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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 ...
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 consu...
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 no...
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...
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 policymak...
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 ext...
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 i...
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...
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 ...
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...
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 e...
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-3...
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 benef...
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 [Agi...
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. T...
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 us...
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 ac...
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 re...
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 “me...
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 c...
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...
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...
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 toge...
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 p...
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 (GAG...
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...
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 obs...
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...
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 ...
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 Ingre...
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 randomize...
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:...
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...
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...
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 res...
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 ...
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 reg...
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 ...
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). Th...
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 perf...
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 observ...
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 colle...
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, Sh...
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 m...
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 wi...
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 def...
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 acti...
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 ...
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...
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 deficie...
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 ...
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 o...
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...
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 0.0...
PMC10629011