Metformin vs Tolvaptan for Treatment of Autosomal Dominant Polycystic Kidney Disease (METROPOLIS)
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|ClinicalTrials.gov Identifier: NCT03764605|
Recruitment Status : Not yet recruiting
First Posted : December 5, 2018
Last Update Posted : December 7, 2018
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).
|Condition or disease||Intervention/treatment||Phase|
|ADPKD||Drug: Metformin Drug: Tolvaptan||Phase 3|
Show Detailed Description
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||150 participants|
|Intervention Model:||Parallel Assignment|
|Intervention Model Description:||Trial will enroll 150 subjects affected by Type I-truncating ADPKD. Their eligibility will be confirmed by the mean of eGFR calculated from the 2 pre-treatment serum creatinine assessments. Once eligibility is assessed, patients will undergo kidneys CTscan. Randomization visit will occur on Day -29. During this visit patients will be randomized (1:1) to each arm of treatment and will start IMP titration. Subjects not tolerating the minimum IMP dose will be considered "Titration failures" and will complete End of Treatment (EoTx) visit and will be followed up after 7 days by phone call. Subjects tolerating the minimum IMP dose enter the unblind run-in period during which, subjects will continue on a stable IMP dose to confirm tolerability over a longer period. At the end of the run-in period subjects not tolerating the minimum IMP dose will be considered "Run-in failures" and will complete EoTx visit. Subjects completing the run-in will start the open-label 24 months treatment period.|
|Masking:||None (Open Label)|
|Official Title:||Metformin vs Tolvaptan for Treatment of Autosomal Dominant Polycystic Kidney Disease. A Phase 3a, Indipendent, Multicentre, Two Parallel Arms, Randomized Controlled Trial|
|Estimated Study Start Date :||January 30, 2019|
|Estimated Primary Completion Date :||September 30, 2021|
|Estimated Study Completion Date :||January 30, 2022|
Patients will take metformin starting from 500 mg a day. They will up-titrate every week, if tolerating IMP, adding one 500 mg dose 8 hours after the former, till reaching 500 mg thrice a day.
The minimum tolerated dose requested in order to be admitted to the study is 500 mg twice a day.
Those reaching eGFR<45 ml/min will reduce the dose by one third. Those reaching eGFR<30 will drop out the study.
Patieny will be treated by using Metformin from 500 mg a day to 500 mg thrice a day.
Other Name: Zuglimet
Active Comparator: Tolvaptan
Patient will start Tolvaptan in a split dose regimen 45 mg as first dose, followed by 15 mg 8 hours later. Those tolerating this dose will uptitrate to 60/30 mg and then to 90/30 mg a day. Those not tolerating 45/15 mg a day will drop out.
Patients will be treated with tolvaptan from 45 mg + 15 mg a day to 90 mg + 30 mg a day
Other Name: Jinarc
- Glomerular Filtration Rate (estimated by CKD-Epi formula) variation [ Time Frame: 25 months ]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.
- Total Kidney Volume variation (measured by non contrast enhanced Kidney CT scan) [ Time Frame: 25 months ]The key secondary endpoint is the percent change from baseline in htTKV as measured by CT-scan at 24 months.
- Blood pressure [ Time Frame: 36 months ]mmHg
- Post void body weight [ Time Frame: 36 months ]Kg
- Change from serum creatinine baseline [ Time Frame: 36 months ]mg/dl
- Serum sodium [ Time Frame: 36 months ]mg/dl
- Blood venous gas lactate levels [ Time Frame: 36 months ]mmol/l
- Bolood Glucose levels [ Time Frame: 36 months ]mg/dl
- Vitamin B12 deficency [ Time Frame: 36 months ]pg/ml
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03764605
|Contact: Loreto Gesualdofirstname.lastname@example.org|
|Bari, Italy, 70124|
|AOUConsorziale Policlinico Di Bari||Not yet recruiting|
|Bari, Italy, 70124|
|Contact: Loreto Gesualdo +390805594040 email@example.com|
|Contact: Giovanni Piscopo +393299664404 firstname.lastname@example.org|
|Principal Investigator:||Loreto Gesualdo||AOUConsorziale Policlinico di Bari|