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References
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PMC10325040
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Background
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cognitive decline, neuronopathic disorders, cognitive impairment
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MUCOPOLYSACCHARIDOSIS II, HUNTER SYNDROME, GCA
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Norm-based scores used to assess cognitive ability have clinical value when describing functioning of patients with neuronopathic disorders compared with unaffected, same-age peers. However, they have limitations when used to assess change in cognitive ability between two timepoints, especially in children with severe cognitive decline. Calculation of Projected Retained Ability Scores (PRAS) is a novel method developed to characterize absolute change in norm-based ability test scores. In this analysis, PRAS were calculated post hoc for children with mucopolysaccharidosis II (MPS II; Hunter syndrome) and early cognitive impairment in a 52-week phase 2/3 randomized controlled trial (RCT) and its extension study of intrathecal idursulfase (idursulfase-IT). Patients completing the first year of the extension after receiving idursulfase-IT in the RCT and extension (n = 32 of 34 enrolled) or the extension only (n = 15 of 15 enrolled) were categorized according to changes in Differential Ability Scales, Second Edition, General Conceptual Ability (DAS-II GCA) scores and PRAS at 1 and 2 years. Analyses were conducted in the overall population and a subpopulation aged < 6 years at baseline (idursulfase-IT in the RCT and extension [n = 27] and extension only [n = 12]).
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PMC10621086
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Results
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deteriorating cognitive functioning
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GCA
|
PRAS methodology differentiated patients with decreases in DAS-II GCA scores into three separate categories reflecting below-average cognitive growth rates, plateauing cognitive development, and deteriorating cognitive functioning. After 1 year in the RCT, 72.4% of patients who initiated idursulfase-IT had above-average or average cognitive growth rates in DAS-II GCA scores compared with 53.3% of those who did not receive idursulfase-IT; 6.9% versus 20.0% experienced deteriorating cognitive functioning. Similar results were seen in children aged < 6 years: 76% (idursulfase-IT group) versus 50% (no idursulfase-IT) had above-average or average cognitive growth rates in DAS-II GCA scores; 4% versus 17% had deteriorating cognitive functioning. The difference in the distributions of cognitive categories at 1 year in children aged < 6 years was significant (
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PMC10621086
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Supplementary Information
|
The online version contains supplementary material available at 10.1186/s13023-023-02957-2.
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PMC10621086
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Keywords
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PMC10621086
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Background
|
cognitive functioning, MPS II, OMIM 309900, X-linked lysosomal storage disease
|
DISEASE, MUCOPOLYSACCHARIDOSIS II, HUNTER SYNDROME, GCA
|
Mucopolysaccharidosis II (MPS II; Hunter syndrome; OMIM 309900) is a rare, X-linked lysosomal storage disease with an estimated worldwide prevalence of between 1 in 100,000 and 1 in 170,000 male live births [The current standard of care for MPS II is intravenous enzyme replacement therapy with recombinant I2S (idursulfase; Takeda Pharmaceuticals USA, Inc., Lexington, MA, USA), which has been shown to be effective in the treatment of somatic manifestations of the disease and in improving survival [Global ability scores are used to assess broad cognitive ability on major intellectual tests such as the Wechsler scales, DAS, Bayley, and Kaufman ability scales [To address this fundamental limitation of using norm-based scores in isolation, the Projected Retained Ability Score (PRAS) methodology has been developed to characterize the absolute change (i.e., change in absolute performance in the same child from baseline to endpoint) in norm-based scores over time. When applied to DAS-II GCA scores, PRAS allows differentiation between below-average cognitive growth rates versus plateauing and deteriorating (i.e., loss of milestones) cognitive functioning in children with MPS II [
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PMC10621086
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Materials and methods
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PMC10621086
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Study design
|
The designs of the phase 2/3 trial and extension study have been described previously [
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PMC10621086
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Endpoints and assessments
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GCA
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In the phase 2/3 trial, the primary endpoint was the change from baseline in DAS-II GCA score at week 52 [The primary objective of the extension study was to assess long-term safety; long-term clinical efficacy measures were also assessed [
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PMC10621086
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Statistical analyses
|
GCA
|
The presented analyses are descriptive. To demonstrate the utility of PRAS in characterizing absolute change in the study samples over time, differences in the distribution of cognitive development categories between treatment groups in the overall population and in the subpopulation younger than 6 years of age were assessed using a post hoc, non-parametric, one-sided Mann–Whitney U-test. No multiplicity adjustments were made; therefore, these results are considered descriptive. Mean GCA scores over time for patients in each cognitive development category are presented graphically.
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PMC10621086
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Distributions of cognitive development categories (patients younger than 6 years of age)
|
In the subpopulation of patients younger than 6 years of age at phase 2/3 baseline, cognitive categories were defined for 25/28 and 12/12 patients in the idursulfase-IT and no idursulfase-IT groups, respectively, at 1 year, and for 25/28 and 11/12 patients in the early idursulfase-IT and delayed idursulfase-IT groups, respectively, at 2 years (Additional file Results for this subpopulation were similar to those for the overall population (Fig. Distribution of, and patient movement between, cognitive categories in the subpopulation aged < 6 years. Graph depicts the movement of individual patients from their cognitive category at 1 year to their cognitive category at 2 years; the width of each band corresponds to the number of patients who changed cognitive category with that movement. At 2 years, the proportions of patients in the different cognitive categories were more similar in the two treatment groups than at 1 year, with no statistically significant difference in category distributions between groups (
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PMC10621086
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DAS-II GCA scores within cognitive development categories
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deteriorating cognitive functioning
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GCA
|
The one patient with above-average cognitive growth rates in DAS-II GCA scores (who received idursulfase-IT in the randomized trial) had an increasing trend in GCA score over the 2 years; there was a relatively flatter trend in GCA scores among patients with average cognitive growth rates in DAS-II GCA scores, and a decreasing trend in GCA scores in patients with below-average cognitive growth rates in DAS-II GCA scores, plateauing cognitive functioning, or deteriorating cognitive functioning (both treatment groups; Fig. DAS-II GCA score
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PMC10621086
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Discussion
|
deteriorating cognitive functioning, neuronopathic MPS II, deteriorating cognitive function
|
GCA
|
PRAS methodology has been developed to overcome the limitations of norm-based ability test scores in characterizing absolute changes over time in cognitive development [After 1 year of treatment, the idursulfase-IT group included a greater proportion of patients with above-average or average cognitive growth rates in DAS-II GCA scores and a lower proportion of patients with deteriorating cognitive functioning than the no idursulfase-IT group. Differences in the distribution of cognitive categories at 1 year did not reach statistical significance in the overall population but did reach statistical significance for the subpopulation aged younger than 6 years at phase 2/3 baseline in this post hoc analysis. Importantly, PRAS analyses allowed the differentiation of patients with declines in GCA scores after 1 year of treatment into the three categories of below-average, plateauing, and deteriorating cognitive functioning, revealing that approximately three times as many patients (proportionally) in the no idursulfase-IT group had deteriorating cognitive functioning after 1 year than patients in the idursulfase-IT group (Table At 2 years, both treatment groups were receiving idursulfase-IT in the extension study. Differences between treatment groups were less pronounced at 2 years than at 1 year, and did not reach statistical significance in either the overall population or the subpopulation younger than 6 years of age. However, many patients remained in the same cognitive category from 1 to 2 years.The findings from PRAS analyses support and extend the results from the primary analyses of the phase 2/3 trial and extension study [An analysis of the same trial and extension study data that categorized patients younger than 6 years old at baseline into three cognitive development categories (above-average, average, or below-average) based on their DAS-II GCA scores alone has also been reported previously [Differences in the proportions of patients with missing data from 1 to 2 years in the two treatment groups may have affected the results. For example, the increase in the proportion of patients with missing data from 1 to 2 years in the delayed idursulfase-IT group mainly comprised patients who had been in the deteriorating cognitive category at 1 year, leading to a possible misinterpretation that the proportion of patients with deteriorating cognitive function had declined. However, approximately half of the patients in the early idursulfase-IT group and most of those in the delayed idursulfase-IT group remained in the same cognitive category at 1 year and 2 years. Moreover, patients typically moved to an adjacent category, with few patients having substantial changes in their cognitive status. The cognitive category with the greatest proportion of patients was that in which DAS-II GCA score cognitive growth rates were average (i.e., they were matching the trajectory of age-matched norms), and this remained the case at 1 year and 2 years.These results should be considered in the context of current knowledge of the natural history of neuronopathic MPS II [Other limitations of the present analysis include those inherent to all post hoc analyses. The duration of follow-up, small sample sizes, and missing data for some patients, particularly at the 2-year timepoint, limit the conclusions that can be drawn regarding patterns and differences between groups and over time. While we considered a difference of > 10 points between endpoint and baseline GCA scores (relative change) or between endpoint GCA score and PRAS (absolute change) to be clinically and statistically meaningful based on our previous analysis, we acknowledge the limitations of this cut-off-based method, which should be taken into account in its application [It is also important to understand the meaning and value of PRAS in the context of other types of scores from cognitive ability tests. Although norm-based scores cannot be used in isolation to evaluate absolute change, other types of scores such as raw scores or item-response theory (IRT)-based scores (e.g., Rasch-scaled scores; referred to as ability scores for the DAS-II subtests) can be used to evaluate absolute change in individual or sample scores over time [Change in raw or IRT-based scores corresponds directly to participant performance on items within a subtest and is straightforward to calculate. However, unlike PRAS (which have meaning based on norm values), raw or IRT-based scores do not have inherent functional or clinical meaning. Thus, reliable and meaningful within-patient change values for raw or IRT-based scores would need to be established for the use of a subtest as a primary endpoint in a clinical trial (and would differ from one subtest to another) [Future large-scale, long-term studies are required to fully assess the role of PRAS methodology in assessing specific profiles of cognitive function in patients with neurodegenerative conditions such as neuronopathic MPS II. When assessing cognitive function over the long term (> 24 months, i.e., a longer time period than in the present study), a combination of PRAS methodology and other established approaches is likely to be required for optimal interpretation of cognitive scores [
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PMC10621086
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Conclusion
|
deteriorating cognitive functioning, early-onset cognitive impairment, neuronopathic MPS II
|
GCA
|
The results from this analysis demonstrate that application of PRAS methodology to DAS-II GCA scores can be used to characterize change in cognitive functioning more specifically in patients with early-onset cognitive impairment reporting a decrease in norm-based scores. PRAS methodology allowed differentiation of patients who were considered to have below-average improvement in cognitive functioning (i.e., declines in GCA scores) into three separate categories reflecting absolute change in cognitive functioning (below-average cognitive development, plateauing cognitive functioning, and deteriorating cognitive functioning). Following 1 year of treatment with idursulfase-IT, a greater proportion of patients had above-average or average cognitive growth rate compared with those who had not received idursulfase-IT treatment, and a smaller proportion of patients who had received idursulfase-IT showed deteriorating cognitive functioning, particularly in patients younger than 6 years of age at phase 2/3 baseline. The differences between treatment groups were less pronounced at 2 years than at 1 year. Compared with a previously reported categorical analysis of the trial data, in which a high proportion of patients younger than 6 years of age at phase 2/3 baseline were categorized as having below-average cognitive development after treatment (reflected by a decline in DAS-II GCA scores), the present analysis demonstrated that only a small proportion of these patients actually had below-average cognitive growth rates in DAS-II GCA scores and, importantly, that the majority had plateauing cognitive functioning and remained in the same cognitive category. These results support further investigation into the role of PRAS methodology in assessing cognitive functioning over time in patients with neuronopathic MPS II.
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PMC10621086
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Acknowledgements
|
We thank all those involved in these studies for their valuable contributions, including the patients and their families, investigators and study coordinators, and staff. We also thank Yuna Wu for valuable contributions to the data analyses and Qihua Feng for help with the PRAS calculations.
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PMC10621086
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Author contributions
|
Conceptualization: KSY, CC, ED, DM, CB, and WGK were involved in the concept development of this analysis, and KSY, ED, and WGK developed the methodology. Formal statistical analysis was conducted by KSY, ED, CC, and WGK. All authors were involved in writing the original draft and reviewing and editing subsequent drafts.
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PMC10621086
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Funding
|
These studies were sponsored by Shire, a Takeda Company. Under the direction of the authors, medical writing support was provided by Mark Rolfe, PhD and Sarah Feeny, BMedSci of Oxford PharmaGenesis, Oxford, UK and was funded by Takeda Development Center Americas, Inc.
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PMC10621086
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Availability of data and materials
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The datasets, including redacted study protocol, redacted statistical analysis plan, and individual participants’ data supporting the results reported in this article, will be made available within 3 months from initial request to researchers who provide a methodologically sound proposal. The data will be provided after its de-identification in compliance with applicable privacy laws, data protection, and requirements for consent and anonymization. For more information, see
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PMC10621086
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Declarations
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PMC10621086
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Ethics approval and consent to participate
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The phase 2/3 trial and its extension were approved by the relevant institutional review boards/independent ethics committees and conducted in accordance with the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice guidelines. Written informed consent was obtained from parents or legal guardians.
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PMC10621086
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Consent for publication
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Not applicable.
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PMC10621086
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Competing interests
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Thrombosis
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HEMOPHILIA, RTI, THROMBOSIS, RARE DISEASE
|
KSY was an employee of Takeda Development Center Americas, Inc. and stockholder of Takeda Pharmaceuticals Company Limited at the time of the analysis (current affiliation is Alexion Pharmaceuticals, Inc., AstraZeneca Rare Disease, Boston, MA, USA). CC, ED, DM, and CB are employees of RTI Health Solutions, and conducted contracted research for Takeda Pharmaceuticals Company Limited. WGK has received consulting fees from Homology Medicines, Indiana Hemophilia and Thrombosis Center, and Takeda Pharmaceuticals Company Limited.
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PMC10621086
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References
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PMC10621086
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Methods
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HSIL
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This 3+3 dose escalation Phase I clinical trial evaluated the safety and tolerability of artesunate suppositories in the treatment of patients with biopsy-proven HSIL.
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PMC10723659
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Results
|
nausea
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ADVERSE EVENTS
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The maximal tolerated dose was 400 mg, administered in 3 cycles. All adverse events associated with the use 200- and 400-mg artesunate suppositories were Grade 1. At the 600-mg dose, patients experienced clinically significant nausea.
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PMC10723659
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Conclusion
|
HSIL
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Artesunate suppositories are a safe treatment option for anal HSIL.
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PMC10723659
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Data Availability
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All relevant data are within the paper and its
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PMC10723659
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Background
|
malaria, HPV-associated anal, HPVs
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ANAL SQUAMOUS CELL CANCER, MALARIA, PERSISTENT INFECTION, HSIL, ANAL CANCERS
|
Up to 95% of anal cancers (anal squamous cell cancers, ASCC) are caused by persistent infection with human papillomaviruses (HPVs) [Artesunate, formulated as a suppository, is approved by the World Health Organization (WHO) as first-line treatment for acute malaria in children who are in remote settings with limited access to healthcare [Studies have demonstrated cytotoxic effects of artesunate on HPV-infected cells while having minimal effect on healthy cells [This open label Phase 1 study investigated the safety and tolerability of a novel non-surgical treatment of HPV-associated anal HSIL, using artesunate suppositories.
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PMC10723659
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Materials and methods
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PMC10723659
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Patient selection and data collection
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HSIL
|
A Phase 1 dose escalation trial of intra-anal artesunate in patients with anal HSIL was conducted (The inclusion criteria were adults who had a positive anal HPV test with anal HSIL biopsies on HRA (
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PMC10723659
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Study schema and timeline.
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HSIL
|
CONSORT diagram of a phase 1 study utilizing artesunate for the treatment of anal HSIL.
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PMC10723659
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Enrollment schema.
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* each treatment cycle consisted of five (5) consecutive nightly artesunate suppositories.
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PMC10723659
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Inclusion and exclusion criteria.
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PMC10723659
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Intervention and mode of delivery (Figs
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toxicity, toxicities, HRA/biopsy
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ANAL DYSPLASIA, ADVERSE EVENT, LOW-GRADE SQUAMOUS INTRAEPITHELIAL LESION, ADVERSE EVENTS, HSIL, ADVERSE EVENT, REGRESSION
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Participants with anal HSIL biopsies in the previous 8 weeks were screened for study participation. At the time of signing consent, the presence of residual HSIL was documented by HRA. The time between screening for study eligibility and week 0 (study commencement) was ≤ 4–6 weeks.Artesunate suppositories (Frantz Viral Therapeutics, LLC) were administered intra-anally through a 3+3 dose escalation schema (doses: 200 mg, 400 mg, 600 mg) in which the maximal tolerated dose was identified, with the safeguard of an integrated de-escalation schema. The lowest dose level was two 5-day cycles of artesunate, followed by three five-day cycles of artesunate. In the absence of toxicity, patients were enrolled at the next highest dose in the same manner.During the week 0 clinic visit, the first suppository of the entire treatment regimen was inserted digitally into the anal canal by the healthcare provider, while the patient was in the left lateral position. Patients were instructed to insert the remaining suppositories at bedtime using the same technique shown by the clinician.The study team performed a follow-up phone call the week after each treatment cycle began to document compliance with the study medication and any adverse events. At weeks 2, 4, 6, the anoscopic exam assessed for the presence of local mucosal reactions, and symptom diary cards were reviewed, graded, and causality to the study drug assessed by the clinician. Initial screening and follow-up (weeks 16, 28, 40) studies included anal cytology, HPV genotyping (AmpFire HPV genotyping assay, Atila Biosystems, Inc, Sunnyvale, CA), and HRA. HRA-directed biopsies were obtained at week 16, and if clinically indicated, at weeks 28 and 40.The primary outcome/endpoint was to evaluate the safety and tolerability of intra-anal artesunate. Safety reporting consisted of all adverse events (AEs) reported by patients during the dosing phase of the study and for one month following the last dose of Artesunate. Relatedness of an AE to study treatment was assessed by the investigator.A dose-limiting toxicity was defined as any drug-related Grade 2 or greater, drug-related toxicities in any organ system as delineated in Common Terminology Criteria for Adverse Events v4.0. Tolerability was defined as the percentage of participants who completed the dosing regimen without any drug-related serious adverse event (SAE).Secondary outcomes/endpoints for efficacy included the following:Complete histologic regression is defined as either regression to LSIL (low-grade squamous intraepithelial lesion) or no anal dysplasia detected by HRA/biopsy and anal cytology at week 16 and over the study window. Partial regression is defined as: (1) clearance of intra-anal HSIL, but not perianal HSIL in a patient who had both or (2) >50% reduction of the area of HSIL lesions compared to the area of anal HSIL seen on screening HRAClearance of detectable HPV genotypes identified at the screening evaluation that became undetectable consistently through serial HPV genotyping over the study window. New genotypes acquired during the study were not included in evaluation.Descriptive summary statistics were used to assess demographic characteristics, safety, and regression of anal HSIL. Categorical data were summarized using frequencies and relative frequencies (i.e., proportions). Continuous data were summarized by mean or median with the range.
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PMC10723659
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Results
|
PMC10723659
|
|||
Baseline patient characteristics (
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PMC10723659
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Safety and tolerability
|
Eighteen out of nineteen patients enrolled in this study completed the full dosing regimens and artesunate treatment was generally well tolerated. One patient did not complete the full dosing regimen due to a mental health issue. A total of 119 AEs were reported in 15 out of the 19 patients who were treated with artesunate [
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PMC10723659
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Adverse events.
|
dose-limiting, nausea, Nausea
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DIABETIC KETOACIDOSIS
|
All AEs associated with the study drug were Grades 1 or 2. Patients in treatment groups receiving 200- and 400-mg suppositories reported a limited number of grade 1 AE’s related to the study medication which were not dose limiting. However, most participants enrolled in the 600 mg arm, reported Grade 1 AEs of nausea and one reported grade 2 nausea, which was controlled with ondansetron. Nausea was considered dose-limiting at the 600 mg dose. No SAEs associated with the study drug were reported by participants in any treatment group. One patient had a non-related SAE (diabetic ketoacidosis) due to non-compliance with insulin treatment.
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PMC10723659
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Efficacy
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PMC10723659
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Histologic regression (
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perianal disease
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DISEASE, HSIL
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At screening HRA, all study participants had residual anal HSIL as documented by HRA, which ranged from minimal disease (1 or 2 small lesions, < 5 mm in size) to extensive intra-anal and perianal disease.
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PMC10723659
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Clearance of HPV
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REGRESSION
|
Three (50%) of the 6 patients who experienced complete histologic regression had clearance of the HPV types that were detected at baseline. Of note, all of them carried non-HPV16 high-risk types. One participant who had HPV clearance was living with HIV.
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PMC10723659
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Subgroup analyses
|
HPV16 mono-infection
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REGRESSION, HSIL, REGRESSION
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One out of six (17%) PLWH in the mITT population had complete regression of anal HSIL; whereas, 8/11 (73%) HIV-negative patients had either partial [3/11 (27%)] or complete [5/11 (46%] regression of their anal HSIL.The highest regression rate occurred in participants who had non-HPV16 types (4/5, 80%), followed by participants who had HPV16 mono-infection (3/4, 75%). Regression rates were lower in those who had HPV16 and other high-risk types (2/8, 25%).
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PMC10723659
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Discussion
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malaria, HPV-related disease, parasitemia, vulvar HPV-related disease, HSIL, anal disease, malarial deaths
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RECURRENCE, MALARIA, PARASITEMIA, MAY, HSIL, SECONDARY
|
In May 2020, the FDA approved intravenous artesunate as first-line treatment for severe malaria, in infants, children, and adults. Between 2000–2020, 10.6 million malarial deaths were averted due to the utilization of artesunate combination therapy [Over the past years, office-based ablation via electrocautery has been used effectively in many HRA clinics and was the main treatment modality in the ANCHOR study [Topical treatments of anal HSIL are preferable for some patients due to ease of use and less invasiveness. Off-label topical treatments of anal HSIL include 5-FU and more commonly the TLR-7 agonists imiquimod, which stimulates anti-viral cytokines and natural killer cell responses against HPV-infected cells [In the current study, 59% of participants treated with artesunate suppositories had a partial or complete response over the study window, and 50% of the complete responders also had viral clearance. While the primary objective of this Phase 1 study was to evaluate safety and tolerability, data suggest that artesunate could be effective in the treatment of intra-anal HSIL. These findings are similar to the phase I study of artesunate vaginal inserts for the treatment of CIN2/3, where 67.9% had complete response, and 47.4% of those with complete response also underwent viral clearance [With the limitation of the small cohort size, subgroup analyses suggest that artesunate may be more effective in the treatment of anal HSIL of HIV negative patients versus PLWH, who are known to have a higher risk of HSIL recurrence and HSIL to ASCC progression [Once a MTD was determined to be 400mg, the study sponsor decided to further evaluate key secondary outcomes in a controlled Phase IIB study. A randomized, placebo-controlled phase IIB study of artesunate suppositories for HIV-negative individuals with intra-anal HSIL is currently open to enrollment. A second controlled Phase IIB study in HIV+ individuals will open soon. Evaluation of the treatment effect of intra-anal artesunate will be the primary focus of the ongoing Phase 2 trial in anal HSIL. Furthermore, clinical trials are ongoing to evaluate the efficacy of topical artesunate in cervical and vulvar HPV-related disease (clinicaltrials.gov: NCT03792516, NCT04098744, NCT05555862)A potential concern with topical artesunate therapy for treatment of HPV-related disease is that it might contribute to malarial resistance if used for patients in malaria endemic regions of the world. Resistance of The use of intra-anal artesunate to treat anal HSIL is not anticipated to contribute to global malarial resistance development, as patients acutely sick with acute malaria would be unlikely to receive simultaneous treatment for anal disease. Systemic absorption of the topical artesunate formulation used in this study will be evaluated during Phase 2; this information will provide further information to assess this risk, including in the setting of asymptomatic parasitemia in malaria endemic regions.
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PMC10723659
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Conclusions
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nausea, HPV-related anogenital disease
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HSIL
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Intra-anal artesunate is a safe and well-tolerated treatment for anal HSIL and may be a promising addition in the therapeutic armamentarium against HPV-related anogenital disease. It is easily self-administered in the suppository form. Due to the frequent nausea that patients experienced at the 600-mg dose, the placebo-controlled, randomized Phase 2B trial will utilize the 400-mg suppository. We would like to thank Dr. Namandje Bumpus and Dr. Craig Hendrix in the Division of Clinical Pharmacology with the Department of Internal Medicine for their contributions to the study design.
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PMC10723659
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Supporting information
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PMC10723659
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Reporting checklist for randomised trial.
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(DOCX)Click here for additional data file.
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PMC10723659
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TREND statement checklist.
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(PDF)Click here for additional data file.(XLSX)Click here for additional data file.(DOC)Click here for additional data file.We would like to thank Dr. Namandje Bumpus and Dr. Craig Hendrix in the Division of Clinical Pharmacology with the Department of Internal Medicine for their contributions to the study design.
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PMC10723659
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Abstract
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The aim of this
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PMC10027098
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Key Words:
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PMC10027098
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Introduction
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tooth enamel Tooth, hypersensitivity Fluoride, tooth enamel, tooth
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DEMINERALIZATION
|
In recent years, the search for a healthy smile that combines the maintenance of oral
hygiene and the esthetic appearance has grown, especially regarding tooth color.
Therefore, the use of toothpastes becomes essential not only to prevent biofilm
accumulation and polish tooth surfaces but also to remove extrinsic stains caused by
pigmentation of the acquired pellicle The demand for increasingly whiter teeth has determined the inclusion of
over-the-counter whitening agents Abrasives and/or chemical agents (such as hydrogen or carbamide peroxides) have been
introduced in their composition to promote this effect. However, Unfortunately, the use of whitening products can cause morphological changes that
compromise the superficial integrity of tooth enamel Tooth appearance also depends on the gloss of the enamel, which is directly related
to the morphology of its surface. There is an inverse linear correlation between the
surface roughness and the gloss Another group of over-the-counter toothpastes are those that provide therapeutic
action in relieving dental hypersensitivity Fluoride can also inhibit dental demineralization. Fluoride ions replace hydroxyl
groups in enamel hydroxyapatite, resulting in the formation of fluorapatite, which
is more resistant to acid attack. Changes in the composition of enamel crystals
through remineralization can alter the physical and chemical properties of the
enamel. The formation of fluoridated apatite results in higher refractive index than
the original carbonated apatite, which consequently would alter the light reflection
and perception of color Regardless of the promising results of these toothpastes regarding their main
mechanism of action, data of crossover clinical trials evaluating their effect on
the physical and mechanical properties of tooth enamel are limited to support their
indication. The aim of this
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PMC10027098
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Material and methods
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PMC10027098
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Experimental design
|
carious lesion, orthodontic
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PERIODONTAL DISEASE
|
The present in situ study was performed in a block design (volunteers) in which
each participant used two removable intraoral devices containing bovine enamel
fragments (Each device with four fragments). The sample size was determined
using a previous study Eighteen individuals from the community of Ribeirão Preto Dentistry School,
University of São Paulo, Brazil, were evaluated for eligibility. The exclusion
criteria were the use of illicit drugs, presence of an active carious lesion,
periodontal disease, or orthodontic appliance to avoid any interference with the
fit of the device or with the salivary flow. One of them had orthodontic braces
and two declined to participate, hence they were excluded. Thus, fifteen
participants were included in the clinical trial after approval from the
Institutional Review Board (CAAE: 79927217.0.0000.5419/ REBEC - RBR-7p87yr). The
participants were healthy adults between 20 and 35 years of age (average age
25,93±3,34 years) and presented unstimulated salivary flow ≥ 1.5 ml for 5
minutes with pH = 7 The study variables were color alteration, gloss, surface roughness, and
microhardness.
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PMC10027098
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Enamel fragments preparation
|
tooth
|
One hundred and twenty sound bovine tooth fragments (6 x 6 x 2 mm), without
cracks and stains, were cut (Isomet 100 Buehler, Illinois, USA). The fragments
were flattened using 320-, 600-and 1200-grit abrasive papers to standardize the
thickness (1 mm of enamel and 1 mm of dentin)
|
PMC10027098
|
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Color analysis
|
For color evaluation, the fragments were placed on a standard white background in
a standardized light chamber (Optical Light Cabin Model CL6I-45S, T&M
Instruments, São Paulo, Brazil) with a D65 illuminant that simulates the
spectrum of daylight. The spectrophotometer (Easyshade, VITA, Bad Säckingen,
Germany) was periodically calibrated. After the treatments, new color readouts
were performed.The color change (ΔE
Where ΔL', ΔC', and ΔH' were the differences in lightness, chroma, and hue
between two specimens and RThe variation of WI
The ΔWI
|
PMC10027098
|
||
Surface gloss analysis gloss
|
The gloss analysis (Micro-Gloss 45º, BYK Gardner, Geretsried, Germany) was
performed with a readout geometry of 45º to measure the light specularly
reflected to the surface
|
PMC10027098
|
||
Surface roughness analysis
|
The surface roughness (Ra) was measured using a rugosimeter (Surftest SJ-201P,
Mitutoyo, Kanagawa, Japan) at a distance of 3.2 mm with 3 cut-offs of 0.8 mm,
totaling a readout length of 2.4 mm at a speed of 0.25 mm/s. Three readouts were
performed for each fragment: One in the center of the samples and two at a
distance of 1 mm to the left and to the right, respectively. The mean of these
values was used as the baseline. After the treatments, final readouts were
accomplished, as previously stated; and the surface roughness was calculated by
the difference between final and initial measurements (ΔRa = Ra
|
PMC10027098
|
||
Microhardness analysis
|
The Knoop microhardness was measured using a microhardness tester (Micro Hardness
Tester HMV-2, Shimadzu, Tokyo, Japan) with a pyramid-shaped diamond indenter set
to a vertical static load of 25 g for 5 seconds. The largest diagonal of the
indention was measured. Three initial readouts were taken for each fragment at
defined locations, as described for the surface roughness, and the mean was
considered the initial microhardness value. After the treatments, final
microhardness readouts were performed. The microhardness alteration was
determined by the difference between the final and initial measurements (ΔKHN =
KHNf - KHNi)
|
PMC10027098
|
||
Intraoral devices preparation and instructions for participants
|
For each participant, two oral acrylic resin devices were obtained from the
impression (Jeltrate Plus, Dentsply Sirona, York, PA, USA) of the maxillary arch
(Each toothpaste was packed in 30 g tubes identical in appearance by a researcher,
different from the operator so that neither he nor the participant knew which
toothpaste was being used, as recommended in a double-blind study. As a
randomized and crossover study, all the participants were randomly assigned to
brush the enamel fragments with all the toothpastes. The participants used one
toothpaste on each side of the device (each side containing two fragments) for
30 days, and a washout period of 7 days was established before and between the
treatments
|
PMC10027098
|
||
Flow diagram showing how the study was conducted.
|
The participants received written instructions explaining the protocol for each
phase. They were instructed to brush each side of the device with ten
anteroposterior movements for 15 seconds, three times a day
|
PMC10027098
|
||
Identification, classification, composition, and abbreviations
used for the studied toothpastes.
|
After the first phase of the study (using a different toothpaste for each side
for 30 days with a washout period of 7 days), participants returned to the
dental office. They received another device to start a new washout period of 7
days. They also received two new tubes of different toothpastes for the second
phase for 30 days. The devices were collected after the second phase, and the
fragments were detached. New color, gloss, microhardness, and roughness
measurements were performed according to the methodology previously
described.The data were normally distributed for color, surface roughness, gloss, and
microhardness (Kolmogorov Smirnov test, p<0.05). Thus, the One-way ANOVA test
was performed with the Geisser-Greenhouse correction, with a level of
significance of 95%, followed by the post hoc Tukey's test. The WI
|
PMC10027098
|
||
Results
|
Eighteen individuals were assessed for eligibility, three of whom were excluded: one
because of not meeting the inclusion criteria and two because they declined to
participate. Thus, the final sample of this study consisted of 15 participants (4
males and 11 females; average age, 25,93±3,34 years). All of them completed the
study.Baseline and final values of the evaluated properties are shown in
|
PMC10027098
|
||
Baseline and final mean (upper - initial/lower - final) and standard
deviation values of L*, a*, b*, gloss (GU), roughness (Ra) and
microhardness (KHN) of the enamel fragments brushed with the studied
toothpastes.
|
PMC10027098
|
|||
Mean values (SD) [CI] of ΔE
|
Different letters between toothpastes indicate statistically
significant differences (p<0.05). Values without letter
indication demonstrate no difference (p>0.05) between the
toothpastes.
|
PMC10027098
|
||
Graph representing superimposition of color change with perceptible
whitening of fragments submitted to brushing with the tested
toothpastes.
|
Regarding the color coordinates ΔL and Δa showed positive values after brushing
(
|
PMC10027098
|
||
Discussion
|
tooth, pigmentations
|
The aim of this Contemporary over-the-counter toothpastes have different formulations and indications
for the diverse needs of consumers. Basically, they are composed of abrasives,
moisturizers, thickeners, detergents, flavorings, preservatives, and can include
therapeutic agents as remineralizing and whitening agents.The abrasive components in every toothpaste play an essential role in removing
extrinsic stains, pigmentations of the tissue, and preventing the accumulation of
new stain molecules In addition to the abrasive particles, toothpaste WTP contains sodium carbonate
peroxide, which is meant to improve tooth whitening. Nevertheless, WTP did not
demonstrate a significant higher color change than the other toothpastes. The fact
that peroxide is unstable in aqueous formulations such as toothpastes Although there was no difference between the groups, in all of them it was possible
to notice an increase in lightning and reduction in yellow chroma that suggests an
increase in whiteness The toothpastes also have certain compounds that would affect color perception, which
can explain the results of the present study. Toothpastes CT and WTP have tetra
potassium pyrophosphate that not only acts as an anti-calculus agent but could also
prevent the formation of extrinsic stains and maximize the action of these
toothpastes on maintaining the luminosity of the teeth The positive change in a* color coordinate may be related to the surface roughness
results found in the study. Changes in surface roughness values were negatives for
all the tested toothpastes, except for WTP, indicating that the enamel was polished
and reduced its surface roughness. Polishing the enamel can reduce the surface
roughness but could also increase enamel wear, changing the final color of the tooth
Regarding WIRegarding gloss, the results of the present study showed an increase in the gloss for
all the toothpastes, without difference among them. Literature shows a relation
between gloss to the light reflection on a determined surface, as greater the
roughness, lower the surface gloss Different from gloss analysis, the surface roughness showed difference among the
toothpastes. Brushing with toothpaste WTP increased the surface roughness of the
enamel, being significant (p=0.049) compared to toothpaste WT. WT has hydrated
silica in its composition, and WTP, aside from having silica, has sodium
bicarbonate, which is frequently used as a component of abrasive systems Toothpastes containing remineralizing agents can change the microhardness of the
tooth enamel surface The sample size was calculated using a previous study, considering only one of the
properties evaluated in the present study (ΔE), as performed by Santana et al. One limitation of the study is the lack of standardization of the applied brushing
force by the participants. Different brushing forces affect the abrasive capacity of
the toothpastes, enhancing or decreasing their action The toothpastes used in the present study did not alter the properties of the dental
enamel, except the roughness. However, the perception of tooth whitening, presented
by the whitening index, was higher than the change in color itself. Toothpaste with
an abrasive system based on sodium bicarbonate and silica, and that contains sodium
carbonate peroxide increased the surface roughness of the enamel.
|
PMC10027098
|
|
Acknowledgments
|
The work was supported in part by Coordination for the Improvement of Higher
Education Personnel, Brazil (CAPES) Finance Code 001.
|
PMC10027098
|
||
References
|
PMC10027098
|
|||
Key Points
|
PMC10099063
|
|||
Question
|
DISORDER
|
Can conditioned open-label placebo (C-OLP) help increase the efficacy of treatment with methadone for opioid use disorder?
|
PMC10099063
|
|
Findings
|
90-day retention
|
In this 2-group, single-blind randomized clinical trial including 131 individuals, 90-day retention in treatment and quality of sleep were significantly improved with C-OLP vs treatment as usual. Methadone dose, the prespecified primary outcome, did not differ significantly between groups.
|
PMC10099063
|
|
Meaning
|
DISORDER
|
The findings of this trial suggest that C-OLP may improve opioid use disorder treatment outcomes; further exploration of C-OLP as an inexpensive, low-risk adjunct to methadone treatment may be beneficial.
|
PMC10099063
|
|
Importance
|
OUD
|
DISORDER
|
Methadone treatment is the most effective evidence-based treatment for opioid use disorder (OUD), but challenges related to dosing and premature treatment dropout argue for adjunct interventions to improve outcomes. One potential behavioral intervention with low risk involves harnessing placebo effects.
|
PMC10099063
|
Objective
|
To determine the effect of a pharmacologically conditioned open-label placebo (C-OLP) on 90-day methadone dose, retention, drug use, withdrawal, craving, quality of life, and sleep.
|
PMC10099063
|
||
Design, Setting, and Participants
|
OUD
|
This 2-arm, open-label, single-blind randomized clinical trial was conducted between December 5, 2017, and August 2, 2019, in an academically affiliated community opioid treatment program. Analyses were conducted between October 1, 2019, and April 30, 2020. A total of 320 newly enrolled adults seeking treatment for moderate to severe OUD were assessed for study eligibility; 131 met eligibility criteria, provided informed consent, and were randomized to either C-OLP or treatment as usual (TAU) in an unequal-block (3:2) manner. Exclusion criteria were pregnancy, hospital/program transfers, and court-ordered treatment.
|
PMC10099063
|
|
Interventions
|
INTERACTIONS
|
Participants randomized to C-OLP received pharmacologic conditioning and a placebo pill and methadone, and participants randomized to TAU were given methadone only. Participants met with the study team 5 times: at baseline (treatment intake) and 2, 4, 8, and 12 weeks postbaseline. Interactions were balanced between the 2 groups.
|
PMC10099063
|
|
Main Outcomes and Measures
|
SECONDARY
|
Outcomes included 90-day methadone dose (primary) and treatment retention, drug use, withdrawal, craving, quality of life, and sleep quality (secondary). Analyses were conducted as intention-to-treat.
|
PMC10099063
|
|
Results
|
Of the 131 people enrolled in the study, 54 were randomized to TAU and 77 to C-OLP. Mean (SD) age was 45.9 (11.2) years; most of the participants were Black or African American (83 [63.4%]) and male (84 [64.1%]). No significant group differences were observed in the mean (SD) 90-day methadone dose (83.1 [25.1] mg for group TAU, 79.4 [19.6] mg for group C-OLP;
|
PMC10099063
|
||
Conclusions and Relevance
|
In this randomized clinical trial, C-OLP had no effect on the primary outcome of 90-day methadone dose. However, C-OLP participants were significantly more likely to remain in treatment. These findings support the use of C-OLP as a methadone treatment adjunct, but larger trials are needed to further examine the use of C-OLP.
|
PMC10099063
|
||
Trial Registration
|
opioid use disorder
|
ClinicalTrials.gov Identifier: This randomized clinical trial examines the use of a pharmacologically conditioned open-label placebo in treatment of opioid use disorder.
|
PMC10099063
|
|
Introduction
|
OUD
|
DISORDER
|
First-line treatments for opioid use disorder (OUD) include medications,One possible intervention involves the harnessing of placebo effects. Broadly defined, placebo effects are improvements in symptoms attributable to the therapeutic encounterAn additional method of harnessing placebo effects implements pharmacologic (pavlovian) conditioning, wherein a medication’s therapeutic effects are conferred to placebos following repeated pairings with the drug.
|
PMC10099063
|
Methods
|
This single-site RCT was conducted between December 5, 2017, and August 2, 2019. Written informed consent was obtained from all participants. The trial protocol (
|
PMC10099063
|
||
Setting and Participants
|
OUD
|
Adults seeking treatment for OUD were recruited from an urban, community-based, academically affiliated opioid treatment program. All participants met
|
PMC10099063
|
|
Study Design and Procedures
|
The 12-week study included 5 individual meetings with study staff at baseline entry into treatment, and 2, 4, 8, and 12 weeks postbaseline. Participants received $25 incentives for each meeting. New patients were recruited on their first day of methadone treatment. At the end of the initial intake procedures, a member of the study team approached interested participants to obtain informed consent and completion of in-person survey and assessment. As in previous studies,
|
PMC10099063
|
||
Placebo Intervention and Open-label Conditioning Procedures
|
The intervention consisted of 2 phases: once-daily placebo conditioning (phase I, first 2 weeks) and twice-daily placebo (phase II, week 3 up to 3 months) (
|
PMC10099063
|
||
Clinic Urine Screen
|
Results from clinic urine drug screens (QuickTox panel; LabCorp) were logged at baseline by study staff. Substances tested included opiates, cocaine, methamphetamine, tetrahydrocannabinol, amphetamine, phencyclidine, benzodiazepine, barbiturates, methadone, oxycodone, methylenedioxymethamphetamine, buprenorphine, and fentanyl.
|
PMC10099063
|
||
Outcomes
|
The primary outcome was 3-month (90th-day) milligram methadone dose. Secondary outcome measures included treatment retention, self-reported drug use, opioid withdrawal, craving, quality of life, and sleep. Outcomes were assessed in person via facilitated self-report at all 5 time points, except sleep (measured only at baseline and 1 and 3 months postbaseline).Three-month retention was assessed as a binomial variable (in treatment at day 90, yes or no). For descriptive purposes, retention was also counted as the number of days retained in treatment, from intake to day 90. We adopted the clinic’s definition of dropout (30 continuous absent days), with the last clinic visit considered the final day in treatment.Drug use was assessed via self-report of past 2-week use of 4 common substances: opioids (including heroin, fentanyl, nonprescribed opioids), cocaine, benzodiazepines, and alcohol; other was a fifth category. Total days used (out of 14) was recorded.Withdrawal was assessed using the objective (range, 0-13) and subjective Opiate Withdrawal Scales. Scores range from 0 to 64, with higher scores on these scales indicating greater withdrawal symptom severity.A craving assessment adapted from previous studiesQuality of life was assessed using the Abbreviated World Health Organization Quality of Life assessment. Scores range from 0 to 100, with higher scores indicating higher quality of life).Sleep was measured using the Pittsburgh Sleep Quality Index (PSQI. Scores range from 0 to 21, with higher scores indicating worse quality of sleep.
|
PMC10099063
|
||
Sample Size
|
Power was calculated a priori for the primary outcome of the 3-month (90-day) dose of methadone. We anticipated that dose escalations after initial titration would be recommended for approximately 70% of participants in the TAU cohort in that time frame, basing this approximation on discussions with clinic staff on the proportion of patients who receive dose increases at this opioid treatment program. Thus, 60 participants per group would yield a power of 0.80 to detect a group difference if the corresponding rate in the intervention group was 44% or lower (a maximum of 26 of 60 participants), using a Fisher exact test with a 2-tailed α level of .05. This is equivalent to an odds ratio of 3.03 or a Cohen
|
PMC10099063
|
||
Randomization
|
unequal block
|
Randomization was performed by a blinded member of the investigation team (L.C.) not directly involved with daily study procedures. A computer-generated random number sequence with unequal block randomization (60% intervention, 40% control) was created, stratified by sex, and placed into sequentially numbered opaque envelopes (n = 30/group/sex for a total of 120 random allocations). Group allocation occurred after day 1 assessment and just before the first dose of methadone with an assignment reveal.
|
PMC10099063
|
|
Blinding
|
At all stages of the study, methadone dose adjustments (ie, manipulations of the primary outcome) were overseen by addiction medicine physicians blinded to treatment allocation. Physicians, nurse practitioners, and counselors were also blinded, as were data analysts. Other study team members were blinded for all of day 1.
|
PMC10099063
|
||
Statistical Analysis
|
Analyses were conducted between October 1, 2019, and April 30, 2020. Outcomes were analyzed in accordance with randomization assignments, following an intention-to-treat approach. Descriptive statistics with central tendencies and spread were used for continuous variables; distributions and percentages were used for categorical variables. Unpaired We adopted a second, more stringent analysis (subanalysis 1) to account for the potential barrier to analyzing group differences on the 90th-day methadone dose: a missed dose on the 90th day or a temporary need for a lower dose on that day due to 2 or more consecutive missed days (in line with standard opioid treatment program dosing protocols) just before the 90th day would preclude a stabilization dose of methadone, which would have potentially hidden any group differences. This analysis included only participants who had been retained for 90 days, who missed no days within the last 14 days preceding the 90th day, and whose daily dose of methadone had been stable for the 2 weeks before day 90. The rationale was that this would allow sufficient time for any therapeutically necessary dose changes to occur. We then assessed between-group differences in mean 90-day methadone dose for stable-dose participants.Group differences were tested with χ
|
PMC10099063
|
||
Results
|
PMC10099063
|
|||
Study Participants
|
Among 320 new patients screened for methadone treatment, 131 individuals (mean [SD] age, 45.9 [11.2] years; 84 [64.1%] men; 47 [35.9%] women; 83 [63.4%] Black or African American) met eligibility criteria, provided informed consented, were randomized to receive C-OLP (n = 77) or TAU (n = 54), and completed all of day 1 and baseline procedures (
|
PMC10099063
|
||
Participant Baseline Characteristics
|
POSITIVE
|
Abbreviations: C-OLP, conditioned open-label placebo; TAU, treatment as usual.One individual self-identified as Pacific Islander and White.Options were not mutually exclusive; 1 participant reported both unemployed and incarcerated.Data missing from 3 participants who were unable to provide a biological sample on the date of intake. Reported percentages are inclusive of missing data.Positive for at least 1 of the following drugs: morphine, oxycodone, fentanyl, buprenorphine, or methadone.
|
PMC10099063
|
|
Flow Diagram of Study Participants
|
C-OLP indicates conditioned open-label placebo; OTP, opioid treatment program; TAU, treatment as usual.
|
PMC10099063
|
||
Primary Outcome: 3-Month Dose of Methadone
|
We report findings for all 131 participants in an intention-to-treat analysis. Fifty-four individuals were randomized to TAU, 77 to C-OLP. Starting methadone doses for both groups ranged from 10 to 40 mg (mode = 25 mg). There were no statistically significant differences between the groups in their mean (SD) dose at day 90: 83.1 (25.1) mg for group TAU (n = 33) and 79.4 (19.6) mg for group C-OLP (n = 60) (
|
PMC10099063
|
||
Mean Methadone Doses at Various Intervals Up to 90 Days
|
Mean group methadone doses are shown for postentry into treatment. Mean values include data that were available for people retained at each time point. Treatment as usual (TAU): 47 individuals retained at 7 days, 43 at 15 days, 38 at 30 days, 37 at 45 days, 34 at 60 days, and 33 at 90 days. Conditioned open-label placebo (C-OLP): 73 individuals retained at 7 days, 71 at 15 days, 67 at 30 days, 65 at 45 days, 64 at 60 days, and 60 at 90 days. Whiskers indicate 95% CIs.Subanalysis 1 included only individuals who had maintained a stable dose of methadone during the last 2 weeks of treatment (15 TAU, 32 C-OLP). There was no significant difference between the groups in mean (SD) 90th-day methadone dose (85.3 [13.4] mg for TAU, 87.0 [15.6] mg for C-OLP; t
|
PMC10099063
|
||
Secondary Outcomes
|
A total of 33 of 54 TAU participants (61.1%) and 60 of 77 C-OLP participants (77.9%) remained in treatment at 90 days (χ
|
PMC10099063
|
||
Probability of Treatment Retention by Group
|
Estimated by the Kaplan-Meier method overall probability function. C-OLP (n = 77) overall probability, 0.75 (95% CI, 0.66-0.86); TAU (n = 54) overall probability, 0.59 (95% CI, 0.48-0.74). C-OLP indicates conditioned open-label placebo; TAU, treatment as usual.Mixed-effects models showed that group C-OLP reported better sleep quality (global C-OLP PSQI score, 8.12 [0.48] vs 9.9 [0.46] for TAU;
|
PMC10099063
|
||
Discussion
|
SECONDARY
|
Our primary aim was to test whether a C-OLP intervention could improve methadone treatment outcomes. Our hypothesis that 90-day methadone doses would be lower for C-OLP than for TAU recipients was not supported. We can only speculate as to why there were no significant differences between the groups, but due to its bioavailability, clearance, and half-life, methadone dosing is highly individualized.Unexpectedly, we found a significant difference in the groups’ 90-day retention rates, with 61.1% retention attrition in the TAU group and 77.9% for group C-OLP (Additionally, secondary analyses suggested another benefit in the C-OLP group: relative to the TAU participants, they reported better sleep over the first 90 days of treatment, with an estimated mean PSQI score difference of 1.78 points (
|
PMC10099063
|
|
Estimated Mean of Secondary Outcomes With Mixed Effects Longitudinal Regression Estimates in the TAU (n = 54) and C-OLP (n = 77) Groups
|
Morales-Quezada, overdose
|
Abbreviations: C-OLP, conditioned open-label placebo; NA, not applicable; PSQI, Pittsburgh Sleep Quality Index; TAU, treatment as usual; WHOQOL-BREF, World Health Organization Quality of Life assessment.Scores range from 0 to 100, with higher scores indicating higher quality of life.Scores range from 0 to 21, with higher scores indicating worse quality of sleep.Our unique implementation combined 2 methods to harness placebo effects: OLP and pharmacologic conditioning. In open-label studies, no pretense is made concerning the fact that the pill or device is physiologically inert. Patient participants are oriented transparently to the possible beneficial effects of placebos. We did not guide participant expectations regarding our specific study aims; rather, participants were informed of the nonspecific therapeutic benefits that can accompany placebo therapy but were not informed of the operationalization of assessments.Few studies have combined conditioning and OLP. In a novel small feasibility study, Morales-Quezada and colleaguesAlthough our results do not speak to mechanism, the beneficial effect of C-OLP on methadone treatment retention could be related to the benefits observed in sleep quality or other not-yet-assessed effects on overall function. As part of this RCT, we also obtained qualitative data from C-OLP participants to understand perceptions of efficacy—data that could help elucidate perceived benefits of C-OLP. A forthcoming study will represent these data in full.The clinical implications of the C-OLP intervention described in this study are great. Retention in treatment is a serious challenge for the field of addiction medicine and calls abound for an all hands on deck approach to identify solutions to stave overdose rates and increase treatment engagement and retention. We have demonstrated the general feasibility of administering a placebo adjunct to standard-of-care methadone in a community-based opioid treatment setting. Our experience running this trial showed us that C-OLP did not produce a significant burden to clinic procedures. Future studies should rigorously evaluate implementation outcomes, however (eg, patient and staff acceptability, measures of feasibility), to better inform the practicality of implementing a placebo adjunct to methadone treatment. Notwithstanding, the low-cost, low-risk nature of this intervention suggests that C-OLP could provide an appealing strategy to target early methadone treatment adherence. Well-powered studies are needed to evaluate this intervention’s efficacy on methadone treatment retention.
|
PMC10099063
|
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