Impact of rosuvastatin on pulse-wave velocity in men with HIV at moderate cardiovascular risk.

This single-centre substudy of a double-blind, randomized, placebo-controlled trial aimed to determine the effect of 96 weeks of rosuvastatin on pulse wave velocity (PWV) in men (n = 55, 54 years) with HIV at moderate cardiovascular risk (Framingham risk score 10-15%). PWV increased in both rosuvastatin [0.54 m/s standard error of difference (SED) 0.26] and placebo [0.50 m/s (SED 0.26), P = 0.896] arms, leading to no difference in PWV at week 96 [rosuvastatin 9.40 m/s (SE 0.31); placebo 9.21 m/s (SE0.31), P = 0.676].

Transcutaneous electrical nerve stimulation (TENS) for pain control in women with primary dysmenorrhoea.

BACKGROUND: Transcutaneous electrical nerve stimulation (TENS) is a non-pharmacological treatment that works by delivering electrical currents via electrodes attached to the skin at the site of pain. It can be an alternative to pharmacological treatments. The mechanism of action of TENS for pain relief is related to the inhibition of the transmission of painful stimuli, release of endogenous opioids, and reduced muscle ischaemia of the uterus. Although it has been used for primary dysmenorrhoea ((PD); period pain or menstrual cramps), evidence of the efficacy and safety of high-frequency TENS, low-frequency TENS, or other treatments for PD is limited. OBJECTIVES: To evaluate the effectiveness and safety of transcutaneous electrical nerve stimulation (TENS) in comparison with placebo, no treatment, and other treatments for primary dysmenorrhoea (PD). SEARCH METHODS: We searched the Gynaecology and Fertility Group's Specialized Register of controlled trials, CENTRAL, MEDLINE, Embase, PsycINFO, AMED, CINAHL, and the Korean and Chinese language databases up to 9 April 2024. We also searched for ongoing trials in trials registries and the reference lists of relevant studies for additional trials. Language restrictions were not applied. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that included women (aged 12 to 49 years) with PD. Included trials compared low-frequency TENS or high-frequency TENS with other TENS, placebo, or other treatment. DATA COLLECTION AND ANALYSIS: Four review authors screened the trials, extracted the data according to the protocol, assessed the risk of bias using RoB 2, and assessed the certainty of evidence for all review comparisons and primary outcomes (i.e. pain relief and adverse effects) using the GRADE approach. MAIN RESULTS: This review replaces the current review, published in 2009. We included 20 RCTs involving 585 randomized women with high-frequency TENS, low-frequency TENS, placebo or no treatment, or other treatment. We included five comparisons: high-frequency TENS versus placebo or no treatment, low-frequency TENS versus placebo or no treatment, high-frequency TENS versus low-frequency TENS, high-frequency TENS versus other treatments, and low-frequency TENS versus other treatments. High-frequency TENS versus placebo or no treatment High-frequency TENS may reduce pain compared with placebo or no treatment (mean difference (MD) -1.39, 95% confidence interval (CI) -2.51 to -0.28; 10 RCTs, 345 women; low-certainty evidence; I2 = 88%). Two out of three RCTs reported no adverse effects and hence we were unable to estimate the effect of high-frequency TENS on adverse effects. Low-frequency TENS versus placebo or no treatment Low-frequency TENS may reduce pain compared with placebo or no treatment (MD -2.04, 95% CI -2.95 to -1.14; 3 RCTs, 645 women; low-certainty evidence; I2 = 0%). No trials reported adverse effects for this comparison. High-frequency TENS versus low-frequency TENS It is uncertain whether high-frequency TENS had an effect on pain relief compared with low-frequency TENS (MD 0.89, 95% CI -0.19 to 1.96; 3 RCTs, 54 women; low-certainty evidence; I2 = 0%). One trial contributed data on adverse effects but no adverse events occurred. High-frequency TENS versus other treatments It is uncertain whether high-frequency TENS had an effect on pain relief compared to acupressure (MD -0.66, 95% CI -1.72 to 0.40; 1 RCT, 18 women; very low-certainty evidence), acetaminophen (paracetamol) (MD -0.98, 95% CI -3.30 to 1.34; 1 RCT, 20 women; very low-certainty evidence), and interferential current therapy (MD -0.03, 95% CI -1.04 to 0.98; 2 RCTs, 62 women; low-certainty evidence; I2 = 0%). The occurrence of adverse effects did not differ significantly between high-frequency TENS and NSAIDs (OR 12.06, 95% CI 0.26 to 570.62; 2 RCTs, 88 women; low-certainty evidence; I2 = 78%). Low-frequency TENS versus other treatments It is uncertain whether low-frequency TENS had an effect on pain relief compared with acetaminophen (MD -1.48, 95% CI -3.61 to 0.65; 1 RCT, 20 women; very low-certainty evidence). No trials reported adverse effects for this comparison. AUTHORS' CONCLUSIONS: High-frequency TENS and low-frequency TENS may reduce pain compared with placebo or no treatment. We downgraded the certainty of the evidence because of the risk of bias. Future RCTs should focus more on secondary outcomes of this review (e.g. requirement for additional analgesics, limitation of daily activities, or health-related quality of life) and should be designed to ensure a low risk of bias.

Placebo immune-related adverse events (irAEs): A neglected phenomenon in cancer immunotherapy trials.

PURPOSE: This study aims to investigate the underexplored prevalence of placebo-reported immune-related adverse events (irAEs) in immune checkpoint inhibitor (ICI) trials. METHODS: We searched public databases for randomized clinical trials (RCTs) involving ICI versus placebo treatments in patients with malignancies. Study characteristics and irAEs occurrences were extracted for meta-analyses using a random-effects model. MAIN OUTCOMES: Proportions of patients reported to experience any grade and grade 3 to 5 placebo irAEs; the risk ratio (RR) of reporting 'false' irAEs in the experiment arm (defined as 'false-irAE ratio', calculated by dividing the proportion of patients documented with irAEs in the placebo arm by that in the experimental arm). RESULTS: 47 RCTs with 30,119 patients were analyzed. The pooled proportion of patients reported to experience any grade and grade 3 to 5 irAEs among placebo participants was 22.85 % (17.33 %-29.50 %) and 3.40 % (2.35 %-4.63 %), respectively. The pooled proportion of placebo-treated patients who experienced serious irAEs was 0.67 % (0.03 %-1.91 %). Treatment discontinuation and death due to placebo irAEs occurred in 0.69 % (<0.01 %-1.30 %) and 0.12 % (<0.01 %-0.40 %) of patients, respectively. The false-irAE ratio for any grade and grade 3 to 5 irAEs were 0.49 and 0.28. The false-irAE ratio was significantly higher in RCTs with control arms of placebo plus non-immunotherapy than in those with placebo alone (any grade: 0.57 vs. 0.32, P < 0.001; grade 3 to 5: 0.36 vs. 0.12, P = 0.009). CONCLUSION: Our analyses of placebo-treated participants in ICI RCTs document the common occurrence of placebo irAEs. These findings are important for interpreting irAE profiles, avoiding inappropriate therapeutic interventions.

Immunosuppressive therapy for IgA nephropathy in children.

BACKGROUND: IgA nephropathy (IgAN) is the most common cause of primary glomerulonephritis. It is a heterogeneous disease with different presentations and high morbidity. Thirty per cent of adults and 20% of children (followed into adulthood) will have a 50% decline in kidney function or develop kidney failure after 10 years. OBJECTIVES: To determine the benefits and harms of immunosuppressive therapy for the treatment of IgAN in children. SEARCH METHODS: We contacted the Information Specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 03 October 2023 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and non-randomised studies of interventions (NRSIs) investigating the treatment of IgAN in children with immunosuppressive therapies compared to placebo, no treatment, supportive care, standard therapy (Japanese protocol), other immunosuppressive therapies or non-immunosuppressive therapies. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed the risk of bias. Random effects meta-analyses were used to summarise estimates of treatment effects. Treatment effects were expressed as risk ratios (RR) and 95% confidence intervals (CI) for dichotomous outcomes, and the mean difference (MD) and 95% CI for continuous outcomes. The risk of bias was assessed using the Cochrane risk of bias tool for RCTs and the ROBIN-I tool for NRSIs. The certainty of the evidence was assessed using Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). MAIN RESULTS: This review included 13 studies with 686 participants. Ten RCTs included 334 children and 191 adults, and three NRSIs included 151 participants, all children. Most participants had mild kidney disease. The risk of bias was unclear for most of the domains relating to allocation concealment, blinding of participants, personnel, and outcome assessment. In children with IgAN, it is uncertain if corticosteroid (steroid) therapy, compared to placebo reduces proteinuria (1 study, 64 children and young adults: RR 0.47, 95% CI 0.13 to 1.72; low certainty evidence) or the decline in estimated glomerular filtration rate (eGFR) (1 study, 64 children and young adults: RR 0.47, 95% CI 0.09 to 2.39; low certainty evidence). It is uncertain if steroids reduce proteinuria compared to supportive care (2 studies, 61 children: RR 0.04, 95% CI -0.83 to 0.72; low certainty evidence). Adverse events associated with steroid therapy were not assessed due to heterogeneity in steroid protocols, including dose and duration, and lack of systematic assessment for adverse events in the included studies. Azathioprine, mycophenolate mofetil, mizoribine, or cyclophosphamide alone or in combination with steroid therapy had uncertain effects on improving proteinuria or preventing eGFR decline in children with IgAN. Fish oil, vitamin E and tonsillectomy had uncertain effects on improving proteinuria or preventing eGFR decline. Effects of other immunosuppressive therapies, secondary outcomes and adverse events were not assessed due to insufficient data. AUTHORS' CONCLUSIONS: There is a lack of high-quality evidence to guide the management of IgAN in children. There is no evidence to indicate that steroids, other immunosuppressive therapies, or tonsillectomy, when added to optimal supportive care, prevent a decline in eGFR or proteinuria in children with IgAN. Available studies were few, with small numbers, low-quality evidence, high or uncertain risk of bias, did not systematically assess harms associated with treatment, or report net benefits or harms. Severe cases and atypical presentations of IgAN were not included in the reviewed studies, and our findings cannot be generalised to these situations.

A systematic review of sham acupuncture validation studies.

BACKGROUND: Acupuncture is widely used worldwide; however, studies on its effectiveness have been impeded by limitations regarding the design of appropriate control groups. In clinical research, noninvasive sham acupuncture techniques can only be applied through validation studies. Therefore, this systematic review aimed to evaluate the scope of existing literature on this topic to identify trends. METHODS: We queried Pubmed, EMBASE, and the Cochrane Central Register of Controlled Trials databases from inception to July 2022 for relevant articles. Author names were used to identify additional relevant articles. Two independent reviewers assessed the identified articles based on the inclusion and exclusion criteria. The following data were extracted: study design, information regarding acupuncturists and participants, general and treatment-related characteristics of the intervention and control groups, participants' experience of acupuncture, and research findings. RESULTS: The database query yielded 673 articles, of which 29 articles were included in the final review. Among these, 18 involved the use of one of three devices: Streitberger (n = 5), Park (n = 7), and Takakura (n = 6) devices. The remaining 11 studies used other devices, including self-developed needles. All the included studies were randomized controlled trials. The methodological details of the included studies were heterogeneous with respect to outcomes assessed, blinding, and results. CONCLUSIONS: Sham acupuncture validation studies have been conducted using healthy volunteers, with a focus on blind review and technological developments in sham acupuncture devices. However, theren may be language bias in our findings since we could not query Chinese and Japanese databases due to language barriers. There is a need for more efforts toward establishing control groups suitable for various acupuncture therapy interventions. Moreover, there is a need for more rigorous sham acupuncture validation studies, which could lead to higher-quality clinical studies.

Synthesizing Subject-matter Expertise for Variable Selection in Causal Effect Estimation: A Case Study.

BACKGROUND: Causal graphs are an important tool for covariate selection but there is limited applied research on how best to create them. Here, we used data from the Coronary Drug Project trial to assess a range of approaches to directed acyclic graph (DAG) creation. We focused on the effect of adherence on mortality in the placebo arm, since the true causal effect is believed with a high degree of certainty. METHODS: We created DAGs for the effect of placebo adherence on mortality using different approaches for identifying variables and links to include or exclude. For each DAG, we identified minimal adjustment sets of covariates for estimating our causal effect of interest and applied these to analyses of the Coronary Drug Project data. RESULTS: When we used only baseline covariate values to estimate the cumulative effect of placebo adherence on mortality, all adjustment sets performed similarly. The specific choice of covariates had minimal effect on these (biased) point estimates, but including nonconfounding prognostic factors resulted in smaller variance estimates. When we additionally adjusted for time-varying covariates of adherence using inverse probability weighting, covariates identified from the DAG created by focusing on prognostic factors performed best. CONCLUSION: Theoretical advice on covariate selection suggests that including prognostic factors that are not exposure predictors can reduce variance without increasing bias. In contrast, for exposure predictors that are not prognostic factors, inclusion may result in less bias control. Our results empirically confirm this advice. We recommend that hand-creating DAGs begin with the identification of all potential outcome prognostic factors.

Was thalidomide a placebo hypnotic?

Six decades ago the world learned that thalidomide, a seemingly non-toxic sedative and hypnotic, caused severe birth defects including the flipper-like deformity of the arms known as phocomelia. When thalidomide was tested against placebo by the trialist Louis Lasagna in 1960 (while the drug was banned from the U.S. marketplace), he found the 100-mg dosage equivalent to placebo, as well as greatly inferior to the 200-mg dosage, in producing sleep. Even as these findings were made known, a 100-mg dose of thalidomide was in general use as a sleep aid for pregnant women. It appears that unbeknownst to themselves, an untold number of pregnant women around the world who were prescribed thalidomide incurred the risks of a teratogen in return for the benefits of a sugar pill.

[Placebo procedures in the operating room: necessary or an unnecessary risk for the patient?] / Placeboprocedures in de operatiekamer.

Sham surgeries, surgical procedures without actually carrying out the intended surgical intervention, are rarely used in research concerning a new surgical or invasive technique. The conflicting needs of minimizing operational risks and maximizing simulation present challenges in designing placebo-controlled surgical trials. It is important to thoroughly consider ethical considerations in the design of studies involving sham surgeries, including the importance of a transparent research design, objective reporting of results, challenges related to the informed consent procedure, and the inherent risks associated with surgical procedures. Furthermore, there exists a societal need to offer patients the most cost-effective intervention. Responsible sham surgeries are therefore crucial for understanding the potential and cost-effectiveness of surgical interventions compared to less invasive placebo conditions. Clinically high-quality studies involving placebo-based interventions can provide clarity regarding the balance between doing good and avoiding harm through surgical interventions.

Differential Outcomes of Placebo Treatment Across 9 Psychiatric Disorders: A Systematic Review and Meta-Analysis.

Importance: Placebo is the only substance systematically evaluated across common psychiatric diagnoses, but comprehensive cross-diagnostic comparisons are lacking. Objective: To compare changes in placebo groups in recent high-quality randomized clinical trials (RCTs) across a broad spectrum of psychiatric disorders in adult patients. Data Sources: MEDLINE and the Cochrane Database of Systematic Reviews were systematically searched in March 2022 for the latest systematic reviews meeting predetermined high-quality criteria for 9 major psychiatric diagnoses. Study Selection: Using these reviews, the top 10 highest-quality (ie, lowest risk of bias, according to the Cochrane Risk of Bias tool) and most recent placebo-controlled RCTs per diagnosis (totaling 90 RCTs) were selected, adhering to predetermined inclusion and exclusion criteria. Data Extraction and Synthesis: Following the Cochrane Handbook, 2 authors independently carried out the study search, selection, and data extraction. Cross-diagnosis comparisons were based on standardized pre-post effect sizes (mean change divided by its SD) for each placebo group. This study is reported following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline. Main Outcome and Measure: The primary outcome, pooled pre-post placebo effect sizes (dav) with 95% CIs per diagnosis, was determined using random-effects meta-analyses. A Q test assessed statistical significance of differences across diagnoses. Heterogeneity and small-study effects were evaluated as appropriate. Results: A total of 90 RCTs with 9985 placebo-treated participants were included. Symptom severity improved with placebo in all diagnoses. Pooled pre-post placebo effect sizes differed across diagnoses (Q = 88.5; df = 8; P < .001), with major depressive disorder (dav = 1.40; 95% CI, 1.24-1.56) and generalized anxiety disorder (dav = 1.23; 95% CI, 1.06-1.41) exhibiting the largest dav. Panic disorder, attention-deficit/hyperactivity disorder, posttraumatic stress disorder, social phobia, and mania showed dav between 0.68 and 0.92, followed by OCD (dav = 0.65; 95% CI, 0.51-0.78) and schizophrenia (dav = 0.59; 95% CI, 0.41-0.76). Conclusion and Relevance: This systematic review and meta-analysis found that symptom improvement with placebo treatment was substantial in all conditions but varied across the 9 included diagnoses. These findings may help in assessing the necessity and ethical justification of placebo controls, in evaluating treatment effects in uncontrolled studies, and in guiding patients in treatment decisions. These findings likely encompass the true placebo effect, natural disease course, and nonspecific effects.

Systemic antibiotics in the surgical treatment of peri-implantitis: A randomized placebo-controlled trial.

AIM: To study the clinical, radiographic and microbiological outcomes after surgical treatment of peri-implantitis, with or without adjunctive systemic antibiotics. MATERIALS AND METHODS: Eighty-four patients (113 implants) with peri-implantitis were randomized into three groups (A, amoxicillin and metronidazole; B, phenoxymethylpenicillin and metronidazole; or C, placebo). Treatment included resective surgery and implant surface decontamination with adjunctive antibiotics or placebo. Primary outcomes were probing pocket depth (PPD) reduction and marginal bone level (MBL) stability. Secondary outcomes were treatment success (defined as PPD ≤ 5 mm, bleeding on probing [BOP] ≤ 1site, absence of suppuration on probing [SOP] and absence of progressive bone loss of >0.5 mm), changes in BOP/SOP, mucosal recession (REC), clinical attachment level (CAL), bacterial levels and adverse events. Outcomes were evaluated for up to 12 months. The impact of potential prognostic indicators on treatment success was evaluated using multilevel logistic regression analysis. RESULTS: A total of 76 patients (104 implants) completed the study. All groups showed clinical and radiological improvements over time. Statistically significant differences were observed between groups for MBL stability (A = 97%, B = 89%, C = 76%), treatment success (A = 68%, B = 66%, C = 28%) and bacterial levels of Aggregatibacter actinomycetemcomitans and Tannerella forsythia, favouring antibiotics compared to placebo. Multiple regression identified antibiotic use as potential prognostic indicator for treatment success. Gastrointestinal disorders were the most reported adverse events in the antibiotic groups. CONCLUSIONS: Adjunctive systemic antibiotics resulted in additional improvements in MBL stability. However, the potential clinical benefits of antibiotics need to be carefully balanced against the risk of adverse events and possible antibiotic resistance.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese: a randomized, double-blind, placebo-controlled, multiple-dose phase 1b study.

BACKGROUND: TG103, a glucagon-like peptide-1 analog, is being investigated as an option for weight management. We aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese without diabetes. METHODS: In this randomized, double-blind, placebo-controlled, multiple-dose phase 1b study, participants aged 18-75 years with a body-mass index (BMI) ≥ 26.0 kg/m2 and body weight ≥ 60 kg were enrolled from three centers in China. The study included three cohorts, and in each cohort, eligible participants were randomly assigned (3:1) to one of three once-weekly subcutaneous TG103 groups (15.0, 22.5 and 30.0 mg) or matched placebo, without lifestyle interventions. In each cohort, the doses of TG103 were escalated in 1-week intervals to the desired dose over 1 to 4 weeks. Then participants were treated at the target dose until week 12 and then followed up for 2 weeks. The primary endpoint was safety and tolerability assessed by the incidence and severity of adverse events (AEs) from baseline to the end of the follow-up period. Secondary endpoints included pharmacokinetic and pharmacodynamic profiles of TG103 and the occurrence of anti-drug antibodies to TG103. RESULTS: A total of 147 participants were screened, and 48 participants were randomly assigned to TG103 (15.0, 22.5 and 30.0 mg groups, n = 12 per group) or placebo (n = 12). The mean (standard deviation, SD) age of the participants was 33.9 (10.0) years; the mean bodyweight was 81.65 (10.50) kg, and the mean BMI was 29.8 (2.5) kg/m2. A total of 466 AEs occurred in 45 of the 48 participants, with 35 (97.2%) in the TG103 group and 10 (83.3%) in the pooled placebo group. Most AEs were grade 1 or 2 in severity, and there were no serious adverse events (SAEs), AEs leading to death, or AEs leading to discontinuation of treatment. The steady-state exposure of TG103 increased with increasing dose and was proportional to Cmax,ss, AUCss, AUC0-t and AUC0-inf. The mean values of Cmax,ss ranged from 951 to 1690 ng/mL, AUC0-t ranged from 150 to 321 µg*h/mL, and AUC0-inf ranged from 159 to 340 µg*h/mL. TG103 had a half-life of 110-116 h, with a median Tmax of 36-48 h. After treatment for 12 weeks, the mean (SD) values of weight loss from baseline in the TG103 15.0 mg, 22.5 mg and 30.0 mg groups were 5.65 (3.30) kg, 5.35 (3.39) kg and 5.13 (2.56) kg, respectively, and that in the placebo group was 1.37 (2.13) kg. The least square mean percent weight loss from baseline to D85 in all the TG103 groups was more than 5% with p < 0.05 for all comparisons with placebo. CONCLUSIONS: In this trial, all three doses of once-weekly TG103 were well tolerated with an acceptable safety profile. TG103 demonstrated preliminary 12-week body weight loss without lifestyle interventions, thus showing great potential for the treatment of overweight and obesity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04855292. Registered on April 22, 2021.

Matched vs Nonmatched Placebos in a Randomized Trial of COVID-19 Treatments.

Importance: Matched placebo interventions are complex and resource intensive. Recent evidence suggests matched placebos may not always be necessary. Previous studies have predominantly evaluated potential bias of nonmatched placebos (ie, differing on dose, frequency of administration, or formulation) in pain and mental health, but to date no systematic examination has been conducted in infectious disease. Objective: To test for differences between nonmatched and matched placebo arms with respect to clinical outcome measures across multiple therapeutics for COVID-19. Design, Setting, and Participants: In a comparative effectiveness research study, a post hoc analysis was conducted of data on individual patients enrolled in a large, multiarm, platform randomized clinical trial in symptomatic adult outpatients with COVID-19 between January 15, 2021, to September 28, 2023, in which the outcomes of both matched and nonmatched placebo groups were reported. Bayesian and frequentist covariate-adjusted techniques were compared with 7 intervention-placebo pairs. Exposures: Seven matched and nonmatched placebo pairs (for a total of 7 comparisons) were evaluated throughout the primary platform trial. Comparisons were made between treatment and its associated matched (concurrent) placebo, as well as with nonmatched placebo (alone and in combination) assessed at a similar time point. Main Outcomes and Measures: Outcomes assessed included hospitalizations, EuroQol 5-Dimension 5-level scores, and PROMIS Global-10 scores. Results: A total of 7 intervention-control pairs (N = 2684) were assessed, including 1620 (60.4%) women, with mean (SD) age, 47 (15.2) years; the most common comorbidities were obesity (41.9%) and hypertension (37.9%). In a meta-analysis with decoupled SEs, accounting for overlapping placebo patients, the overall odds ratio (OR) of nonmatched compared with matched placebo was 1.01 (95% credible interval, 0.77-1.32), with posterior probability of equivalence, defined as 0.8 ≤ OR ≤ 1.2 (a deviation from perfect equivalence ie, OR = 1, by no more than 0.2) of 85.4%, implying no significant difference. Unadjusted analysis of the event rate difference between all nonmatched and matched placebo groups did not identify any notable differences across all 7 treatment-placebo combinations assessed. Similar analysis that was conducted for patient-reported quality of life outcomes did not yield statistically significant differences. Conclusions and Relevance: In this post hoc study of a randomized clinical platform trial, pooling matched and nonmatched placebo patient data did not lead to inconsistencies in treatment effect estimation for any of the investigational drugs. These findings may have significant implications for future platform trials, as the use of nonmatched placebo may improve statistical power, or reduce barriers to placebo implementation.

History of Rectal Product Use and Country of Residence Influence Preference for Rectal Microbicide Dosage Forms Among Young Sexual and Gender Minorities: A Multi-country Trial Comparing Placebo Douche, Suppository, and Insert Products.

The DESIRE Study (MTN-035) explored product preference among three placebo rectal microbicide (RM) formulations, a rectal douche (RD), a suppository, and an insert, among 210 sexually active transgender people and men who have sex with men in five counties: the United States, Peru, Thailand, South Africa, and Malawi. Participants used each product prior to receptive anal sex (RAS) for 1 month, following a randomly assigned sequence, then selected their preferred product via computer assisted self-interview. In-depth interviews examined reasons for preference. We compared product preference and prior product use by country to explore whether geographic location and experience with the similar products impacted preference. A majority in the United States (56%) and Peru (58%) and nearly half in South Africa (48%) preferred the douche. Most in Malawi (59%) preferred the suppository, while half in Thailand (50%) and nearly half in South Africa (47%) preferred the insert. Participants who preferred the douche described it as quick and easy, already routinized, and serving a dual purpose of cleansing and protecting. Those who preferred the insert found it small, portable, discreet, with quick dissolution. Those who preferred the suppository found the size and shape acceptable and liked the added lubrication it provided. Experience with product use varied by country. Participants with RD experience were significantly more likely to prefer the douche (p = 0.03). Diversifying availability of multiple RM dosage forms can increase uptake and improve HIV prevention efforts globally.

RESUMEN: El estudio DESIRE (MTN-035) exploró la preferencia de producto entre tres formulaciones de microbicida rectal (MR) de placebo, una ducha rectal, un supositorio y un inserto, entre 210 personas transgénero y hombres que tienen sexo con hombres en cinco países: los Estados Unidos, Perú., Tailandia, Sudáfrica y Malawi. Los participantes utilizaron cada producto antes del sexo anal receptive (SAR) durante un mes, siguiendo una secuencia asignada al azar, luego seleccionaron su producto preferido mediante una autoentrevista asistida por computadora. Las entrevistas en profundidad examinaron los motivos de preferencia. Comparamos la preferencia de producto y el uso previo del producto por país para explorar si la ubicación geográfica y la experiencia con la forma farmacéutica impactaron la preferencia. Una mayoría en los Estados Unidos (56%) y Perú (58%) y casi la mitad en Sudáfrica (48%) prefirieron la ducha rectal. La mayoría en Malawi (59%) prefirió el supositorio, mientras que la mitad en Tailandia (50%) y casi la mitad en Sudáfrica (47%) prefirió el inserto. Los participantes que prefirieron la ducha rectal la describieron como rápida y fácil, ya parte de su rutina y que tenía el doble propósito de limpiar y proteger. Los que prefirieron el inserto lo consideraron pequeño, portátil, discreto y de rápida disolución. Los que prefirieron el supositorio encontraron que tenía un tamaño y forma aceptables y proveía lubricación adicional. La experiencia con el uso del producto varió según el país. Los participantes con experiencia con duchas rectales tenían significativamente más probabilidades de preferir la ducha rectal (p = 0,03). Diversificar la disponibilidad de múltiples formas farmacéuticas de MR puede aumentar la aceptación y mejorar los esfuerzos de prevención del VIH a nivel mundial.

A reactogenic "placebo" and the ethics of informed consent in Gardasil HPV vaccine clinical trials: A case study from Denmark.

BACKGROUND: Medical ethics guidelines require of clinical trial investigators and sponsors to inform prospective trial participants of all known and potential risks associated with investigational medical products, and to obtain their free informed consent. These guidelines also require that clinical research be so designed as to minimize harms and maximize benefits. OBJECTIVE: To examine Merck's scientific rationale for using a reactogenic aluminum-containing "placebo" in Gardasil HPV vaccine pre-licensure clinical trials. METHODS: We examined the informed consent form and the recruitment brochure for the FUTURE II Gardasil vaccine trial conducted in Denmark; and we interviewed several FUTURE II trial participants and their treating physicians. We also reviewed regulatory documentation related to Gardasil vaccine approval process and the guidelines on evaluation of adjuvants used in human vaccines. RESULTS: It was found that the vaccine manufacturer Merck made several inaccurate statements to trial participants that compromised their right to informed consent. First, even though the study protocol listed safety testing as one of the study's primary objectives, the recruitment brochure emphasized that FUTURE II was not a safety study, and that the vaccine had already been proven safe. Second, the advertising material for the trial and the informed consent forms stated that the placebo was saline or an inactive substance, when, in fact, it contained Merck's proprietary highly reactogenic aluminum adjuvant which does not appear to have been properly evaluated for safety. Several trial participants experienced chronic disabling symptoms, including some randomized to the adjuvant "placebo" group. CONCLUSION: In our view, the administration of a reactive placebo in Gardasil clinical trials was without any possible benefit, needlessly exposed study subjects to risks, and was therefore a violation of medical ethics. The routine use of aluminum adjuvants as "placebos" in vaccine clinical trials is inappropriate as it hinders the discovery of vaccine-related safety signals.

Antioxidant supplementation for sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) refers to a group of genetic disorders characterized by the presence of an abnormal haemoglobin molecule called haemoglobin S (HbS). When subjected to oxidative stress from low oxygen concentrations, HbS molecules form rigid polymers, giving the red cell the typical sickle shape. Antioxidants have been shown to reduce oxidative stress and improve outcomes in other diseases associated with oxidative stress. Therefore, it is important to review and synthesize the available evidence on the effect of antioxidants on the clinical outcomes of people with SCD. OBJECTIVES: To assess the effectiveness and safety of antioxidant supplementation for improving health outcomes in people with SCD. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 15 August 2023. SELECTION CRITERIA: We included randomized and quasi-randomized controlled trials comparing antioxidant supplementation to placebo, other antioxidants, or different doses of antioxidants, in people with SCD. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed the risk of bias and certainty of the evidence, and reported according to Cochrane methodological procedures. MAIN RESULTS: The review included 1609 participants in 26 studies, with 17 comparisons. We rated 13 studies as having a high risk of bias overall, and 13 studies as having an unclear risk of bias overall due to study limitations. We used GRADE to rate the certainty of evidence. Only eight studies reported on our important outcomes at six months. Vitamin C (1400 mg) plus vitamin E (800 mg) versus placebo Based on evidence from one study in 83 participants, vitamin C (1400 mg) plus vitamin E (800 mg) may not be better than placebo at reducing the frequency of crisis (risk ratio (RR) 1.18, 95% confidence interval (CI) 0.64 to 2.18), the severity of pain (RR 1.33, 95% CI 0.40 to 4.37), or adverse effects (AE), of which the most common were headache, nausea, fatigue, diarrhoea, and epigastric pain (RR 0.56, 95% CI 0.31 to 1.00). Vitamin C plus vitamin E may increase the risk of SCD-related complications (acute chest syndrome: RR 2.66, 95% CI 0.77 to 9.13; 1 study, 83 participants), and increase haemoglobin level (median (interquartile range) 90 (81 to 96) g/L versus 93.5 (84 to 105) g/L) (1 study, 83 participants) compared to placebo. However, the evidence for all the above effects is very uncertain. The study did not report on quality of life (QoL) of participants and their caregivers, nor on frequency of hospitalization. Zinc versus placebo Zinc may not be better than placebo at reducing the frequency of crisis at six months (rate ratio 0.62, 95% CI 0.17 to 2.29; 1 study, 36 participants; low-certainty evidence). We are uncertain whether zinc is better than placebo at improving sickle cell-related complications (complete healing of leg ulcers at six months: RR 2.00, 95% CI 0.60 to 6.72; 1 study, 34 participants; very low-certainty evidence). Zinc may be better than placebo at increasing haemoglobin level (g/dL) (MD 1.26, 95% CI 0.44 to 1.26; 1 study, 36 participants; low-certainty evidence). The study did not report on severity of pain, QoL, AE, and frequency of hospitalization. N-acetylcysteine versus placebo N-acetylcysteine (NAC) 1200 mg may not be better than placebo at reducing the frequency of crisis in SCD, reported as pain days (rate ratio 0.99 days, 95% CI 0.53 to 1.84; 1 study, 96 participants; low-certainty evidence). Low-certainty evidence from one study (96 participants) suggests NAC (1200 mg) may not be better than placebo at reducing the severity of pain (MD 0.17, 95% CI -0.53 to 0.87). Compared to placebo, NAC (1200 mg) may not be better at improving physical QoL (MD -1.80, 95% CI -5.01 to 1.41) and mental QoL (MD 2.00, 95% CI -1.45 to 5.45; very low-certainty evidence), reducing the risk of adverse effects (gastrointestinal complaints, pruritus, or rash) (RR 0.92, 95% CI 0.75 to 1.14; low-certainty evidence), reducing the frequency of hospitalizations (rate ratio 0.98, 95% CI 0.41 to 2.38; low-certainty evidence), and sickle cell-related complications (RR 5.00, 95% CI 0.25 to 101.48; very low-certainty evidence), or increasing haemoglobin level (MD -0.18 g/dL, 95% CI -0.40 to 0.04; low-certainty evidence). L-arginine versus placebo L-arginine may not be better than placebo at reducing the frequency of crisis (monthly pain) (RR 0.71, 95% CI 0.26 to 1.95; 1 study, 50 participants; low-certainty evidence). However, L-arginine may be better than placebo at reducing the severity of pain (MD -1.41, 95% CI -1.65 to -1.18; 2 studies, 125 participants; low-certainty evidence). One participant allocated to L-arginine developed hives during infusion of L-arginine, another experienced acute clinical deterioration, and a participant in the placebo group had clinically relevant increases in liver function enzymes. The evidence is very uncertain whether L-arginine is better at reducing the mean number of days in hospital compared to placebo (MD -0.85 days, 95% CI -1.87 to 0.17; 2 studies, 125 participants; very low-certainty evidence). Also, L-arginine may not be better than placebo at increasing haemoglobin level (MD 0.4 g/dL, 95% CI -0.50 to 1.3; 2 studies, 106 participants; low-certainty evidence). No study in this comparison reported on QoL and sickle cell-related complications. Omega-3 versus placebo Very low-certainty evidence shows no evidence of a difference in the risk of adverse effects of omega-3 compared to placebo (RR 1.05, 95% CI 0.74 to 1.48; 1 study, 67 participants). Very low-certainty evidence suggests that omega-3 may not be better than placebo at increasing haemoglobin level (MD 0.36 g/L, 95% CI -0.21 to 0.93; 1 study, 67 participants). The study did not report on frequency of crisis, severity of pain, QoL, frequency of hospitalization, and sickle cell-related complications. AUTHORS' CONCLUSIONS: There was inconsistent evidence on all outcomes to draw conclusions on the beneficial and harmful effects of antioxidants. However, L-arginine may be better than placebo at reducing the severity of pain at six months, and zinc may be better than placebo at increasing haemoglobin level. We are uncertain whether other antioxidants are beneficial for SCD. Larger studies conducted on each comparison would reduce the current uncertainties.