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Data management and analyses | CRF | DISEASE, CRF | We will develop a case report form (CRF) that contains information needed for study visits. During the screening, we will collect data on the date of informed consent, demographics, disease and treatment, including current antiretroviral regimen and dosing schemes. Furthermore, the phone number of the participants and treatment supporters will be recorded. In follow-up visits, we will collect data about a change in the ARV regimen. In addition, we will collect information about pharmacy refills and self-reported adherence. Viral load will be measured and recorded at study entry and after follow-up. In addition, the infant of breastfeeding mothers will be tested for HIV according to standard care at week 6, month 9 and month 18. We will use Redcap®, an open-source database management system for randomization and data management. Data will be stored anonymously; whereby personal identifiers are stored on the participant screening log. The study’s data manager oversees all procedures considering data management and randomization. We will use intention-to-treat analyses comparing the two arms on the mentioned outcomes in each sub-study. We will also use intention-to-treat analyses comparing the two arms on the mentioned primary study outcomes. Therefore, we will use chi-square analyses to compare the percentage of women retained in care at 18 months and the percentage of children and adolescents having 95% adherence during the study period of 12 months. Also, we will do Student’s | PMC10120095 |
Roles and responsibilities | A steering committee has been set up consisting of the principal investigator (MS), co-principal investigator (KN), study doctor (IS), pharmacist (LM) and ICT person (RM). They meet on a bi-weekly basis to provide oversight of the trial progress. Furthermore, an ethical mentor is assigned to the study who will be consulted by the steering committee in case of ethical considerations. The study doctor serves as the study coordinator with the help from the pharmacist and the ICT person. In the field sites, regular nurse counsellors and physicians in caring for and treating people living with HIV are responsible for identifying potential participants, informed consent procedures and data collection. Besides the steering committee, there is a study team consisting of the steering committee, data manager, ethics mentor, research assistants, nurse and financial administrator. Each field site has been assigned a study team member responsible for overseeing the data collection processes and study procedures. Close communication with community advisory boards that exist in our field sites. | PMC10120095 | ||
Monitoring | An internal monitor has been assigned to assess the study data and ensure that study procedures follow protocol and good clinical practice. As we are not investigating an invasive intervention and based on recommendations from the ethical boards, we decided not to have an independent data safety monitoring board and not to perform an interim analysis. This is also because there are no anticipated problems detrimental to the participant, but please include in the protocol. However, we will use an external monitor on an ad hoc basis provided by the reciprocal monitoring scheme of the East African Consortium of Clinical Research (EACCR). There are no further procedures and no auditing trial conduct. | PMC10120095 | ||
Protocol amendments and deviations | In case of needed amendments to the protocol, the funder will first be asked for permission. Based on their decision, we will seek amendment permission from the local and national ethical boards. After their permission, we will implement the amended protocol using a new version number with an adapted date and add it to the trial master file and investigator site files. We will also use a protocol breach form to record any protocol deviations. In addition, mitigation plans, including refresher trainings will be implemented to reduce and avoid frequently recorded deviations. | PMC10120095 | ||
Discussion | PMC10120095 | |||
Introduction | HIV in Kilimanjaro, Tanzania. | We believe our study will demonstrate the effect of a customized DAT on adherence to treatment among breastfeeding women, children and adolescents living with HIV in Kilimanjaro, Tanzania. Furthermore, it will give more insights into the acceptability of the tools in specific groups. These results will inform policymakers to advocate for using DAT to improve adherence to treatment. | PMC10120095 | |
Limitations | Opening the Wisepill® box does not necessarily imply ingestion of pills. Furthermore, the pillbox can only contain a limited number of pills. That would mean a participant will have to refill it every 2 weeks. Although we can show a possible effect, there are several groups for which the effect will be difficult to extrapolate. One group is those who are not able to read and understand SMS. Later, we may develop an interactive voice response calling system to overcome this problem. In addition, those without a phone will not be able to participate. This will be mitigated by providing them with a simple mobile phone feature. Another limitation is that in the currently proposed study, we will still work with a pre-defined SMS structure whereby participants will receive the same messages over a given period that only intervenes on missed intakes. Messages could be more personalized and tailored by using a learning mechanism that will send messages completely tailored towards the adherence pattern of a participant. | PMC10120095 | ||
Strengths | Strengths of our study include the formative part, in which we investigate the user’s experience of the DAT, their preference for the type of SMS to be received, and the timing of such SMS. Therefore, the intervention has been developed based on input from end-users. Another strength is that we will conduct the study in three groups, considered vulnerable and often overlooked in research. | PMC10120095 | ||
Dissemination | We plan to disseminate our study at different levels starting with the target group through the participants and community advisory boards. We will also disseminate results to the scientific community through peer-reviewed manuscripts and abstract presentations at conference proceedings. Nationally, we will disseminate to the Ministry of Health and National Aids Control Programme and regionally through the East African Consortium on Clinical Research (EACCR). On an international level, we will inform the World Health Organization of our results. We will develop different kinds of policy briefs for all levels to communicate and disseminate our study. In addition, the data management plan will provide for the accessibility of data and sharing. Initially, meta-data will be fully accessible without the identifiable or sensitive information about participants. The full dataset will be available upon request from the principal investigator. However, a number of conditions apply, which are (1) completion of the Kilimanjaro Clinical Research Institute (KCRI) data sharing permission form, (2) a study team member be a co-author of any planned publication on the data and (3) specific objectives to justify why sharing data is important and the advantages you anticipate to bring society at large and (4) a signed and authorities-approved data transfer agreement (DTA) form as provided by the Tanzanian national ethical review committee. | PMC10120095 | ||
Conclusion | Our study will give clear insights into the needs and contents of a digital tool and the effect of customization of that tool on adherence to treatment among breastfeeding women, children and adolescents living with HIV. | PMC10120095 | ||
Trial status | RECRUITMENT | Current status: data was analysed for the formative study. We have started recruitment for the trial and expect to finalize recruitment by February 2024 and follow-up by August 2024. | PMC10120095 | |
Acknowledgements | MARION | We thank the Kilimanjaro Clinical Research Institute administration for assisting us in conducting this study. We are grateful to EDCTP, who have agreed to fund this study under the Senior Fellowship Plus TMA2818 of Marion Sumari-de Boer. | PMC10120095 | |
Authors’ contributions | RA | MSB wrote the initial paper together with KM. PN and RA were involved in the mentorship during research proposal design and write-up of the paper. All authors are involved in the conduct of the study, and they have read and approved the final manuscript. | PMC10120095 | |
Funding | MARION | The project is funded through a senior fellowship plus from the European and Developing Countries Clinical Trials Partnership awarded to Marion Sumari-de Boer (TMA2818). The funder had no role in the design of the study and collection, analysis, and interpretation of data, and writing; the manuscript should be declared. | PMC10120095 | |
Availability of data and materials | Data will be made available according to the Tanzanian guidelines for data sharing including using a data transfer agreement form. | PMC10120095 | ||
Declarations | PMC10120095 | |||
Ethics approval and consent to participate | Our proposal has been approved by the College Research and Ethical Review Committee (CRERC) of Kilimanjaro Christian Medical University College (KCMUCo), the National Health Research Ethics Sub-Committee (NatHREC) of the National Medical Research Institute (NIMR) of Tanzania. Informed consent will be obtained from all study participants. | PMC10120095 | ||
Consent for publication | Not applicable. | PMC10120095 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10120095 | ||
References | PMC10120095 | |||
Background | osteoarthritis, impairments of the musculoskeletal system, pain | OSTEOARTHRITIS | Aging is frequently associated with impairments of the musculoskeletal system and many elderly people experience joint discomfort or pain which might reduce their ability to move and consequently alter their quality of life. A beneficial effect of fish cartilage hydrolysate (FCH) on pain and joint function has recently been shown in an ACLT/pMMx osteoarthritis rat model. | PMC10512646 |
Methods | We therefore performed an exploratory, non-comparative, multi-centric clinical trial including 33 subjects with moderate knee joint discomfort and loss of functionality to investigate the efficacy of FCH on their algo-functional status. We further determined the potential health benefit of FCH in an original clinical ex vivo study investigating the role of FCH human metabolites on primary human chondrocytes. | PMC10512646 | ||
Results | Knee injury, Osteoarthritis, knee pain, pain | OSTEOARTHRITIS, PGA | FCH significantly improved knee pain and function, as assessed by the Knee injury and Osteoarthritis Outcome Score (KOOS). Moreover, FCH significantly reduced pain at rest and while walking, and patient global assessment (PGA), as assessed by the Visual Analogue Scale (VAS), and improved patients’ quality of life (SF-36). FCH metabolites decreased the synthesis of catabolic factors (MMP-13) and pro-inflammatory mediators (NO, PGE2) and limited the inhibitory effect of IL-1β on the synthesis of cartilage matrix components (GAG and collagen). | PMC10512646 |
Conclusions | pain | KNEE DISCOMFORT | Thus, these data provide insights on the mode of action of FCH in humans and contribute to explain how FCH may relieve pain and improve joint function in subjects with knee discomfort. Although these preliminary data need to be confirmed in a randomized controlled trial, they strongly support the potential health benefit of such an active ingredient. | PMC10512646 |
Supplementary Information | The online version contains supplementary material available at 10.1186/s12891-023-06800-4. | PMC10512646 | ||
Keywords | PMC10512646 | |||
Background | inflammation, impairments of the musculoskeletal system, pain | INFLAMMATION, JOINT DISORDERS | Modern Western societies are facing the challenges of an ever-aging population, where life expectancy and the proportion of older people in the population continue to increase. According to the United Nations, at least 1.5 billion people aged 65 years or older are expected for 2050, compared to 703 million in 2019 [Aging is frequently associated with impairments of the musculoskeletal system (joints, bones, and muscles), and many elderly people experience joint discomfort or pain which might reduce their ability to move [Current medical treatments of joint discomfort are mainly symptoms-oriented and rely on analgesic and nonsteroidal anti-inflammatory drugs (NSAIDs) to relieve pain and inflammation [As an alternative, high-quality food supplements are being explored for the prevention and management of joint discomfort [Glucosamine sulfate (GS) and chondroitin sulfate (CS) are important basic natural components of cartilage. They are naturally formed by the body but can also be provided in the diet. Supplementation may be especially beneficial when there is a disturbed balance between catabolic and anabolic processes. While several in vitro and in vivo experiments have shown that these compounds taken alone or in combination can modify or stabilize joint disorders, conflicting and controversial results have been observed in clinical trials with regards to their symptomatic and structure-modifying effect [A dried and concentrated fish cartilage hydrolysate (FCH) including the glycosaminoglycans GS and CS together with collagen hydrolysate to support joint cartilage has recently been demonstrated to have beneficial effects on pain and joint function in an in vivo efficacy study [ | PMC10512646 |
Materials and methods | PMC10512646 | |||
Study design and selection of subjects of the exploratory clinical study | AIDS | This study was an exploratory, non-comparative, multi-centric trial in a minimum of 30 free-living healthy male and female subjects with moderate knee joint discomfort and loss of functionality. It included subjects from 2 centers in Belgium who were enrolled in the study from June 11th, 2020, to December 17th, 2020. The main inclusion criteria were age between 40 and 80 years with a body mass index (BMI) ≤ 35 kg/mAll subjects enrolled in the study were taking 2 capsules of FCH 500 mg each, once daily in the morning, preferably during a meal, with water, for 3 months. The FCH (Cartidyss® NG, Abyss Ingredients, Caudan, France) is a powder obtained from a standardized manufacturing process based on enzymatic hydrolysis of fish cartilage without preservatives or processing aids. Its natural composition contains collagen peptides (< 3000 Da), chondroitin sulfate and minerals, respectively 65%, 26%, and 9%, given as an indicative value. Written informed consent to participate in the study was obtained from all subjects before enrolment. | PMC10512646 | |
Outcome measures | Rheumatoid Arthritis, knee pain, pain | RHEUMATOID ARTHRITIS, SECONDARY, OSTEOARTHRITIS, PGA | The primary objective was to evaluate the effect of FCH on knee pain and function after 3 months of supplementation using the self-administered questionnaire KOOS. The secondary objectives were to evaluate the effects of FCH on knee pain and function using KOOS, knee pain at rest or while walking, PGA using VAS, QoL using SF-36, and the responder rate based on the Osteoarthritis Research Society International - Outcome Measures in Rheumatoid Arthritis Clinical Trials (OARSI-OMERACT) criteria after 1 month and 3 months. Product satisfaction and tolerance by self-administered questionnaires, as well as subjects’ compliance based on tablet counts and consumption of pain killers, were also assessed. | PMC10512646 |
Study design and selection of the ex vivo study | The study was conducted in accordance with the Declaration of Helsinki of 1975 (Relevance of such a clinical | PMC10512646 | ||
Human primary chondrocyte cultures | Human articular chondrocytes (HACs) were harvested from tibial plateau and femoral condyles following knee replacement surgery and isolated as previously described previously [ | PMC10512646 | ||
Cell viability | The | PMC10512646 | ||
NO, PGE2, MMP-13, collagen II and aggrecan quantification | Nitrate/Nitrite colorimetric assay and prostaglandin E2 Enzyme Immunoassay (EIA) kits were obtained from Cayman Chemical (Ann Arbor-MI, USA). Human ELISA Kits for MMP-13, Collagen II and Aggrecan detection were purchased from Abcam® (Paris, France). The NO, PGE2, MMP-13 and Aggrecan level measurements were performed according to manufacturer’s instructions in cell supernatants whereas collagen II amount was measured in cell lysate. For human serum, measurements were performed in quadruplicates for each sample of the ten volunteers. | PMC10512646 | ||
GAG assay | A dimethylmethylene blue (DMB) assay was used to detect GAG production in cell lysates as previously described [ | PMC10512646 | ||
Cell lysis | LYSED, LYSIS | Cells were lysed using lysis buffer (50 mmol/L Tris pH 7.8, 150 mmol/L NaCl, 0.5% sodium deoxycholate, 1% NP40), and each fraction was stored at − 80℃ until analyses. | PMC10512646 | |
Protein quantification | Protein contents were determined by the BCA Protein Assay Kit (Millipore 71285-M). The BCA protein assay is based on a biuret reaction, which is the reduction of Cu2 + to Cu + by proteins in an alkaline solution with concentration-dependent detection of the monovalent copper ions. Bicinchoninic acid is a chromogenic reagent that chelates the reduced copper, producing a purple complex with strong absorbance at 562 nm. | PMC10512646 | ||
Statistical analysis | Pain, ICH, pain, articular disorders, subscale;Knee pain, knee pain | PGA | For the exploratory clinical study, statistical analysis was performed on the full analysis set (FAS) population following the guidelines on statistical principles for clinical trials (ICH E9). Due to the exploratory nature of the study, the number of subjects to be recruited has been estimated based on a potential “medium” effect size of 0.60, which is more than the commonly observed effect of the placebo in clinical trials on articular disorders in the knee (0.50) [Quantitative variables were summarized with classical descriptive statistics (n, arithmetic mean, standard deviation, median, interquartile range) at each time point. Counts and percentages were reported at each time for qualitative variables. Median (P25-P75) was also reported for ordinal variables. Assessment of the normality of the distribution of the quantitative variable was investigated numerically by comparing mean and median and graphically using histogram and quantile-quantile plot. Shapiro-Wilk normality test completed the assessment of the normality. In results tables, quantitative variables with a normal distribution were expressed as mean (± SD). Median (Q1-Q3) was used when normality was not fulfilled.The primary target variable, KOOS global score, was analyzed using a Student t-test for paired samples. The time evolution of the following quantitative variables was analyzed using repeated-measures ANOVA model when normality distribution was fulfilled, and Friedman’s test for variables with dissymmetric distribution:
The global score of the KOOS and its five subscales: Pain, Symptom, Activity of Daily Living, Sport and Recreation function and Quality of Life (the global score was calculated by summing up the score of all five subscales);Each subscale of the 36-item Short-Form Health Survey (SF36) and the global score of quality of life obtained by summing up the score of each subscale;Knee pain at rest and while walking using the Visual Analog Scale (VAS);VAS for PGA.When appropriate, a natural logarithmic transformation was performed to achieve residuals normality assumption. Multiple pairwise comparisons between time points were performed in case of significant time evolution. Effect size between baseline and the end time point was calculated for KOOS global score and subscales, for knee pain at rest and while walking, and for PGA. Effect size calculated as Cohen’s d was obtained by dividing the mean difference by its standard deviation. For effect size associated to knee pain at rest and while walking and for effect size associated to PGA, the absolute value of the mean difference was considered.Compliance and subjects’ satisfaction were compared between the first and the second follow-up using Wilcoxon’s sum of rank test. The rate of supplementation responder was compared between the first and the second follow-up with McNemar’s test. Time evolution of the use of pain killers for knee pain (yes/no) was analyzed using a generalized linear model for repeated measures. Time evolution of the number of days of rescue treatments uptake was modeled using a Friedman’s test.Statistical significance was achieved at 95% confidence (p-value significance < 0.05). Due to the exploratory nature of the study, no multiplicity adjustment was implemented.For the | PMC10512646 |
Results | PMC10512646 | |||
Exploratory clinical study | PMC10512646 | |||
Demographics and other baseline characteristics | knee pain | PGA | Out of the pre-screened subjects, 33 were included in the intention-to-treat (ITT) group. A total of 32 subjects were included in the study without any eligibility violation and took at least one dose of the product, constituting the FAS population. The per-protocol (PP) population included 24 subjects of the FAS who completed the study and did not have any major protocol deviation (Fig.
Flow-chart of subject disposition. ITT, intention to treat; FAS, full analysis set; PP, per protocol. Safety population n = 32
Demographic characteristics of the subjects – FAS populationAmong the 32 subjects included in the FAS population at baseline, the mean score of the Visual Analogue Scale (VAS) for knee pain at rest was 53.66 ± 11.95, and the mean score of the VAS for knee pain while walking was 61.56 ± 21.30. The mean for the Patient Global Assessment (PGA) scale was 64.3 ± 12.9 mm (Table | PMC10512646 |
KOOS global score and subscales – pain and function | SE, Knee injury, Osteoarthritis, pain | OSTEOARTHRITIS | Global Knee injury and Osteoarthritis Outcome Score (KOOS) and its five subscales concerning pain, symptoms, activity of daily living, sport and recreation function, and quality of life increased significantly over time (Table
Mean evolution (± SE) of the KOOS global score over time – FAS population. ***p ≤ 0.001; **p ≤ 0.01
Results of the repeated measures ANOVA models for KOOS global score and each subscale, and mean difference and effect size between baseline and 3 months of follow-up – FAS population*log-transformed variable | PMC10512646 |
SF-36 global score and subscales – quality of life | SE | The Short Form [
Mean evolution (± SE) of the SF-36 global score over time – FAS population. **p ≤ 0.01; ns, not significant
Results of the repeated measures ANOVA models for SF-36 global score and each subscale – FAS population* Friedman’s test p-value | PMC10512646 | |
VAS – pain and function | SE, knee pain | PGA | In comparison to baseline, VAS knee pain at rest and while walking decreased significantly after 1 month and 3 months of follow-up (Table
Mean evolution (± SE) of (
Results of the repeated measures ANOVA models for knee pain at rest and while walking and PGA using VAS scale, and mean difference and effect size between baseline and 3 months of follow-up – FAS population*log-transformed variable | PMC10512646 |
Responder rate | The ratio of OARSI-OMERACT responders in the FAS population was 46.1% after 1 month and 65.4% after 3 months of FCH supplementation. This difference was however not statistically significant (Table
Comparison of subjects’ supplementation response between the first and the second follow-up – FAS population | PMC10512646 | ||
Compliance, subjects’ satisfaction, and pain killer use | Compliance was high at each visit and did not significantly differ after 1 month or 3 months of follow-up (97.65–100.00% vs. 95.24–100.00% respectively) (Table | PMC10512646 | ||
Adverse events | ADVERSE EVENT, MINOR, SKIN DISORDERS, HEART ATTACK | Only one Serious Adverse Event (SAE) (a heart attack) was reported during the study, but it was unrelated to the FCH. Only a few minor Adverse Events (AE) (i.e., gastro-intestinal, urinary, or skin disorders, see Table
Distribution of the link of AE and SAE with FCH– Safety population – N = 28 adverse eventsTaken together, our data suggest an improvement of the articular function. In order to further demonstrate the biological activity of FCH on cartilage tissue and provide clues on the mechanisms likely contributing to its benefits for human articular function, we investigated the influence of human circulating metabolites following FCH ingestion on primary human articular chondrocytes behavior | PMC10512646 | |
Pharmacokinetic and ex vivo study | PMC10512646 | |||
Kinetic Profile of FCH absorption | Briefly, fasted volunteers received 12 g of FCH, and the absorption profile was monitored during a 240 min time period by measuring hydroxyproline blood levels. Analyses showed that following ingestion of FCH, circulating concentration of hydroxyproline continuously increases to reach a maximum of 117.7 µM at 140 min post ingestion (+ 87.5% compared to basal level), before returning to almost basal level by the end of the kinetics (Fig.
Evolution of the concentration of circulating hydroxyproline in blood. Values are presented as mean ± SEM. The differences were considered statistically significant at p < 0.05 with * for p < 0.05; ** for p < 0.01; *** for p < 0.001; **** for p < 0.0001 and ns for p > 0.05 [Based on these results, both naïve and enriched serum with FCH metabolites for the ex vivo cultures were subsequently collected before ingestion (naïve serum) and at 140 min post-ingestion (enriched serum). | PMC10512646 | ||
FCH human metabolites limit unbalanced metabolism upon inflammatory stress | To ensure the physiological relevance of our As expected and shown in Fig.
Primary human chondrocytes were incubated in the presence or absence of rhIL-1b (1ng/ml) in combination with either human naive serum (H-NAIVE) or human serum enriched with metabolites derived from FCH ingestion (H-FCH). Glycosaminoglycans (GAGs) ( | PMC10512646 | ||
FCH human metabolites temper the production of secondary inflammatory mediators by human primary chondrocytes | As described in the literature and acknowledged in clinic [
Primary human chondrocytes were incubated in the presence or absence of rhIL-1b (1ng/ml) in combination with either human naive serum (H-NAIVE) or human serum enriched with metabolites derived from FCH ingestion (H-FCH). PGE2 ( | PMC10512646 | ||
Discussion | fatigue, pain | REGRESSION | In this study, we report the data of an exploratory, non-comparative, multi-centric trial investigating the effect of daily supplementation with FCH on subjects with moderate knee joint discomfort and loss of functionality.KOOS global score and subscales improved significantly between baseline, 1 month, and 3 months of supplementation, underlining a positive impact of the supplement on joint mobility. Interestingly, an effect was already observed after 1 month of supplementation, which increased with intake duration. While the quality of life of the subjects regarding physical functioning, role limitation due to physical health, energy and fatigue, pain, and general health significantly improved over time, no impact of FCH on the role limitation due to emotional problems, emotional well-being, and social functioning was observed. This could indicate that the effect of FCH on pain is independent of any psychological factors. On the other hand, subjects were selected and thus enriched for physiological parameters such as pain, and results measuring these outcomes are therefore prone to regression to the mean [In this context, determination of biological activities of FCH on inflammatory and catabolic pathways may provide further clues. Therefore, to strengthen our conclusions, we designed an An anti-inflammatory effect has also been described for eggshell membrane hydrolysate in vitro, another food supplement containing glycosaminoglycans and collagen type I used for the treatment of joint discomfort [Besides, it is worth noting that even though not statistically significant, a reduction in the use of pain killers could be observed (1 subject took paracetamol after one month and 2 subjects took paracetamol after 3 months, vs. 5 subjects taking paracetamol and 2 subjects taking AINS at baseline). The lack of significance probably stems from the facts that relatively few subjects took pain killers at baseline and any decrease did therefore not have a statistically significant impact due to the overall small sample size. In addition, the safety profile of FCH was found to be very good, which is in line with what has been described for other food supplements [ | PMC10512646 |
Conclusions | reduced pain | In conclusion, FCH significantly improved mobility and joint comfort, and reduced pain. It also had a significant impact on the quality of life, highlighted by an improvement of physical health and function. Biological activity of human FCH metabolites give us clues on the mechanisms potentially contributing to the observed articular improvement following FCH supplementation. The observed effects of FCH on mobility and joint comfort will need to be confirmed in a larger randomized placebo-controlled clinical trial, ideally including radiographic or structural changes as well as biochemical markers of joint deterioration. This study will be especially useful for the design of such a randomized placebo-controlled clinical trial, particularly regarding the choice of the primary outcome. | PMC10512646 | |
Acknowledgements | The authors wish to thank Sandra Pietri for reading the manuscript and the clinical staff who contributed to the study. A special thanks goes to Dr. Chapelle who sadly passed away during the study. | PMC10512646 | ||
Authors’ contributions | Conceptualization, Y.H., E.B., Y.W., F.W., L.B.W. and B.C.; methodology, Y.H., Y.W., J.H. and B.C.; formal analysis, A.-F.D., F.W. and J.M.; investigation, Y.H., L.B.W., M.D., and M.W.; writing—original draft preparation, M.U. and Y.H.; writing—review and editing, J.H., E.B., and B.C.; project administration, J.H., M.U., V.M.F. and B.C. All authors have read and agreed to the published version of the manuscript. | PMC10512646 | ||
Funding | This study was funded by Abyss Ingredients. | PMC10512646 | ||
Data availability | The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. | PMC10512646 | ||
Declarations | PMC10512646 | |||
Ethical approval and consent to participate | HPS | Both clinical studies were conducted in accordance with the Declaration of Helsinki. Study #1 was approved by the Ethics Committee of the University Hospital of Liège in Belgium (Comité d’Ethique Hospitalo-Facultaire Universitaire de Liège) (protocol code B707202042984 on April 17th, 2020). The study was registered on clinicaltrials.gov with the identifier NCT04420091 on 09/06/2020. Study #2 was approved by the French Ethical Committee (2021-ND77 RIPH2 HPS / N° SI RIPH: 21.01436.000014 / N° EudraCT/ID RCB: 2021-A01773-38 / Comité de Protection des Personnes CPP Paris, Ile-de-France 1; approved 08 October 2021). Written informed consent to participate in the study was obtained from all subjects before enrolment. | PMC10512646 | |
Consent for publication | Not applicable. | PMC10512646 | ||
Competing interests | FOUNDER | YH is the founder and president of Artialis SA, a spin-off company of the University of Liège. YH has also received consulting and speaker fees from Tilman SA, Nestlé, Laboratoire Expanscience, Heel, Megalab, Genequine, LABHRA, and Biose. JH, MU, VMF and BC are employees of Artialis SA. EB is an employee of Abyss Ingredients. F.W. and L.W.-B. work for Clinic’n’Cell SAS (Faculty of Medicine and Pharmacy Clermont-Ferrand- France); Y.W. provides scientific consulting for Clinic’n’Cell SAS. M.W., A.F.D. and J.M. have no competing interests. | PMC10512646 | |
References | PMC10512646 | |||
Background | PD, hypothyroid | HYPOTHYROID | Understanding pharmacokinetics (PK) and pharmacodynamics (PD) of the sustained-release liothyronine (SR-T3) is of paramount importance to design therapeutic regimens that are able to simulate normal thyroid hormone secretion while avoiding excursions in the T3 serum concentration. Here, we designed a parallel randomized clinical trial to characterize the PK and PD of the combined preparations of LT4 + SR-T3 in hypothyroid patients. | PMC10463362 |
Methods | hypothyroid, PD, euthyroidism | HYPOTHYROID | Radioiodine-treated hypothyroid patients over 20 years of age, who attained euthyroidism with LT4 monotherapy were recruited from the Endocrine Clinic in Tehran. The patients were allocated to two intervention groups of group A: 9 µg SR-T3 plus 68.5 μg LT4 (ratio 1:7.5) and group B: 12 µg SR-T3 plus 60 µg LT4 (ratio 1:5), and a control group with LT4 monotherapy. For PD study, thyroid hormone profile was evaluated at 8 and 12 weeks intervals after intervention. To assess PK properties of SR-T3, T3-Cmax, T3-Tmax and AUC | PMC10463362 |
Results | Serum T4 and FT4 concentrations decreased in the intervention groups after 3 months. No significant difference was observed in serum T3 and FT3 concentrations before and after intervention. Serum T3/T4 ratio increased significantly in the intervention groups after intervention, with the highest increase in group B from 8.6 ± 2.03 at baseline to 12.2 ± 1.6. Comparison of trial groups at follow-up showed no differences in serum TSH, T4, T3 and T3/T4 concentrations among different groups. During 24 h, minimal variation in serum T3 concentration was observed in group B with mean ∆T3 of 15.4 ± 10.5 ng/dl. T3-Tmax, T3-Cmax and AUC | PMC10463362 | ||
Conclusion | HYPOTHYROIDISM | Combined treatment with a single dose of SR-T3 plus LT4 is associated with increased serum T3/T4 ratio and minimal excursions in serum T3 concentration during 24 h; however, it was not significantly different from the control group. To incorporate sustained-release T3 in the management of hypothyroidism, a higher ratio of SR-T3 to LT4 than that of the previously recommended by the international organizations is suggested. | PMC10463362 | |
Supplementary Information | The online version contains supplementary material available at 10.1186/s12902-023-01434-y. | PMC10463362 | ||
Keywords | PMC10463362 | |||
Introduction | euthyroidism, hypothyroidism | HYPOTHYROIDISM | Levothyroxine monotherapy is considered the standard of care for hypothyroidism by professional organizations, whereby the patients achieve the state of euthyroidism through the normalization of TSH, a reliable proxy of euthyroidism [Clinically, a sizable minority of patients adequately treated with LT4 complain of residual symptoms [The above-mentioned evidence led to the growing interest in combination therapy with LT4 plus liothyronine(LT3); however, multiple randomized controlled clinical trials addressing objective and subjective clinical outcomes did not provide conclusive results [To design clinical trials with a greater likelihood of indicating efficacy, the American, European, and British thyroid associations have recently published a consensus statement to promote the development of future clinical trials [ | PMC10463362 |
Patients and methods | hypothyroid, kidney or liver disease, cancer | HYPOTHYROID, CANCER, CONGESTIVE HEART FAILURE | The study was conducted at the Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran, from January 1, 2022 to 31 June, 2022. Radioiodine-treated hypothyroid patients over 20 years of age, who attained euthyroid status with LT4 monotherapy and serum TSH concentration of 0.5-5 mU/L were recruited from the Endocrine Clinic and referred to the Research Institute for Endocrine Sciences (RIES). The patients with pregnancy, chronic kidney or liver disease, congestive heart failure, cancer, and those taking methimazole, propylthiouracil (PTU), tamoxifen, estrogen, progesterone, and corticosteroids were excluded. Dorsa Pharmaceutical Company and Tavan Institute formulated sustained-release tablets with 7.5, 9 and 12 µg potency.A parallel randomized controlled clinical trial was applied. Initially, the patients were allocated to the three intervention and one control groups. Intervention groups received three different combinations of LT4 + LT3 yielding ratios of 1:10 (75 µg LT4 + 7.5 µg SR-T3), 1:7.5(9 µg SR-T3 + 68.5 µg LT4) and 1:5 (12 µg SR-T3 + 60 µg LT4). As during follow-up, serum TSH concentration significantly increased in the patients who received 75 µg LT4 + 7.5 µg SR-T3, this group were excluded from the study. Therefore, trial groups in this survey consisted of group A with a daily intake of 9 µg SR-T3 plus 68.5 µg LT4 (ratio 1:7.5), group B with a daily intake of 12 µg SR-T3 plus 60 µg LT4 (ratio 1:5) and a control group with LT4 monotherapy (group C).Figure
Participants’ flow-diagramAt the baseline visit, after taking informed written consent, blood pressure, weight, and height were measured. The trained staff filled the questionnaire regarding demographic and thyroid symptoms. Patients were allocated to three intervention groups and one control group using stratified randomization. Two stratifications were made based on gender. Under each sex subgroup, patients were randomly assigned to three treatment groups using the random table allocation.After implementation of randomization and specific coding, the subjects were assigned to two intervention and one control groups using allocation concealment. The standard method of ensuring allocation concealment was sequentially numbered. The staff member not involved in the trial was instructed to keep the list private and only revealed a treatment allocation after receiving information showing that the patient is eligible and has consented to the trial. The patients and the investigators were kept from knowing who was assigned to which treatment. All groups received identical tablets in physical appearance, taste, and smell to fulfill blinding.The participants were evaluated at baseline and two consequent follow-ups on the 8 | PMC10463362 |
Outcome measures | Primary outcome was set to find the best LT4 + SRT3 combination to maintain normal serum concentration of TSH, T4, T3, free T4, free T3 and T3/T4 ratio. Secondary outcome was to find the best LT4 + SRT3 combination which provide most favorable T3- Cmax, T3-Tmax, and AUC and patient preferences. The study design was registered by the Iranian Registry of Clinical Trials, IRCT20100922004794N13 (dated: 08/12/2021) available at: “ | PMC10463362 | ||
Drug formulation and dosing | The formulation of liothyronine sodium sustained-release tablets was developed by Noor Research & Educational Institute (TAVAN). Using Avicel PH-102 and HPMC in formulation of tablets sustained the drug release of T3 for over 10 h. The in vitro dissolution study was carried out in 500 ml, pH 6.8 phosphate buffer using United States Pharmacopeia Apparatus I, basket method, at a speed of 100 rpm and temperature of 37 C. Levothyroxine sodium (LT4) plus SR-T3 was administered based on the previous levothyroxine dosage which was at a weight-based dose of ~ 1.6 mcg/kg. Each combination was equal to 100 µg Levothyroxine.The 2012 ETA, suggested L-T4 + L-T3 combination treatment with a dose ratio between 13:1 and 20:1 by weight [ | PMC10463362 | ||
Laboratory measurements | THYROID | All laboratory measurements were determined on -20ºC stored serum samples. The thyroid function tests including TSH, T3, T4, and free hormones were measured by electrochemiluminescence immunoassay method using Roche Diagnostics kits on the Cobas e- 411 automated analyzer (Roche Diagnostics, GmbH, Mannheim, Germany). The sensitivity of TSH, T3, T4, FT3, and FT4 assays were 0.005 µIU/mL, 0.195 ng/mL, 0.420 µg/dL, 0.6 pmol/L, and 0.5 pmol/L, respectively. Lyophilized quality control materials (Lyphochek Immunoassay Plus Control, Bio-Rad Laboratories) in three different concentrations were used to monitor accuracy of measurements. The intra- and inter-assay coefficients of variation (CVs) were respectively 2.8% and 3.1%.for TSH, 2.3% and 3.0% for T3, 1.7% and 2.6% for T4, 2.1% and 3.9% for FT3, and 1.0% and 2.9% for FT4. Mean values and the reference ranges of thyroid hormones obtained from the Tehran Thyroid Study (TTS) were TSH (1.77 ± 1.24; 0.32–5.06 mU/L) and FT4 (1.19 ± 0.16; 0.91–1.55 ng/dl) [ | PMC10463362 | |
Statistical analysis | All analyzes were performed using STATA software version 14. Quantitative variables were summarized using mean, standard deviation and median. Qualitative variables were reported in frequency and percentage. Baseline characteristics between the three groups were tested using ANOVA. The comparison within groups was performed by two-tailed paired Student’s t-test or with the Wilcoxon rank t test. Chi-square person test were used to compare the frequencies between classification variables. The difference between the three groups was tested using the ANOVA test and Benferoni post hoc test. P value less than 0.05 was considered statistically significant. The maximum observed concentration (C-max) and the time at which this occurred (T-max) were calculated. The area under the plasma concentration–time curves from zero to the last sampling time AUC0-24 was calculated according to the trapezoidal rule using the actual times of measurements. Analysis of covariance (ANCOVA) was performed on AUC, Tmax and Cmax using STATA software version 14. ANOVA results revealed the effect of the sources of variation like sequence, subjects in a sequence, period and formulation on the bioequivalence data. The results of ANCOVA were calculated at 5% level of significance. | PMC10463362 | ||
Discussion | hypothyroid, primary hypothyroidism, euthyroidism, Graves’ Disease | HYPOTHYROID, PRIMARY HYPOTHYROIDISM | Decreased serum T4 concentrations and increased serum T3 concentration in treatment with 12 µg SR-T3 plus 60 µg LT4 led to a significant increase in serum T3/T4 ratio after intervention; however, serum T3/T4 ratio was lower than the normal serum T3/T4 ratio in euthyroid subjects (~ 1:14–15) and no difference was observed in serum T3, T4 and T3/T4 ratio after intervention between CBT (combination therapy) and LT4 monotherapy groups. Single dose administration of LT4 + SR-T3 was associated with more improved T3-derived Tmax(~ 4–5 h) and Cmax (~ 105 ng/dl) while serum T3 concentration remained within normal ranges with no fluctuation for 24 h after achieving maximum level.The only study by Hennemann et al. with randomized crossover design on fifteen patients (mean age of 50 y.) with primary hypothyroidism showed that T4 plus sustained-release T3 (1:20 ratio) improved serum TSH, T4, and T3 concentrations and the T4/T3 ratio compared to treatment with LT4 alone, while non-physiologic T3 peaks were avoided [Although serum TSH values are comparable and within normal ranges in LT4-treated patients, LT4 as an exogenous pro-drug cannot simulate serum thyroid hormone profile and circadian rhythm in the native euthyroid state.Serum TSH values in the previous clinical trials varied in patients under LT4 + LT3 combination therapy [The studies on the PK properties of sustained-release liothyronine are more coordinated; however, apart from the current study, there is only one other study which assessed PK of SR-T3 in combined preparation with LT4 [The current study is strengthened by including hypothyroid patients under LT4 monotherapy due to radioactive iodine intake for treating Graves’ Disease with no or negligible residual secretion of endogenous T3 and T4 and using the modern technique for measurement of thyroid hormones. Evaluation of the two combinations of the LT4 + SR-T3 enabled us to choose a more appropriate combination based on the participant’s body weight and not a fixed dosage such as the previous studies. Also, to achieve equilibrium in thyroid hormones, the PK study was performed after three months of treatment and not by a single-dose drug intake. However, the study is limited by evaluating PK study only within 24 h and the low potency of the LT4 component in the combined therapy which made us to increase the total dosage to restore euthyroidism.In conclusion, combined treatment with levothyroxine plus sustained-release liothyronine in hypothyroid patients with ratios of 1:5 might restore euthyroidism in hypothyroid patients yielding more improved T3/T4 serum ratio and T3-derived pharmakikinetics,while keeping serum T3 concentrations relatively stable within 24 h with minimal excursions. Single dose administration of LT4 + SR-T3 maintains serum T3 concentration approximate to normal ranges up to 24 h with minimal variation in serum T3 not exceeding 25 ng/dl indicates longer duration of the SR-T3 release in the intestine compared to other preparations. Although maximum serum T3 concentration (Tmax) achieves during 3–4 h, there is minimal difference in serum T3 concentrations at serial measurements during 24 h. Significant increase in serum T3/T4 ratio in combined therapy which is still lower than mean values in euthyroid individuals, could be translated into the assumption that administration of higher ratios of SR-T3 in combination therapy should be provided to achieve the physiological ratio of T3/T4 in treated hypothyroid patients. After attainment of the best appropriate preparation, designing and conducting appropriate randomized controlled clinical trials to compare the efficacy outcomes of combination therapy with sustained- release liothyronine are highly warranted to ensure sustainable delivery of T4 and T3 to thyroid hormone target issues. | PMC10463362 |
Acknowledgements | We express our appreciation to participants and the research team members for their contribution to the study. | PMC10463362 | ||
Author’ Contributions | All authors contributed to writing the manuscript. A.F.: Conceptualization, designing; M. L.: Project administration, original draft preparation and investigation; A.A.: Methodoly, editing the final draft; F. SM.: Drug formulation; M.S.: Data analysis; M. T.: Laboratory supervisor and data validation; A. H.: Data collection; A.A.: Drug formulation; S. AE.: Supervision on drug formulation and funder. | PMC10463362 | ||
Funding | This research received grant from Dorsa Pharmaceutical Co. Tehran, Iran. | PMC10463362 | ||
Data Availability | Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on a reasonable request. | PMC10463362 | ||
Declarations | PMC10463362 | |||
Ethics approval and consent to participate | This study was conducted in concordance with the Helsinki Declaration ethical principles, and all procedures on the study participants were approved by the National Research Council of the Islamic Republic of Iran (IR.SBMU.ENDOCRINE.REC.1400.031), the Human Research Review Committee of the Endocrine Research Center, Shahid Beheshti University, Tehran, Iran. Trial participants signed informed consent forms at baseline, and their personal information would remain strictly confidential. | PMC10463362 | ||
Consent for publication | “Not applicable”. | PMC10463362 | ||
Competing interests | On behalf of all authors, the corresponding author states that there is no conflict of interest. | PMC10463362 | ||
References | PMC10463362 | |||
Background | hypoxia, CKD, chronic kidney disease, PD | HYPOXIA | Roxadustat is an oral hypoxia inducing factor-prolyl hydroxylase inhibitor (HIF-PHI) that regulates iron metabolism in patients with chronic kidney disease (CKD) primarily by reducing hepcidin levels and mobilizing internal iron stores. More data are needed to demonstrate the efficacy of roxadustat in regulating iron metabolism in patients with peritoneal dialysis (PD) compared with erythropoiesis stimulating agents (ESAs). | PMC10629011 |
Methods | PD | IRON DEFICIENCY | This prospective cohort study enrolled PD patients with a mean hemoglobin level of 60–100 g/L. All subjects were randomized into two groups at a ratio of 2:1 the roxadustat group (106 cases), and the ESA group (53 cases). The primary endpoint was the change in the iron biomarker levels and the proportion of patients with absolute iron deficiency and functional iron deficiency. | PMC10629011 |
Results | IRON DEFICIENCY | Compared with ESAs, roxadustat significantly decreased hepcidin level (difference, − 20.09 ng/mL; 95% CI, − 30.26 to − 9.92), attenuated the increase in serum soluble transferrin receptor (sTFR) level (difference, − 7.87 nmol/L; 95% CI, − 12.11 to − 3.64), and reduced the proportion of patients with functional iron deficiency (roxadustat, 11.43%; ESA, 33.33%). There was no significant difference in safety of the two groups over the duration of the study. | PMC10629011 | |
Graphical abstract | PMC10629011 | |||
Keywords | PMC10629011 | |||
Background | CKD, transfusion-related iron, anemia | HYPOXIC, ANEMIA | The prevalence of anemia increases with the progression of CKD [The clinical application of ESAs can increase hemoglobin concentration without the risk of transfusion-related iron overload, substantially improving patients' quality of life [By simulating hypoxic environment, roxadustat effectively inhibits HIF-PHD activity and increases the accumulation of HIF [ | PMC10629011 |
Methods | PMC10629011 | |||
Study design and population | PD, renal anemia, organic dysfunction, Kidney Anemia | RENAL ANEMIA | This trial evaluated the efficacy and safety of roxadustat in regulating iron metabolism in PD patients through 24 weeks of observation. The eligible patients who agreed to participate in the study were numbered according to the time of visit to the hospital, and were divided into roxadustat group and ESA group with a ratio of 2:1 by random number table. This study was approved by the Ethics Committee of the Affiliated Hospital of Xuzhou Medical University (XYFY-KL39-01) and completed Chinese Clinical Trial Registration (registration number: ChiCTR2200057231), and all the enrolled patients signed an informed consent form. Eligible patients ranged in age from 18 to 75, had received stable PD for > 6 weeks, did not receive ESAs, roxadustat, and iron supplementation within 6 weeks before enrollment, and met the clinical diagnosis criteria of renal anemia as stipulated in the Chinese Expert Consensus on the Diagnosis and Treatment of Kidney Anemia (2018 Revision). Exclusion criteria included severe organic dysfunction of the heart, liver, lung, and brain, a change in the dialysis method, transfusion, and intravenous iron. | PMC10629011 |
Calculation sample size | Sample sizes ( | PMC10629011 | ||
Study drug administration | Patients in the roxadustat group were treated with roxadustat capsules [Enambojin (China) Pharmaceutical Technology Development Co., LTD., Sinopharm H20180024 (50 mg), H20180023 (20 mg)], administered three times a week at 70 mg (< 45 kg), 100 mg (45 to < 60 kg) or 120 mg (≥ 60 kg). The dose was adjusted according to a preset dosing ladder as follows: 20, 40, 50, 70, 100, 120, 150, and 200 mg. The maximum dose was 2.5 mg/kg. If the patient's hemoglobin increase was greater than 20 g/L within 2 weeks and the hemoglobin value was greater than 90 g/L, the dose was lowered by one step. Only one dose reduction over 4 weeks was recommended when hemoglobin rose too rapidly. Patients in the ESA group were treated with generic epoetin alpha [Sansheng Pharmaceutical Co., LTD., S19980073 (2000 IU), S19980074 (3000 IU), S19980072 (4000 IU), S20010001 (10000 IU)] at 75–100 IU/kg/week. The maximum dose of each adjustment was 30 IU/kg/week. The initial treatment target was an increased hemoglobin level of 10–20 g/L per month, and subsequent adjustments would be made according to the patient's hemoglobin level, speed of hemoglobin change, and treatment response. Oral iron can be accepted when STAT ≤ 20% or sFt ≤ 100 µg/L while intravenous iron is not permitted during the study. The use of statins and phosphate binders was allowed. | PMC10629011 | ||
End points | metabolic acidosis, hyperkalemia, peritonitis | METABOLIC ACIDOSIS, IRON DEFICIENCY, PERITONITIS | The primary efficacy endpoints were the changes of iron biomarker levels from baseline to week 24 including hepcidin, sTFR, serum iron (SI), sFt, TSAT, total iron binding capacity (TIBC), and the proportion of patients with absolute iron deficiency (defined as TSAT < 20% and sFt < 100 ng/mL) and functional iron deficiency (defined as TSAT < 20% and sFt ≥ 100 ng/mL). Secondary efficacy endpoints were as follows: the hemoglobin levels at weeks 8 and 24, the proportion of patients who achieved the treatment target (defined as a mean hemoglobin level greater than or equal to 100 g/L but less than 120 g/L), the mean changes from baseline in lipid metabolism levels, and the incidence of hyperkalemia, metabolic acidosis and peritonitis. | PMC10629011 |
Statistical analysis | hyperkalemia, peritonitis | METABOLIC ACIDOSIS, PERITONITIS | All the data were processed with SPSS 25.0. Measurement data with a normal distribution were expressed as means ± standard deviation, and comparisons between groups were analyzed using independent sample t-tests. Nonnormally distributed data were expressed as medians and interquartile ranges. The enumeration data were expressed as percentages, and the Chi-squared test was used to compare groups. We used the mixed-effects repeated-measures model to analyze the mean changes from baseline in iron biomarker levels, hemoglobin levels and lipid metabolism levels over week 24. Before analyzing the above parameters, logarithmic transformation of the values of sFt and EPO were carried out to make them meet the normal distribution. Safety was monitored by assessment of changes in blood pressure and the incidence of hyperkalemia, metabolic acidosis, and peritonitis during treatment. Bitailed | PMC10629011 |
Results | PMC10629011 | |||
Baseline characteristics of the patients | PD | From June 2021 through April 2022, 159 patients underwent randomization (roxadustat, 106; ESA, 53). Of these patients, 106 completed the 24-week study (roxadustat, 70; ESA, 36) (Fig. Patient disposition. Among 391 PD patients regularly followed up, 159 eligible patients were grouped [roxadustat group, Characteristics of the patients at baselineMeasurement data with a normal distribution are expressed as means ± standard deviation, and nonnormally distributed data are expressed as medians and interquartile range. No significant differences between group were found in the baseline characteristics. BMI denotes body mass index, sTFR denotes serum soluble transferrin receptor, SI denotes serum iron, sFt denotes serum ferritin, TSAT denotes transferrin saturation, TIBC denotes total iron-binding capacity, RBC denotes red blood count, EPO denotes erythropoietin, K | PMC10629011 | |
Hemoglobin levels | PD, anemia | ANEMIA | At baseline, the logEPO level was 0.77 ± 0.30 mIU/mL in the roxadustat group and 0.78 ± 0.31 mIU/mL in the ESA group. At week 24, the increase from baseline was 0.13 ± 0.42 mIU/mL and 0.78 ± 0.62 mIU/mL in the roxadustat and ESA groups. The difference between groups was -0.65 mIU/mL (95% CI, − 0.85 to − 0.45). Although the increase of logEPO levels in roxadustat group was much smaller than that in ESA group, no significant difference was observed in the improvement of anemia in PD patients between two groups. At week 24, hemoglobin levels increased 23.89 ± 17.87 g/L in roxadustat group and 19.73 ± 20.67 g/L in ESA group. The difference between groups was 4.16 g/L (95% CI, − 3.51 to 11.83). The percentage of patients with a hemoglobin level greater than or equal to 100 g/L but less than 120 g/L was 44.29% in the roxadustat group, and 47.22% in the ESA group in week 24 (Fig. Hemoglobin level and roxadustat dose in roxadustat group | PMC10629011 |
Lipid metabolism levels | At week 24, the mean decreases in the lipid levels in the roxadustat group were as follows: 0.26 ± 0.98 mmol/L in the total cholesterol level (treatment difference, − 0.28 mmol/L; 95% CI, − 0.72 to 0.16), 0.39 ± 0.78 mmol/L in the low-density lipoprotein level (treatment difference, − 0.28 mmol/L; 95% CI, − 0.64 to 0.07), 0.10 ± 0.22 mmol/L in the high-density lipoprotein level (treatment difference, − 0.06 mmol/L; 95% CI, − 0.16 to 0.05), and 0.19 ± 0.55 mmol/L in the triglyceride level (treatment difference, − 0.59 mmol/L; 95% CI, − 1.07 to − 0.12). | PMC10629011 |
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