Ignite Creation Date:
2024-10-25 @ 8:05 PM
Last Modification Date:
2024-10-26 @ 3:42 PM
Study NCT ID:
NCT06641128
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-10-09
Brief Title:
The Possible Efficacy and Protective Effect of Empagliflozin in Rheumatoid Arthritis Patients Treated with Methotrexate
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Clinical Study Evaluating the Possible Efficacy and Protective Effect of Empagliflozin in Rheumatoid Arthritis Patients Treated with Methotrexate
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The primary aim of this clinical trial is to Evaluate the Possible Efficacy and Protective Effect of Empagliflozin in Rheumatoid Arthritis Patients Treated with Methotrexate
Methodology
This is a randomized double blind placebo controlled parallel study that will be conducted on 44 patients with active rheumatoid arthritis
Group1 placebo group n22 which will receive IM or SC Methotrexate plus placebo tablet once daily for 3 months
Group2 Empa group n22 which will receive IM or SC Methotrexate plus Empa tablets 25 mg once daily for 3 months
Duration 3 months
Monitoring
Participants will be followed up by weekly telephone calls and monthly direct meeting at scheduled visits to assess their adherence and to report any drug related adverse effects
In summary this clinical trial is designed to determine if empagliflozin is a safe and effective treatment for Rheumatoid Arthritis Patients Treated with Methotrexate by comparing its effects to a placebo and closely monitoring participants throughout the study
Methodology
This is a randomized double blind placebo controlled parallel study that will be conducted on 44 patients with active rheumatoid arthritis
Group1 placebo group n22 which will receive IM or SC Methotrexate plus placebo tablet once daily for 3 months
Group2 Empa group n22 which will receive IM or SC Methotrexate plus Empa tablets 25 mg once daily for 3 months
Duration 3 months
Monitoring
Participants will be followed up by weekly telephone calls and monthly direct meeting at scheduled visits to assess their adherence and to report any drug related adverse effects
In summary this clinical trial is designed to determine if empagliflozin is a safe and effective treatment for Rheumatoid Arthritis Patients Treated with Methotrexate by comparing its effects to a placebo and closely monitoring participants throughout the study
Detailed Description:
Increasing evidence suggests that the nucleotide-binding domain leucine-rich-containing family pyrin domain-containing-3 NLRP3 inflammasome is involved in the pathogenesis of RA Anti-citrullinated protein antibodies ACPA are a group of autoantibodies against citrullinated proteinspeptides and are biomarkers of RA ACPA promotes IL-1 production in rheumatoid arthritis by activating the NLRP3 inflammasome Several studies have shown an upregulation of NLRP3 mRNA and NLRP3-associated proteins in monocytes macrophages and dendritic cells in RA patients Polymorphisms in the NLRP3 gene indirectly reflect the susceptibility disease severity and treatment effect of RA
Methotrexate MTX is a folic acid antagonist-an antiproliferative drug as it is known MTX is a gold-standard antirheumatic agent in the treatment of rheumatoid arthritis Various side effects may occur during the treatment of inflammatory diseases ranging from mild to severe side effects and even leading to treatment discontinuation
The complications of chronic MTX toxicity include kidney injury hepatotoxicity mucositis neurotoxicity hyperglycemia hematologic complications and myelosuppression Chronically MTX-poisoned patient is the one with a long-standing RA or psoriasispsoriatic arthritis presenting with sudden onset of erosions or ulcers in psoriatic plaques andor sudden onset of severe mucosal ulceration in the oral cavity with or without diarrhea and fever secondary to infection Mucosal ulceration was seen in most chronic cases
The reason that MTX-induced renal dysfunction is a fundamental problem is that renal function in RA patients is already compromised Because the renal tubules excrete more than 90 of MTX MTX toxicity is enhanced by drugs that reduce renal elimination including sulfonamides aminoglycosides cisplatin penicillins and colchicine as well as by drugs that displace methotrexate from protein binding sites in plasma including sulfonamides phenytoin retinoids and barbiturates
Gastrointestinal side effects of MTX is the main dose-limiting issue for the use of MTX is gastrointestinal toxicity
MTX has been elucidated to exhibit a negative effect on the mitochondrial respiratory chain and hence induce excessive production of reactive oxygen species ROS leading to oxidative stress ROS can initiate cellular macromolecule damage and induce lipid peroxidation leading to cell death MTX showed a significant increase in liver lipid peroxidation indicator Malondialdehyde in rats Therefore attenuating the formation of ROS and inhibiting oxidative stress has been introduced as a suitable option to protect the organ against MTX-induced toxicity
Empagliflozin Empa belongs to a novel class of anti-hyperglycemic drugs which was approved by the FDA on August 1 2014 Contrary to conventional hypoglycemic agents Empa lowers blood glucose by inhibiting the activity of sodium-glucose cotransporter-2 SGLT-2 in proximal renal tubules The SGLT2 transporter is mostly expressed in the proximal tubules in the kidney but is found also in other organs such as the liver thyroid muscle and heart The receptors function is to reabsorb glucose coupled with sodium ion from the excreted urine back to the blood
Apart from glucose lowering Empa has other pleiotropic effects and antioxidant effects These benefits lead to cardiovascular protection through decreasing weight lowering blood pressure increasing the elasticity of the arteries and reducing its stiffness lowering lipid production decreasing systemic inflammation and the release of inflammatory biomarkers increasing insulin production decreasing insulin resistance and decreasing uric acid levels Furthermore different studies have elucidated that Empa exerts beneficial roles in the brain peripheral neurons kidneys liver and gastrointestinal tract
Empa reduced proinflammatory cytokines such as interleukin-1β IL-1β IL-6 and IL-8 in doxorubicin-treated mice model through affecting the expressions of NLRP3 and MyD88 related pathways which are also involved in pathophysiology of rheumatoid arthritis
Several studies have shown the protective effects of Empa on different liver-related pathologies induced by ethanol and high-fat diets in rats Regarding the possible molecular mechanisms of Empa attenuation of oxidative stress has been presented as the underlying mechanism It has been reported that the protective effects of Empa are associated with its ability to reduce ROS generation and induction of cellular antioxidant defense In rats Empa increase activity of superoxide dismutase SOD catalase CAT and glutathione peroxidase GPX which are a first line antioxidant defense system
Several studies showed that marked increase in both alanine transaminase ALT and aspartate transaminase AST serum concentrations in patients treated with MTX However Empa treatment significantly reduced the elevation of serum concentrations of AST and ALT induced by MTX in rats Aim of the study This study aimed to investigate the possible efficacy and protective effect of Empagliflozin in rheumatoid arthritis patients treated with methotrexate
Patients and method
Study design and study population
The patients will be recruited from Outpatient Clinic of Internal Medicine Rheumatology and Immunology Department Mansoura University Hospital Mansoura Egypt The study duration will be 3 months The blindness will be maintained by the similarity between the placebo and Empa tablets The patients will be randomized using sealed envelope method with assigned code into two groups
Ethical approval
The study will be conducted following the ethical standards of Helsinki declaration in 1964 and its later amendments The study will be approved by the Research Ethics Committee of Tanta University and Mansoura University The study will be registered as a clinical trial on ClinicalTrialsgov All participants will be informed about the benefits and risks of the study Any unexpected risks that will appear during the research will be clarified to the participant and to the concerned ethical committee on time The privacy of all participants will be respected and all data will be confidential A written informed consent will be obtained from all patients or their caregivers if the patient is unable to write or is cognitively impaired The study will be conducted between 2024 - 2026
Inclusion criteria
Patients with active rheumatoid arthritis not in remission according to 28 joints disease activity score DAS-28 26 Aletaha et al 2010
Age range between 18 and 60 years old Both sexes Body mass index BMI age disease activity and disease duration matched patients
Patients receive methotrexate and other conventional DMARDs
Exclusion criteria
Patients with renal or hepatic diseases chronic liver disease liver cirrhosis alcoholic hepatitis or chronic alcoholism
Patients receiving biological DMARDs during 4 weeks before the first dose of Empa
Patients with hypersensitivity to study medications Patients using antioxidants except Empa Pregnant and lactating females Pre-existing blood disorders such as bone marrow hypoplasia leukopenia thrombocytopenia or significant anemia
Patient with HIVAIDS blood dyscrasias or radiotherapy
Methods
All participants included in this study will be subjected to the following
History demography and anthropometric data collection All participants will be submitted to physical and clinical examination demographic data collection age sex and history and measurement of weight and height with subsequent calculation of body mass index according to the following formula BMIweight Kgheight2 m2
Blood sample collection and biological assessment Before and 3 months after the intervention 10 ml of venous blood will be withdrawn by antecubital venipuncture from each participant after overnight fasting 10-12 h fasting period between 830 and 1030 am 5 ml of blood will be used for evaluation of the following parameters
Routine laboratory tests Erythrocyte sedimentation rate ESR C-reactive protein CRP Rheumatic factor RF Liver function test Kidney function test
Then the remaining 5 ml of blood will be transferred into a plain test tube and centrifuged at 3000 rpm for 10 min and then serum samples will be kept frozen at -80 C until analysis of biological markers
NOD-like receptor protein 3 NLRP3 Interleukin-1β IL-1β Superoxide dismutase SOD Clinical assessment Before and 3 months after the intervention calculation of 28-joint count Disease Activity Score DAS28 using C-reactive protein CRP where high disease activity 51 low disease activity 32 and remission 26
Assessment of participants adherence side effects and tolerability Empa and placebo tablets will be provided on monthly intervals and the participants adherence will be assessed through counting the returned pills and through the medication refilling rate Participants will be followed up by weekly telephone calls and monthly direct meeting at scheduled visits to assess their adherence and to report any drug related adverse effects The adverse effects will be collected using adverse effect check list Participant was considered non-adherent and excluded from the study if consumed less than 90 of the study medications or lost the follow-up meetings at any month of intervention
Sample size calculation
Using SPSS program version 25 SPSS Inc Chicago IL USA 2017 and with the assumption of significance level of 005 confidence interval of 95 and statistical power of 80 which in turn will provide a large effect size of 080 to detect the difference in the outcome measured between the two groups using independent Unpaired t-test the total sample size will be 36 patients in both arms 18 per group Assuming that the attrition rate is 20 the total sample size will be 44 patients 22 patients per group
Statistical analysis The collected data will be tabulated using Microsoft Office Excel 2019 Microsoft Corporation
The statistical analysis will be performed using IBM SPSS Statistics version 28 software IBM Corp Armonk NY USA
All graphs will be created with graph Pad prism 601 software Graph pad Software La Jolla CA USA
Data will be tested for normality using Shapiro-Wilk test or Kolmogorov-Smirnov test
Parametric data will be analyzed using Paired and Un-Paired t-test to compare the means within the same group and to compare the means of the two groups respectively
Non- Parametric data will be analyzed using Mann Whitney U test to compare the means within the same group and to compare the means between groups
Categorical data will be analyzed using Chi-Square test Fishers exact test will be used to analyses the reported adverse effects Correlation between variables will be assessed using Pearson or Spearman correlation coefficient which appropriate
Data will be expressed as the mean SD medians range number and percent as appropriate
The significance level will be set at p 005
Methotrexate MTX is a folic acid antagonist-an antiproliferative drug as it is known MTX is a gold-standard antirheumatic agent in the treatment of rheumatoid arthritis Various side effects may occur during the treatment of inflammatory diseases ranging from mild to severe side effects and even leading to treatment discontinuation
The complications of chronic MTX toxicity include kidney injury hepatotoxicity mucositis neurotoxicity hyperglycemia hematologic complications and myelosuppression Chronically MTX-poisoned patient is the one with a long-standing RA or psoriasispsoriatic arthritis presenting with sudden onset of erosions or ulcers in psoriatic plaques andor sudden onset of severe mucosal ulceration in the oral cavity with or without diarrhea and fever secondary to infection Mucosal ulceration was seen in most chronic cases
The reason that MTX-induced renal dysfunction is a fundamental problem is that renal function in RA patients is already compromised Because the renal tubules excrete more than 90 of MTX MTX toxicity is enhanced by drugs that reduce renal elimination including sulfonamides aminoglycosides cisplatin penicillins and colchicine as well as by drugs that displace methotrexate from protein binding sites in plasma including sulfonamides phenytoin retinoids and barbiturates
Gastrointestinal side effects of MTX is the main dose-limiting issue for the use of MTX is gastrointestinal toxicity
MTX has been elucidated to exhibit a negative effect on the mitochondrial respiratory chain and hence induce excessive production of reactive oxygen species ROS leading to oxidative stress ROS can initiate cellular macromolecule damage and induce lipid peroxidation leading to cell death MTX showed a significant increase in liver lipid peroxidation indicator Malondialdehyde in rats Therefore attenuating the formation of ROS and inhibiting oxidative stress has been introduced as a suitable option to protect the organ against MTX-induced toxicity
Empagliflozin Empa belongs to a novel class of anti-hyperglycemic drugs which was approved by the FDA on August 1 2014 Contrary to conventional hypoglycemic agents Empa lowers blood glucose by inhibiting the activity of sodium-glucose cotransporter-2 SGLT-2 in proximal renal tubules The SGLT2 transporter is mostly expressed in the proximal tubules in the kidney but is found also in other organs such as the liver thyroid muscle and heart The receptors function is to reabsorb glucose coupled with sodium ion from the excreted urine back to the blood
Apart from glucose lowering Empa has other pleiotropic effects and antioxidant effects These benefits lead to cardiovascular protection through decreasing weight lowering blood pressure increasing the elasticity of the arteries and reducing its stiffness lowering lipid production decreasing systemic inflammation and the release of inflammatory biomarkers increasing insulin production decreasing insulin resistance and decreasing uric acid levels Furthermore different studies have elucidated that Empa exerts beneficial roles in the brain peripheral neurons kidneys liver and gastrointestinal tract
Empa reduced proinflammatory cytokines such as interleukin-1β IL-1β IL-6 and IL-8 in doxorubicin-treated mice model through affecting the expressions of NLRP3 and MyD88 related pathways which are also involved in pathophysiology of rheumatoid arthritis
Several studies have shown the protective effects of Empa on different liver-related pathologies induced by ethanol and high-fat diets in rats Regarding the possible molecular mechanisms of Empa attenuation of oxidative stress has been presented as the underlying mechanism It has been reported that the protective effects of Empa are associated with its ability to reduce ROS generation and induction of cellular antioxidant defense In rats Empa increase activity of superoxide dismutase SOD catalase CAT and glutathione peroxidase GPX which are a first line antioxidant defense system
Several studies showed that marked increase in both alanine transaminase ALT and aspartate transaminase AST serum concentrations in patients treated with MTX However Empa treatment significantly reduced the elevation of serum concentrations of AST and ALT induced by MTX in rats Aim of the study This study aimed to investigate the possible efficacy and protective effect of Empagliflozin in rheumatoid arthritis patients treated with methotrexate
Patients and method
Study design and study population
The patients will be recruited from Outpatient Clinic of Internal Medicine Rheumatology and Immunology Department Mansoura University Hospital Mansoura Egypt The study duration will be 3 months The blindness will be maintained by the similarity between the placebo and Empa tablets The patients will be randomized using sealed envelope method with assigned code into two groups
Ethical approval
The study will be conducted following the ethical standards of Helsinki declaration in 1964 and its later amendments The study will be approved by the Research Ethics Committee of Tanta University and Mansoura University The study will be registered as a clinical trial on ClinicalTrialsgov All participants will be informed about the benefits and risks of the study Any unexpected risks that will appear during the research will be clarified to the participant and to the concerned ethical committee on time The privacy of all participants will be respected and all data will be confidential A written informed consent will be obtained from all patients or their caregivers if the patient is unable to write or is cognitively impaired The study will be conducted between 2024 - 2026
Inclusion criteria
Patients with active rheumatoid arthritis not in remission according to 28 joints disease activity score DAS-28 26 Aletaha et al 2010
Age range between 18 and 60 years old Both sexes Body mass index BMI age disease activity and disease duration matched patients
Patients receive methotrexate and other conventional DMARDs
Exclusion criteria
Patients with renal or hepatic diseases chronic liver disease liver cirrhosis alcoholic hepatitis or chronic alcoholism
Patients receiving biological DMARDs during 4 weeks before the first dose of Empa
Patients with hypersensitivity to study medications Patients using antioxidants except Empa Pregnant and lactating females Pre-existing blood disorders such as bone marrow hypoplasia leukopenia thrombocytopenia or significant anemia
Patient with HIVAIDS blood dyscrasias or radiotherapy
Methods
All participants included in this study will be subjected to the following
History demography and anthropometric data collection All participants will be submitted to physical and clinical examination demographic data collection age sex and history and measurement of weight and height with subsequent calculation of body mass index according to the following formula BMIweight Kgheight2 m2
Blood sample collection and biological assessment Before and 3 months after the intervention 10 ml of venous blood will be withdrawn by antecubital venipuncture from each participant after overnight fasting 10-12 h fasting period between 830 and 1030 am 5 ml of blood will be used for evaluation of the following parameters
Routine laboratory tests Erythrocyte sedimentation rate ESR C-reactive protein CRP Rheumatic factor RF Liver function test Kidney function test
Then the remaining 5 ml of blood will be transferred into a plain test tube and centrifuged at 3000 rpm for 10 min and then serum samples will be kept frozen at -80 C until analysis of biological markers
NOD-like receptor protein 3 NLRP3 Interleukin-1β IL-1β Superoxide dismutase SOD Clinical assessment Before and 3 months after the intervention calculation of 28-joint count Disease Activity Score DAS28 using C-reactive protein CRP where high disease activity 51 low disease activity 32 and remission 26
Assessment of participants adherence side effects and tolerability Empa and placebo tablets will be provided on monthly intervals and the participants adherence will be assessed through counting the returned pills and through the medication refilling rate Participants will be followed up by weekly telephone calls and monthly direct meeting at scheduled visits to assess their adherence and to report any drug related adverse effects The adverse effects will be collected using adverse effect check list Participant was considered non-adherent and excluded from the study if consumed less than 90 of the study medications or lost the follow-up meetings at any month of intervention
Sample size calculation
Using SPSS program version 25 SPSS Inc Chicago IL USA 2017 and with the assumption of significance level of 005 confidence interval of 95 and statistical power of 80 which in turn will provide a large effect size of 080 to detect the difference in the outcome measured between the two groups using independent Unpaired t-test the total sample size will be 36 patients in both arms 18 per group Assuming that the attrition rate is 20 the total sample size will be 44 patients 22 patients per group
Statistical analysis The collected data will be tabulated using Microsoft Office Excel 2019 Microsoft Corporation
The statistical analysis will be performed using IBM SPSS Statistics version 28 software IBM Corp Armonk NY USA
All graphs will be created with graph Pad prism 601 software Graph pad Software La Jolla CA USA
Data will be tested for normality using Shapiro-Wilk test or Kolmogorov-Smirnov test
Parametric data will be analyzed using Paired and Un-Paired t-test to compare the means within the same group and to compare the means of the two groups respectively
Non- Parametric data will be analyzed using Mann Whitney U test to compare the means within the same group and to compare the means between groups
Categorical data will be analyzed using Chi-Square test Fishers exact test will be used to analyses the reported adverse effects Correlation between variables will be assessed using Pearson or Spearman correlation coefficient which appropriate
Data will be expressed as the mean SD medians range number and percent as appropriate
The significance level will be set at p 005
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None