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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
Sponsor:
Information provided by (Responsible Party):
Loreto GESUALDO, Azienda Ospedaliero-Universitaria Consorziale

Brief Summary:

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
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)
Primary Purpose: Treatment
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

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Diseases

Arm Intervention/treatment
Experimental: Metformin

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.

Drug: Metformin
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.
Drug: Tolvaptan
Patients will be treated with tolvaptan from 45 mg + 15 mg a day to 90 mg + 30 mg a day
Other Name: Jinarc




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.


Other Outcome Measures:
  1. Blood pressure [ Time Frame: 36 months ]
    mmHg

  2. Post void body weight [ Time Frame: 36 months ]
    Kg

  3. Change from serum creatinine baseline [ Time Frame: 36 months ]
    mg/dl

  4. Serum sodium [ Time Frame: 36 months ]
    mg/dl

  5. Blood venous gas lactate levels [ Time Frame: 36 months ]
    mmol/l

  6. Bolood Glucose levels [ Time Frame: 36 months ]
    mg/dl

  7. Vitamin B12 deficency [ Time Frame: 36 months ]
    pg/ml



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

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


Contacts
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Contact: Loreto Gesualdo +390805594040 loretoge60@gmail.com

Locations
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Italy
AOUC "Policlinico"
Bari, Italy, 70124
AOUConsorziale Policlinico Di Bari Not yet recruiting
Bari, Italy, 70124
Contact: Loreto Gesualdo    +390805594040    trialnefrobari@gmail.com   
Contact: Giovanni Piscopo    +393299664404    giopiscopo@gmail.com   
Sponsors and Collaborators
Azienda Ospedaliero-Universitaria Consorziale
Investigators
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Principal Investigator: Loreto Gesualdo AOUConsorziale Policlinico di Bari
  Study Documents (Full-Text)

Documents provided by Loreto GESUALDO, Azienda Ospedaliero-Universitaria Consorziale:

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Responsible Party: Loreto GESUALDO, Head of Nephrology, Azienda Ospedaliero-Universitaria Consorziale
ClinicalTrials.gov Identifier: NCT03764605     History of Changes
Other Study ID Numbers: Eudract2018-000477-77
First Posted: December 5, 2018    Key Record Dates
Last Update Posted: December 7, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Kidney Diseases
Polycystic Kidney Diseases
Polycystic Kidney, Autosomal Dominant
Urologic Diseases
Kidney Diseases, Cystic
Abnormalities, Multiple
Congenital Abnormalities
Ciliopathies
Genetic Diseases, Inborn
Metformin
Tolvaptan
Hypoglycemic Agents
Physiological Effects of Drugs
Antidiuretic Hormone Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Natriuretic Agents