve as sample sizes and longitudinal follow‐up increases.

Adherence to heart failure therapy influences LV recovery in women with PPCM

Abstract Introduction Peripartum cardiomyopathy (PPCM) is characterised by left ventricular (LV) dilatation and dysfunction developing towards the end of pregnancy or in the first months postpartum. Although about 60% of women with PPCM, the majority on evidence based (EBM) heart failure medications, show LV recovery within six to twelve months, others remain with persistently impaired LV function. Poor adherence to EBM represents a major cause of avoidable hospitalizations, disability and death in other cardiovascular conditions. Purpose We aimed to study drug adherence to heart failure (HF) therapy of women with PPCM and to identify possible associations between drug adherence and LV recovery, functional status and psychosocial factors. Methods In this prospective, observational study, we included 36 consecutive women with PPCM, who returned for their regular follow-up visit. Adherence to HF treatment was assessed by self-reported adherence, pharmacy refills of HF drugs [ACE-i/ARB, BB, MRA] and drug levels by means of liquid chromatography high-resolution mass spectrometry (LC-HRMS) of plasma. Participants were classified as following: "adherent" (all prescribed HF drugs were detectable by LC-HRMS), "partially adherent" (at least one prescribed drug detectable) and "non-adherent" (none of the prescribed drugs were detectable). Health state index scores were assessed by EQ5D including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Results Patients’ median age was 32.4 years (IQR 27.6-36.1) with a median time of 16 months (IQR 5-45) between the first presentation and the adherence visit. Prescription at the adherence visit included 77.8% BB, 75% ACE-i/ARB, 47.2% MRA and 95.2% loop diuretics. The median LVEF at follow-up was 46% (IQR 34-55). Self-reported adherence was 50% and 66.7% of patients collected all pharmacy refills in 6 months prior to follow-up. According to LC-HRMS, 23.5% participants were classified as adherent, 53% as partially adherent, and 23.5% as non-adherent. Adherent patients showed significantly lower LVEDD at follow-up (47 mm [IQR 46-52), vs 56 mm [IQR 49-64] in partially adherent, and 62 mm [IQR 55-64] in non-adherent, p=0.022) and had a higher LVEF at follow up (60% [IQR 41-65]), vs partially adherent (46% [IQR 34-50]) and non-adherent patients (41% [IQR 29-47], p=014). Adherent patients had a lower overall EQ5D score (5.5 [IQR 5-7.5], vs 6 [IQR 5-7] in partially adherent, and 10 [IQR 8-15] non-adherent patients, p=0.032) suggestive of a better self-rated health status (Figure 1). Conclusion For the first time, we show that drug adherence in PPCM is sub-optimal. High adherence to HF therapy was associated with favourable LV remodeling. A better self-rated health status was associated with adherence. Our study highlights the importance of drug adherence for functional recovery in PPCM. Drug adherence should be an important component of patient communication and specific interventions in PPCM.Figure 1

Atorvastatin for Anthracycline-Associated Cardiac Dysfunction

Anthracyclines treat a broad range of cancers. Basic and retrospective clinical data have suggested that use of atorvastatin may be associated with a reduction in cardiac dysfunction due to anthracycline use. To test whether atorvastatin is associated with a reduction in the proportion of patients with lymphoma receiving anthracyclines who develop cardiac dysfunction. Double-blind randomized clinical trial conducted at 9 academic medical centers in the US and Canada among 300 patients with lymphoma who were scheduled to receive anthracycline-based chemotherapy. Enrollment occurred between January 25, 2017, and September 10, 2021, with final follow-up on October 10, 2022. Participants were randomized to receive atorvastatin, 40 mg/d (n = 150), or placebo (n = 150) for 12 months. The primary outcome was the proportion of participants with an absolute decline in left ventricular ejection fraction (LVEF) of ≥10% from prior to chemotherapy to a final value of <55% over 12 months. A secondary outcome was the proportion of participants with an absolute decline in LVEF of ≥5% from prior to chemotherapy to a final value of <55% over 12 months. Of the 300 participants randomized (mean age, 50 [SD, 17] years; 142 women [47%]), 286 (95%) completed the trial. Among the entire cohort, the baseline mean LVEF was 63% (SD, 4.6%) and the follow-up LVEF was 58% (SD, 5.7%). Study drug adherence was noted in 91% of participants. At 12-month follow-up, 46 (15%) had a decline in LVEF of 10% or greater from prior to chemotherapy to a final value of less than 55%. The incidence of the primary end point was 9% (13/150) in the atorvastatin group and 22% (33/150) in the placebo group (P = .002). The odds of a 10% or greater decline in LVEF to a final value of less than 55% after anthracycline treatment was almost 3 times greater for participants randomized to placebo compared with those randomized to atorvastatin (odds ratio, 2.9; 95% CI, 1.4-6.4). Compared with placebo, atorvastatin also reduced the incidence of the secondary end point (13% vs 29%; P = .001). There were 13 adjudicated heart failure events (4%) over 24 months of follow-up. There was no difference in the rates of incident heart failure between study groups (3% with atorvastatin, 6% with placebo; P = .26). The number of serious related adverse events was low and similar between groups. Among patients with lymphoma treated with anthracycline-based chemotherapy, atorvastatin reduced the incidence of cardiac dysfunction. This finding may support the use of atorvastatin in patients with lymphoma at high risk of cardiac dysfunction due to anthracycline use. ClinicalTrials.gov Identifier: NCT02943590.

Analysis of serious adverse events in a pediatric community-acquired pneumonia randomized clinical trial in Malawi

Amoxicillin is recommended as first-line antibiotic treatment for community-acquired pneumonia, the leading infectious cause of mortality in children aged less than 5 years. We conducted a double-blind, randomized controlled non-inferiority trial comparing 3- to 5-day amoxicillin treatment for non-severe chest-indrawing pneumonia in HIV-negative children aged 2 to 59 months in Malawi. In a secondary analysis, we assessed the frequency of serious adverse events (SAEs) during the trial to evaluate the safety of treatment with amoxicillin. Enrolled children with non-severe chest-indrawing pneumonia were randomized to either 3- or 5-day amoxicillin and followed for 14 days to track clinical outcomes. In addition to evaluation for treatment failure (primary endpoint, day 6), relapse, and study drug adherence, children were assessed for adverse events, including SAEs, which were managed per local standard clinical practice until resolution or stabilization. Between March 2016 and April 2019, 3000 children were enrolled, with male and younger children (aged less than 24 months) demonstrating more SAEs (10.3% for males vs 8.1% for females, p = 0.04; 10.0% for 2–6 months, 10.8% for 7–11 months, 9.7% for 12–23 months and 5.6% for 24–59 months, p = 0.01). The most common SAEs were progression of or recurrent pneumonia (220 SAEs in 217 children), acute gastroenteritis (14 SAEs in 14 children), and fever (8 SAEs in 8 children); however, there were no significant or substantive differences in the percentage of children with pneumonia-related, acute gastroenteritis, or fever SAEs noted between the 3- versus 5-day amoxicillin treatment groups. In our pediatric community-acquired pneumonia trial evaluating amoxicillin treatment, there were relatively few SAEs overall and very few attributed to amoxicillin. Duration of amoxicillin treatment did not impact the frequency of SAEs. We found male and younger children appear to be more vulnerable to SAEs in our trial; however, our data support previous data demonstrating the safety of amoxicillin use in children with pneumonia.Clinical trial registration: ClinicalTrials.gov (NCT02678195).

SAT-447 PER TREATMENT POST-HOC ANALYSIS OF CLINICAL TRIAL OUTCOMES WITH TOLVAPTAN (TLV) IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)

Clinical trials (TEMPO 3:4 [NCT00428948]; REPRISE [NCT02160145]) demonstrated that TLV significantly slowed the decline in estimated glomerular filtration rate (eGFR) in ADPKD. Given the slight difference in TLV treatment effects between studies, a post hoc analysis evaluated whether the effects of TLV on eGFR were attenuated by the higher rate of TLV discontinuation in TEMPO 3:4 (23.0%) compared to REPRISE (15.0%). In TEMPO 3:4, eligible subjects (aged 18-50 years) had earlier-stage chronic kidney disease (CKD) associated with ADPKD (>80% had stage 1 or 2 CKD) with high risk of disease progression and were randomized to TLV or placebo (PBO) for 36 months. REPRISE randomized an older ADPKD population (aged 18-65 years) with more advanced CKD (75% had stage 3 and 20% had stage 4 CKD) to 12 months of TLV or PBO. For this analysis, a subgroup of treatment completers was identified, defined as participants who had 1) taken ≥70% of prescribed doses, 2) not discontinued study drug for ≥30 days, and 3) remained on study drug to end of study. The treatment effect of TLV vs PBO on kidney function (for TEMPO 3:4, slope of change in eGFR; for REPRISE, annualized change in eGFR) was compared between the subgroup of TLV completers and PBO completers within each study. Further, the treatment effect of TLV vs PBO on eGFR slope was compared between subjects from TEMPO 3:4 and REPRISE who were matched by propensity score for gender, age, and baseline eGFR. The number of subjects from the total population of each study who met completer criteria was 713/961 (74.2%) in the TLV arm and 410/484 (84.7%) in the PBO arm of TEMPO 3:4 and 576/683 (84.3%) in the TLV arm and 634/687 (92.3%) in the PBO arm of REPRISE. Rates of eGFR decline (in ml/min/1.73 m2) in TLV-treated subjects were similar between the total study population and the completer subgroup in both TEMPO 3:4 (total population, -2.72; completers -2.74) and REPRISE (total population, -2.34; completers -2.38), yielding similar treatment differences between completers and the total population within each study (Table). Propensity score matching generated an analysis set of 108 subjects for each study (54 in each of the TLV and PBO arms). The mean baseline eGFR for the matched subjects from each study (~53 ml/min/1.73 m2) fell within CKD stage 3a. In the matched population, the treatment difference (TLV vs PBO) was 1.41 ml/min/1.73 m2 for TEMPO 3:4, and 1.89 ml/min/1.73 m2 for REPRISE (P=NS for the comparison between studies). TLV effect size on eGFR was similar between study completers and the overall study populations within each of TEMPO 3:4 and REPRISE. Propensity-matched subjects from both studies with similar baseline CKD (i.e., within the area of overlap in the study populations between subjects with early to moderate stage CKD [TEMPO 3:4] and moderate to late stage CKD [REPRISE]) exhibited similar treatment effects. These results suggest that differences in TLV treatment effects between TEMPO 3:4 and REPRISE were due less to study drug adherence level than to variances in subject CKD stage distribution between the studies. Consistent with earlier data (Torres VE et al Clin J Am Soc Nephrol 2016;11:803-11), these results indicate that the effects of TLV in slowing eGFR decline are most easily discernible in later-stage patients, given that kidney function decline accelerates with ADPKD progression.

Association of Black Race With Early Recurrence After Minor Ischemic Stroke or Transient Ischemic Attack

Stroke incidence is higher among black than white individuals in the United States. It is unclear whether black individuals have a higher risk of stroke recurrence after a minor ischemic stroke or transient ischemic attack (TIA), a high-risk setting in which focused preventive efforts can be effective. To examine the association between black race and early ischemic stroke recurrence. This cohort study analyzed data from the Platelet Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial conducted at 269 sites from May 28, 2010, to December 19, 2017. The trial enrolled 4881 adults within 12 hours of onset of a minor ischemic stroke (National Institutes of Health Stroke Scale score, 0-3) or high-risk TIA (ABCD2 score, ≥4). For this analysis, we excluded 598 patients enrolled outside the United States and 239 US patients with missing race/ethnicity data. The primary outcome for this analysis was ischemic stroke within 90 days after randomization. Covariates included age, sex, Hispanic ethnicity, study assignment to take clopidogrel vs placebo, index stroke vs TIA, vascular risk factors, statin use, study drug adherence, and index event etiological subtype. Among 4044 patients included in the analysis, 918 (22.7%) were black. In an adjusted Cox model, black race was associated with a higher risk of recurrence compared with white race (hazard ratio, 1.6; 95% CI, 1.1-2.3). Findings were similar in subgroup analyses and in analyses limited to sites that enrolled black patients. Among US participants in the POINT trial, black individuals faced a higher risk of early stroke recurrence after a minor ischemic stroke or TIA. Our findings support research into black-white racial differences in the underlying mechanisms of recurrent stroke. In the meantime, extra effort should be made to ensure that black patients have access to proven secondary prevention measures. clinicaltrials.gov Identifier: NCT00991029.

1965. Safety and Efficacy of Glecaprevir/Pibrentasvir in Patients With Chronic Hepatitis C Virus Genotypes 1–6 and Human Immunodeficiency Virus-1 Co-Infection: An Integrated Analysis of Two Phase 3 Clinical Trials

BackgroundPeople co-infected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV)-1 may be treated for HCV without special considerations apart from drug interactions with antiretroviral therapies (ART). The once-daily, all-oral, ribavirin-free, pangenotypic combination of glecaprevir (identified by AbbVie and Enanta) and pibrentasvir has shown high sustained virologic response at post-treatment Week 12 (SVR12) in HCV mono-infected patients. We evaluated the safety/efficacy of glecaprevir/pibrentasvir in patients co-infected with HCV/HIV-1.MethodsData were pooled from two Phase 3 trials for treatment-naïve and -experienced patients co-infected with HCV genotypes (GT) 1–6/HIV-1 without cirrhosis or with compensated cirrhosis who received glecaprevir/pibrentasvir for 8 or 12 weeks. Virologic response, adverse events (AEs), and laboratory abnormalities were evaluated.ResultsAcross the two trials, 152 patients without cirrhosis and 16 with compensated cirrhosis received glecaprevir/pibrentasvir for 8 and 12 weeks, respectively. Baseline demographics are shown in Tables 1 and 2. The overall intention-to-treat (ITT) SVR12 rate was 98.2% (165/168), with no virologic failures among non-cirrhotic patients treated for 8 weeks; mITT rate (excluding non-virologic failures) was 99.4% (167/168). Reasons for nonresponse were breakthrough (n = 1; patient with incomplete study drug adherence), premature study drug discontinuation (n = 1), and missing SVR12 data (n = 1). Safety analyses included the additional 18 non-cirrhotic GT1-infected patients treated for 12 weeks (all achieved SVR12). AEs occurring in ≥5% of patients were fatigue, headache, nausea, and nasopharyngitis. Serious AEs and AEs leading to discontinuation were rare; none were related to study drug. Grade 3 or higher laboratory abnormalities were infrequent. All patients maintained HIV-1 suppression (<200 copies/mL) during treatment.ConclusionGlecaprevir/pibrentasvir was highly efficacious and well tolerated in patients co-infected with HCV GT1–6/HIV-1 without or with cirrhosis following 8 or 12 weeks of treatment, respectively, and could be the first 8-week pangenotypic treatment option for HCV/HIV-1 co-infected patients without cirrhosis. Disclosures J. K. Rockstroh, Gilead, Abbott, AbbVie, BMS, Bionor, Cipla, Janssen, Merck, ViiV: Consultant, Grant Investigator, Research Contractor and Scientific Advisor, Consulting fee, Research grant, Research support and Speaker honorarium. S. R. Bhagani, AbbVie, BMS, Gilead, Janssen, Merck, ViiV: Board Member, Consultant, Scientific Advisor and Speaker’s Bureau, Consulting fee and Speaker honorarium. C. Orkin, AbbVie, Abbott, Boehringer Ingelheim, BMS, Gilead, GSK, Janssen, ViiV: Grant Investigator and Research Contractor, Research grant and Research support. R. Soto-Malave, AbbVie, Janssen, Merck: Consultant, Grant Investigator, Research Contractor and Scientific Advisor, Consulting fee, Research grant and Research support. K. Lacombe, AbbVie, BMS, Gilead, Janssen, Merck: Board Member, Consultant and Scientific Advisor, Consulting fee and Speaker honorarium. Z. Zhang, AbbVie Inc.: Employee and Shareholder, Salary and Stock and/or options. S. Wang, AbbVie Inc.: Employee and Shareholder, Salary and Stock and/or options. F. Mensa, AbbVie Inc.: Employee and Shareholder, Salary and Stock and/or options. R. Trinh, AbbVie Inc.: Employee and Shareholder, Salary and Stock and/or options.

Racial Differences in Characteristics and Outcomes of Patients With Heart Failure and Preserved Ejection Fraction in the Treatment of Preserved Cardiac Function Heart Failure Trial.

Black patients have been shown to have different baseline characteristics and outcomes compared with nonblack patients in cohort studies. However, few studies have focused on heart failure (HF) with preserved ejection fraction (HFpEF) patients. We aimed to determine the difference in cardiovascular outcomes in black and nonblack patients with HFpEF and to determine the relative efficacy and safety of spironolactone in black and nonblack patients. Patients with HFpEF, randomized to spironolactone versus placebo in the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) in North and South America, were grouped according to self-described black and nonblack race. Black HFpEF patients (n=302) were younger and were more likely to have diabetes mellitus and hypertension than nonblack patients but had similar HFpEF severity. Black patients had higher risk for the primary outcome (hazard ratio [HR], 1.34; 95% confidence interval, 1.06-1.71; P=0.02) and first HF hospitalization (HR, 1.51; 95% confidence interval, 1.167-1.97; P=0.002)], but no significant difference in cardiovascular mortality risk (HR, 0.78; 95% confidence interval, 0.51-1.20; P=0.326). In black and nonblack patients, randomization to spironolactone conferred similar efficacy in the primary outcome (HR, 0.83 versus 0.79; P for interaction=0.49), HF hospitalization (HR, 0.67 versus 0.82; P for interaction=0.76), and cardiovascular mortality (P for interaction=0.19). The risk of hyperkalemia and worsening renal function with spironolactone and study drug adherence were also similar. Black patients with HFpEF have a higher HF hospitalization risk than nonblack patients, but spironolactone is similarly effective and safe in both groups. URL: https://www.clinicaltrials.gov. Unique identifier: NCT00094302.

Case Study: Community Engagement and Clinical Trial Success: Outreach to African American Women.

This brief report examines how the use of community engagement principles and approaches enhanced clinical trial recruitment and retention. The Community-Engaged Research Core (CERC), a CTSA-supported resource designed to facilitate community involvement in clinical and translational research, was consulted to provide assistance with the implementation of the clinical trial, and specifically to enhance participation of the target population-African American women. CERC's key recommendations included: (1) convene a Community Engagement Studio, (2) redesign the recruitment advertisement, (3) simplify the language used to explain the scope of the study, and (4) provide transportation for participants. As a result of these interventions, a comprehensive strategy to recruit, enroll, and retain participants was formulated. After implementation of the plan by the study team, enrollment increased 78% and recruitment goals were met 16 months ahead of schedule. Participant retention and study drug adherence was 100%. We conclude that community engagement is essential to the development of an effective multifaceted plan to improve recruitment of underrepresented groups in clinical trials.

Pregnancy and Contraceptive Use Among Women Participating in the FEM-PrEP Trial

Pregnancy among study participants remains a challenge for trials of new HIV prevention agents despite promotion and provision of contraception. We evaluated contraceptive use, pregnancy incidence, and study drug adherence by contraceptive method among women enrolled in the FEM-PrEP trial of once-daily oral tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) for HIV prevention. We required women to be using effective non-barrier contraception at enrollment. At each monthly follow-up visit, women were counseled on contraceptive use and tested for pregnancy. TDF-FTC adherence was determined by measuring plasma drug concentrations at 4-week intervals. We used Cox proportional hazards models to assess factors associated with incident pregnancy and multivariate logistic regression to examine the relationship between contraceptive method used at enrollment and TDF-FTC adherence. More than half of women were not using effective contraception before enrollment. Ninety-eight percent of these women adopted either injectable (55%) or oral (43%) contraceptives. The overall pregnancy rate was 9.6 per 100 woman-years. Among injectable users and new users of combined oral contraceptives (COCs), the rates were 1.6 and 35.1, respectively. New users of injectables had significantly greater odds of adhering to TDF-FTC than new COC users [odds ratio (95% confidence interval): 4.4 (1.7 to 11.6), P = 0.002], existing COC users [3.1 (1.3 to 7.3), P = 0.01], and existing injectable users [2.4 (1.1 to 5.6), P = 0.04]. Women using COCs during FEM-PrEP, particularly new adopters, were more likely to become pregnant and less likely to adhere to study product than injectable users. HIV prevention trials should consider requiring long-acting methods, including injectables, for study participation.

Knowledge, Attitudes, and Experiences of HIV Pre-Exposure Prophylaxis (PrEP) Trial Participants in Botswana.

Recent clinical trials have shown that a daily dose of oral TDF/FTC pre-exposure prophylaxis (PrEP) is effective in reducing human immunodeficiency (HIV) risk. Understanding trial participants’ perspectives about retention and PrEP adherence is critical to inform future PrEP trials and the scale-up and implementation of PrEP programs. We analyzed 53 in-depth interviews conducted in April 2010 with participants in the TDF2 study, a Phase 3, randomized, double-blind, placebo-controlled clinical trial of daily oral TDF/FTC with heterosexual men and women in Francistown and Gaborone, Botswana. We examined participants’ knowledge, attitudes, and experiences of the trial, identified facilitators and barriers to enrollment and retention, and compared participant responses by study site, sex, and study drug adherence. Our findings point to several factors to consider for participant retention and adherence in PrEP trials and programs, including conducting pre-enrollment education and myth reduction counseling, providing accurate estimates of participant obligations and side effect symptoms, ensuring participant understanding of the effects of non-adherence, gauging personal commitment and interest in study outcomes, and developing a strong external social support network for participants.

The effect of hormone therapy on mean blood pressure and visit-to-visit blood pressure variability in postmenopausal women: results from the Women's Health Initiative randomized controlled trials.

Mean and visit-to-visit variability (VVV) of blood pressure (BP) are associated with an increased cardiovascular disease risk. We examined the effect of hormone therapy on mean and VVV of BP in postmenopausal women from the Women's Health Initiative (WHI) randomized controlled trials. BP was measured at baseline and annually in the two WHI hormone therapy trials, in which 10 739 and 16 608 postmenopausal women were randomized to conjugated equine estrogens (CEEs, 0.625 mg/day) or placebo, and CEEs and medroxyprogesterone acetate (MPA, 2.5 mg/day) or placebo, respectively. At the first annual visit (year 1), mean SBP was 1.04 mmHg [95% confidence interval (CI) 0.58, 1.50] and 1.35 mmHg (95% CI 0.99, 1.72) higher in the CEEs and CEEs and MPA arms, respectively, compared with the corresponding placebos. These effects remained stable after year 1. CEEs also increased the VVV of SBP (ratio of VVV in CEEs vs. placebo, 1.03; P < 0.001), whereas CEEs and MPA did not (ratio of VVV in CEEs and MPA vs. placebo, 1.01; P = 0.20). After accounting for study drug adherence, the effects of CEEs and CEEs and MPA on mean SBP increased at year 1, and the differences in the CEEs and CEEs and MPA arms vs. placebos also continued to increase after year 1. Further, both CEEs and CEEs and MPA significantly increased the VVV of SBP (ratio of VVV in CEEs vs. placebo, 1.04; P < 0.001; ratio of VVV in CEEs and MPA vs. placebo, 1.05; P < 0.001). Among postmenopausal women, CEEs and CEEs and MPA at conventional doses increased mean and VVV of SBP.

A Randomized, Double-blind Comparison of Single-Tablet Regimen Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF vs Ritonavir-Boosted Atazanavir Plus Emtricitabine/Tenofovir DF for Initial Treatment of HIV-1 Infection

A Randomized, Double-blind Comparison of Single-Tablet Regimen Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF vs Ritonavir-Boosted Atazanavir Plus Emtricitabine/Tenofovir DF for Initial Treatment of HIV-1 Infection

A Post-Trial Assessment of Factors Influencing Study Drug Adherence in a Randomized Biomedical HIV-1 Prevention Trial

High adherence and maintenance of blinding are critical for placebo-controlled efficacy trials of HIV-1 biomedical prevention strategies. We assessed adherence to study drug and factors affecting adherence, including perceived randomization group, in a post-trial questionnaire of participants who completed HPTN 039, a randomized, placebo-controlled trial of HSV-2 suppression with twice-daily acyclovir to reduce HIV-1 acquisition. Of the 3172 trial participants, 2003 (63%) completed the post-trial questionnaire. Of these 2003, 72% reported missing a dose of study drug less than twice a week. Study drug adherence was not compromised by perceived randomization or genital ulcer symptoms during the study. Alcohol use was cited as an adherence barrier in some populations. Assessment of study drug adherence during and at the end of trials can evaluate perceptions of randomization and adherence by randomization arm, help to better understand barriers to and motivations for adherence, and develop interventions to increase adherence for future trials.

Study Drug and Visit Adherence: Data from the BABY HUG Trial.

BABY HUG (NCT00006400) is an NHLBI-NICHD sponsored Phase III multi-center, randomized, double blind placebo controlled study of daily oral hydroxyurea in infants 9–17 months of age with sickle cell anemia. Subject retention and adherence are essential to maintain the power and validity of the trial. Initially, we hypothesized that families with higher socioeconomic status (SES) and advanced education would be better able to comply with the complex study procedures. We evaluated SES and other demographic factors which may influence adherence in the ongoing study. Both study drug adherence and visit adherence were examined. Study visits occurred every two weeks until a stable dose was reached and then every four weeks unless toxicity was encountered. Subjects remained on study for two years. Study drug adherence was monitored by measuring liquid in returned bottles at each visit. Bottles were included in the analysis if the subject was dispensed a bottle at a visit, returned it at the next scheduled visit with a non-zero volume, and did not have a drug stop order between the visits. From these bottles, each subject's median drug adherence was calculated. Drug adherence (%) was defined as the amount consumed divided by the amount which should have been consumed. Visit adherence (%) was based on expected routine study visits. Subjects were withdrawn from the study upon family request or if they continually missed visits. We defined ‘good adherence’ as taking ≥80% study drug and attending ≥90% study visits. Adherence data was available on 186 of the 193 randomized infants. The median drug adherence was 101.7%, with 88.9% of subjects having drug adherence of ≥80%, and three infants having drug adherence >150%. The mean visit adherence was 97.3% ± 8.4 SD, with 82.3 % of subjects having no missed visits. Thirteen infants had a visit adherence of <90%; six were withdrawn from the study due to inactive follow-up status. Early withdrawal from the study was not significantly associated with drug adherence. However, infants on a stable dose who had visits every four weeks had a small but significantly worse drug adherence than infants whose dose was being titrated and had visits every two weeks (i.e. infants became less adherent over time in taking their study drug). Drug adherence and visit adherence were not significantly associated with the number of children or adults in the household, the primary caregiver's employment or education level, or household income. To date, none of the patients have been nonadherent with both study visits and drug administration. A few subjects appeared to take more study drug than prescribed, which may be related to spilled doses. Although we hypothesized that higher SES would be associated with better adherence, we did not find this to be the case, suggesting that socioeconomic factors should not be used to prejudge the suitability of subjects for a randomized clinical trial. Our findings also suggest that special efforts are needed to maintain drug adherence, particularly when study visits become less frequent.

Does vitamin D stop inpatients falling? A randomised controlled trial

Vitamin D deficiency is common in older people and may increase risk of falls and fracture. Hospital inpatients are at particular risk of falling. Previous studies suggest that vitamin D improves neuromuscular function and reduces falls. To determine whether routine supplementation with vitamin D plus calcium reduces numbers of fallers and falls in a cohort of hospital admissions while they are inpatients. Randomised, double-blind, controlled study. two hundred and five acute admissions >65 years to a geriatric medical unit. Patients were randomised to intervention of daily vitamin D 800 iu plus calcium 1,200 mg or control group of daily calcium 1,200 mg, until discharge or death. Baseline characteristics were similar in both groups with a median age 84 years and a median length of stay = 30 days (IQR 14.75-71.00). In a pre-selected sub-group (54/205 participants), median admission vitamin D level = 22.00 nmol/l (IQR 15.00-30.50). This did not significantly increase in the treatment versus control group. Median study drug adherence = 88%, with no significant difference between study groups (Mann-Whitney: P = 0.711). Although there were fewer fallers in the vitamin D cohort, this did not reach statistical significance (vitamin D: calcium = 36:45 fallers; RR 0.82 (CI 0.59-1.16). Neither the mean number of falls (vitamin D: calcium = 1.040:1.155; Mann-Whitney P = 0.435) or time to first fall (Log-rank test P = 0.377) differed between groups. In a population of geriatric hospital inpatients, vitamin D did not reduce the number of fallers. Routine supplementation cannot be recommended to reduce falls in this group.