ADPKD Clinical Trial
— METROPOLISOfficial title:
Metformin vs Tolvaptan for Treatment of Autosomal Dominant Polycystic Kidney Disease. A Phase 3a, Indipendent, Multicentre, Two Parallel Arms, Randomized Controlled Trial
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal
disorder occurring in 1:400-1:1.000 live births and affects 4 to 6 million persons worldwide
and about 205.000 people in Europe (EU). This figure is equivalent to 4 in 10.000 people and
thus below the prevalence threshold of 5 in 10.000 used to designate a disease as rare in EU.
Renal cyst development and expansion in ADPKD involves both fluid secretion and abnormal
proliferation of cyst-lining epithelial cells. The chloride channel of the cystic fibrosis
transmembrane conductance regulator (CFTR) participates in secretion of cyst fluid, and the
mammalian target of rapamycin (mTOR) pathway may drive proliferation of cyst epithelial
cells. CFTR and mTOR are both negatively regulated by AMP-activated protein kinase (AMPK).
Metformin, a drug widely used, is a pharmacological activator of AMPK. The investigators
found that metformin stimulates AMPK, resulting in inhibition of both CFTR and the mTOR
pathways. Metformin induces significant arrest of cystic growth in both in vitro and ex vivo
models of renal cystogenesis. In addition, metformin administration produces a significant
decrease in the cystic index in two mouse models of ADPKD. These results suggest a possible
role for AMPK activation in slowing renal cystogenesis as well as the potential for
therapeutic application of metformin in the context of ADPKD.
Thus this study aims to evaluate metformin efficacy in slowing renal cystogenesis in ADPKD as
compared to the actual gold standard (Tolvaptan).
Status | Not yet recruiting |
Enrollment | 150 |
Est. completion date | January 30, 2022 |
Est. primary completion date | September 30, 2021 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years to 50 Years |
Eligibility |
Inclusion Criteria: 1. Men and women aged between 18 and 50 years 2. eGFR (CKD-EPI) = 45 ml/min/1,73 m2 3. Genetic Diagnosis of Type I ADPKD truncating mutation 4. Signed and dated informed consent Exclusion Criteria: 1. Women of childbearing potential (WOCBP) who do not agree to practice 2 different methods of birth control or remain abstinent during the trial and for 30 days after the last dose of IMP. If employing birth control, 2 of the following precautions must be used: vasectomy of partner, tubal ligation, vaginal diaphragm, intrauterine device, birth control implant, condom, or sponge with spermicide. Non-childbearing potential in women is defined as female subjects who are surgically sterile (ie, have undergone bilateral oophorectomy or hysterectomy) or female subjects who have been postmenopausal for at least 12 consecutive months. 2. Women who are breast-feeding and/or who have a positive pregnancy test result prior to receiving investigational medical product (IMP). 3. Treatment with acarbose, guar gum, cimetidin, phenprocoumon, oral anticoagulants, thrombolytic drugs, diuretics, ranolazin, cephalexin. 4. Evidence of active systemic or localized major infection at the time of screening. 5. Hepatic impairment or liver function abnormalities other than that expected for ADPKD with typical cystic liver disease during the screening period as defined by: - AST O ALT >8x UNL - AST O ALT >5x UNL >2 WEEKS - AST O ALT >3x UNL E BT >2x UNL OR INR >1,5 - AST O ALT >3x UNL E SIGNS AND SYMPTOMS OF LIVER DAMAGE (fatigue, anorexy, nausea, vomiting, right hypocondrium pain, fever, jaundice, skin rash, itching) 6. Acute or chronic disease causing tissue hypoxia (e.g.: myocardial failure, severe arythmias, myocardial infarction, respiratory failure, liver failure, alcohol acute intoxication, alcoholism, dehydration). 7. Previously diagnosed diabetes already in treatment with other hypoglycemic drugs. 8. Ongoing breast feeding. 9. Use of any other investigational drug or treatment up to 4 weeks before enrollment and during the treatment phase. 10. Known hypersensitivity to metformin and its derivatives. 11. Psychiatric disorders and any condition that might prevent full comprehension of the purposes and risks of the study. 12. Malignancies within three years before enrolment in the study. 13. HIV, HBV, HCV infection. 14. Urinary tract obstruction. |
Country | Name | City | State |
---|---|---|---|
Italy | AOUC "Policlinico" | Bari | |
Italy | AOUConsorziale Policlinico Di Bari | Bari |
Lead Sponsor | Collaborator |
---|---|
Azienda Ospedaliero-Universitaria Consorziale |
Italy,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Blood pressure | mmHg | 36 months | |
Other | Post void body weight | Kg | 36 months | |
Other | Change from serum creatinine baseline | mg/dl | 36 months | |
Other | Serum sodium | mg/dl | 36 months | |
Other | Blood venous gas lactate levels | mmol/l | 36 months | |
Other | Bolood Glucose levels | mg/dl | 36 months | |
Other | Vitamin B12 deficency | pg/ml | 36 months | |
Primary | Glomerular Filtration Rate (estimated by CKD-Epi formula) variation | Primary outcome of the study is to evaluate the difference between Metformin and Tolvaptan in annualized slope of eGFR (CKD-EPI) for individual subjects, that will be calculated using an appropriate baseline and post-randomization assessment. | 25 months | |
Secondary | Total Kidney Volume variation (measured by non contrast enhanced Kidney CT scan) | The key secondary endpoint is the percent change from baseline in htTKV as measured by CT-scan at 24 months. | 25 months |
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