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References
PMC10325040
Background
cognitive decline, neuronopathic disorders, cognitive impairment
MUCOPOLYSACCHARIDOSIS II, HUNTER SYNDROME, GCA
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 ...
PMC10621086
Results
deteriorating cognitive functioning
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-averag...
PMC10621086
Supplementary Information
The online version contains supplementary material available at 10.1186/s13023-023-02957-2.
PMC10621086
Keywords
PMC10621086
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 (idursulf...
PMC10621086
Materials and methods
PMC10621086
Study design
The designs of the phase 2/3 trial and extension study have been described previously [
PMC10621086
Endpoints and assessments
GCA
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 [
PMC10621086
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 as...
PMC10621086
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, ...
PMC10621086
DAS-II GCA scores within cognitive development categories
deteriorating cognitive functioning
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 de...
PMC10621086
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 D...
PMC10621086
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 pati...
PMC10621086
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.
PMC10621086
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 draft...
PMC10621086
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.
PMC10621086
Availability of data and materials
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 afte...
PMC10621086
Declarations
PMC10621086
Ethics approval and consent to participate
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 o...
PMC10621086
Consent for publication
Not applicable.
PMC10621086
Competing interests
Thrombosis
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...
PMC10621086
References
PMC10621086
Methods
HSIL
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.
PMC10723659
Results
nausea
ADVERSE EVENTS
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.
PMC10723659
Conclusion
HSIL
Artesunate suppositories are a safe treatment option for anal HSIL.
PMC10723659
Data Availability
All relevant data are within the paper and its
PMC10723659
Background
malaria, HPV-associated anal, HPVs
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 ac...
PMC10723659
Materials and methods
PMC10723659
Patient selection and data collection
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 (
PMC10723659
Study schema and timeline.
HSIL
CONSORT diagram of a phase 1 study utilizing artesunate for the treatment of anal HSIL.
PMC10723659
Enrollment schema.
* each treatment cycle consisted of five (5) consecutive nightly artesunate suppositories.
PMC10723659
Inclusion and exclusion criteria.
PMC10723659
Intervention and mode of delivery (Figs
toxicity, toxicities, HRA/biopsy
ANAL DYSPLASIA, ADVERSE EVENT, LOW-GRADE SQUAMOUS INTRAEPITHELIAL LESION, ADVERSE EVENTS, HSIL, ADVERSE EVENT, REGRESSION
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...
PMC10723659
Results
PMC10723659
Baseline patient characteristics (
PMC10723659
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 artesu...
PMC10723659
Adverse events.
dose-limiting, nausea, Nausea
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 an...
PMC10723659
Efficacy
PMC10723659
Histologic regression (
perianal disease
DISEASE, HSIL
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.
PMC10723659
Clearance of HPV
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.
PMC10723659
Subgroup analyses
HPV16 mono-infection
REGRESSION, HSIL, REGRESSION
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 part...
PMC10723659
Discussion
malaria, HPV-related disease, parasitemia, vulvar HPV-related disease, HSIL, anal disease, malarial deaths
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...
PMC10723659
Conclusions
nausea, HPV-related anogenital disease
HSIL
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...
PMC10723659
Supporting information
PMC10723659
Reporting checklist for randomised trial.
(DOCX)Click here for additional data file.
PMC10723659
TREND statement checklist.
(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.
PMC10723659
Abstract
The aim of this
PMC10027098
Key Words:
PMC10027098
Introduction
tooth enamel Tooth, hypersensitivity Fluoride, tooth enamel, tooth
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 stain...
PMC10027098
Material and methods
PMC10027098
Experimental design
carious lesion, orthodontic
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 Dent...
PMC10027098
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
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 perio...
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 distanc...
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 d...
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 to...
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 fo...
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 complete...
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....
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 mod...
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...
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 g...
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 ...
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...
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 ...
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 f...
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 ...
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...
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 en...
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...
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 ca...
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...
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 d...
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 da...
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 place...
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 bette...
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 bio...
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 high...
PMC10099063