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IMPORTANCE: Individuals with Down syndrome (DS) are at high risk of developing Alzheimer disease due to an increased dose of the amyloid precursor protein gene, APP, which leads to increased levels of full-length APP and its products, including amyloid-β (Aβ). The liposome-based antiamyloid ACI-24 vaccine is intended to treat neurological disorders caused by misfolded Aβ pathological protein. However, the safety, tolerability, and immunogenicity of the ACI-24 vaccine among adults with DS have not been fully examined. OBJECTIVE: To assess the safety and tolerability of the ACI-24 vaccine among adults with DS as well as its ability to induce immunogenicity measured by anti-Aβ immunoglobulin G titers. DESIGN, SETTING, AND PARTICIPANTS: This multicenter double-blind placebo-controlled dose-escalation phase 1b randomized clinical trial was conducted at 3 US academic medical centers with affiliated Down syndrome clinics between March 30, 2016, and June 29, 2020. A total of 20 adults with DS were screened; of those, 16 adults were eligible to participate. Eligibility criteria included men or women aged 25 to 45 years with cytogenetic diagnosis of either trisomy 21 or complete unbalanced translocation of chromosome 21. Between April 27, 2016, and July 2, 2018, participants were randomized 3:1 into 2 dose-level cohorts (8 participants per cohort, with 6 participants receiving the ACI-24 vaccine and 2 receiving placebo) in a 96-week study. Participants received 48 weeks of treatment followed by an additional 48 weeks of safety follow-up. INTERVENTIONS: Participants were randomized to receive 7 subcutaneous injections of ACI-24, 300 μg or 1000 μg, or placebo. MAIN OUTCOMES AND MEASURES: Primary outcomes were measures of safety and tolerability as well as antibody titers. RESULTS: Among 16 enrolled participants, the mean (SD) age was 32.6 (4.4) years; 9 participants were women, and 7 were men. All participants were White, and 1 participant had Hispanic or Latino ethnicity. Treatment adherence was 100%. There were no cases of meningoencephalitis, death, or other serious adverse events (AEs) and no withdrawals as a result of AEs. Most treatment-emergent AEs were of mild intensity (110 of 132 events [83.3%]) and unrelated or unlikely to be related to the ACI-24 vaccine (113 of 132 events [85.6%]). No amyloid-related imaging abnormalities with edema or cerebral microhemorrhage and no evidence of central nervous system inflammation were observed on magnetic resonance imaging scans. Increases in anti-Aβ immunoglobulin G titers were observed in 4 of 12 participants (33.3%) receiving ACI-24 (2 receiving 300 μg and 2 receiving 1000 μg) compared with 0 participants receiving placebo. In addition, a greater increase was observed in plasma Aβ1-40 and Aβ1-42 levels among individuals receiving ACI-24. CONCLUSIONS AND RELEVANCE: In this study, the ACI-24 vaccine was safe and well tolerated in adults with DS. Evidence of immunogenicity along with pharmacodynamic and target engagement were observed, and anti-Aβ antibody titers were not associated with any adverse findings. These results support progression to clinical trials using an optimized formulation of the ACI-24 vaccine among individuals with DS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02738450

Author(s): Rafii, Michael S; Mobley, William C; Skotko, Brian G; Sabbagh, Marwan N; Burke, Anna D; Yuan, Shauna; Rissman, Robert A; Chavez, Ronelyn; Delpretti, Saskia; Sol, Olivier; Beth, Greg; Gray, Julian JG; dos Santos, Antonio Melo; Hliva, Valerie; Vukicevic, Marija; Kosco‐Vilbois, Marie; Pfeifer, Andrea; Feldman, Howard H

Background: Knowledge of the fetal effects of maternal medication use in pregnancy is often inadequate and current pregnancy pharmacovigilance (PV) surveillance methods have important limitations. Patient self-reporting may be able to mitigate some of these limitations, providing an adequately sized study sample can be recruited. Objective: To compare the ability and cost-effectiveness of several direct-to-participant advertising methods for the recruitment of pregnant participants into a study of self-reported gestational exposures and pregnancy outcomes. Methods: The Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) pregnancy study is a non-interventional, prospective pilot study of self-reported medication use and obstetric outcomes provided by a cohort of pregnant women that was conducted in Denmark, the Netherlands, Poland, and the United Kingdom. Direct-to-participant advertisements were provided via websites, emails, leaflets, television, and social media platforms. Results: Over a 70-week recruitment period direct-to-participant advertisements engaged 43,234 individuals with the study website or telephone system; 4.78% (2065/43,234) of which were successfully enrolled and provided study data. Of these 90.4% (1867/2065) were recruited via paid advertising methods, 23.0% (475/2065) of whom were in the first trimester of pregnancy. The overall costs per active recruited participant were lowest for email (€23.24) and website (€24.41) advertisements and highest for leaflet (€83.14) and television (€100.89). Website adverts were substantially superior in their ability to recruit participants during their first trimester of pregnancy (317/668, 47.5%) in comparison with other advertising methods (P

Background: Little is known about the effects of human fetal exposure when a new drug is authorized unless it was specifically developed for use in pregnancy. Since many factors may contribute to adverse fetal effects, having comprehensive information about in utero exposures will enhance our ability to make correct determinations about causality. Objective: The objective of the study was to assess the extent to which women, recruited without the intervention of health care professionals (HCPs), will provide information, suitable for research purposes, via the Internet or by phone on some potential risk factors in pregnancy. Methods: To pilot direct-to-patient research for pharmacovigilance, we conducted a prospective, noninterventional study of medication use and lifestyle factors as part of the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) Consortium. Consenting women who self-identified as pregnant and residing in the United Kingdom (UK), Denmark (DK), The Netherlands, or Poland were recruited and could then choose to provide data every 2 or 4 weeks via the Internet or a telephonic interactive voice response system (IVRS). Self-reported drug use was compared with pharmacy register data in DK and with electronic health records in the UK. Results: Recruited women were on average older and more highly educated than the general population. Most respondents chose a frequency of every 4 weeks (56.99%, 1177/2065). Only 29.83% (464/1555) of women with due dates occurring during the study provided information on pregnancy outcome. For those responding by Internet, over 90.00% (1915/2065) reported using >1 pregnancy-related medication, 83.34% (1721/2065) reported using >1 other medicine, and 23.53% (486/2065) reported only over-the-counter medications, not counting herbals and dietary supplements. Some respondents (7.16%, 148/2065) reported that they chose not to take a prescribed medication (mostly medicines for pain or inflammation, and for depression) and 1.30% (27/2065) reported using medicines that had been prescribed to a friend or family member (oxycodone, paracetamol, and medications for acid-related problems). Relatively few respondents reported using fish oil (4.60%, 95/2065), other dietary supplements (1.88%, 39/2065), herbal products (7.07%, 146/2065), or homeopathic products (1.16%, 24/2065). Most medications for chronic conditions that were listed in the Danish prescription registry were also self-reported (83.3%, 145/174 agreement), with larger discrepancies for medications indicated for short-term use (54.0%, 153/283 agreement) and pregnancy-related medications (66.1%, 78/118). Conclusions: Self-reported information on medication use as well as other potential teratogenic factors can be collected via the Internet, although recruitment costs are not insubstantial and maintaining follow-up is challenging. Direct data collection from consumers adds detail, but clinical input may be needed to fully understand patients’ medical histories and capture birth outcomes. [JMIR Public Health Surveill 2015;1(2):e22]

Obtaining data without the intervention of a health care provider represents an opportunity to expand understanding of the safety of medications used in difficult-to-study situations, like the first trimester of pregnancy when women may not present for medical care. While it is widely agreed that personal data, and in particular medical data, needs to be protected from unauthorized use, data protection requirements for population-based studies vary substantially by country. For public-private partnerships, the complexities are enhanced. The objective of this viewpoint paper is to illustrate the challenges related to data protection based on our experiences when performing relatively straightforward direct-to-patient noninterventional research via the Internet or telephone in four European countries. Pregnant women were invited to participate via the Internet or using an automated telephone response system in Denmark, the Netherlands, Poland, and the United Kingdom. Information was sought on medications, other factors that may cause birth defects, and pregnancy outcome. Issues relating to legal controllership of data were most problematic; assuring compliance with data protection requirements took about two years. There were also inconsistencies in the willingness to accept nonwritten informed consent. Nonetheless, enrollment and data collection have been completed, and analysis is in progress. Using direct reporting from consumers to study the safety of medicinal products allows researchers to address a myriad of research questions relating to everyday clinical practice, including treatment heterogeneity in population subgroups not traditionally included in clinical trials, like pregnant women, children, and the elderly. Nonetheless, there are a variety of administrative barriers relating to data protection and informed consent, particularly within the structure of a public-private partnership.