Metformin vs Tolvaptan for Treatment of Autosomal Dominant Polycystic Kidney Disease

NCT03764605 | Unknown Phase 3

• 1 other identifier: Eudract2018-000477-77
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 2

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).

Conditions

ADPKD

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (1)

• Total Kidney Volume variation (measured by non contrast enhanced Kidney CT scan)

  25 months

Other Outcomes (7)

• Blood pressure

  36 months

• Post void body weight

  36 months

• Change from serum creatinine baseline

  36 months

Study Arms (2)

Metformin

EXPERIMENTAL

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

Tolvaptan

ACTIVE COMPARATOR

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

Interventions

Metformin DRUG

Patieny will be treated by using Metformin from 500 mg a day to 500 mg thrice a day.

Also known as: Zuglimet

Metformin

Tolvaptan DRUG

Patients will be treated with tolvaptan from 45 mg + 15 mg a day to 90 mg + 30 mg a day

Also known as: Jinarc

Tolvaptan

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Men and women aged between 18 and 50 years
• eGFR (CKD-EPI) ≥ 45 ml/min/1,73 m2
• Genetic Diagnosis of Type I ADPKD truncating mutation
• Signed and dated informed consent

You may not qualify if:

• 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.
• Women who are breast-feeding and/or who have a positive pregnancy test result prior to receiving investigational medical product (IMP).
• Treatment with acarbose, guar gum, cimetidin, phenprocoumon, oral anticoagulants, thrombolytic drugs, diuretics, ranolazin, cephalexin.
• Evidence of active systemic or localized major infection at the time of screening.
• 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)
• Acute or chronic disease causing tissue hypoxia (e.g.: myocardial failure, severe arythmias, myocardial infarction, respiratory failure, liver failure, alcohol acute intoxication, alcoholism, dehydration).
• Previously diagnosed diabetes already in treatment with other hypoglycemic drugs.
• Ongoing breast feeding.
• Use of any other investigational drug or treatment up to 4 weeks before enrollment and during the treatment phase.
• Known hypersensitivity to metformin and its derivatives.
• Psychiatric disorders and any condition that might prevent full comprehension of the purposes and risks of the study.

Sponsors & Collaborators

• Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari: lead

Study Sites (2)

AOUC "Policlinico"

Bari, 70124, Italy

Location

AOUConsorziale Policlinico Di Bari

Bari, 70124, Italy

Location

Related Publications (1)

• El-Damanawi R, Stanley IK, Staatz C, Pascoe EM, Craig JC, Johnson DW, Mallett AJ, Hawley CM, Milanzi E, Hiemstra TF, Viecelli AK. Metformin for preventing the progression of chronic kidney disease. Cochrane Database Syst Rev. 2024 Jun 4;6(6):CD013414. doi: 10.1002/14651858.CD013414.pub2.

  PMID: 38837240 DERIVED

MeSH Terms

Conditions

Polycystic Kidney, Autosomal Dominant

Interventions

Metformin; Tolvaptan

Condition Hierarchy (Ancestors)

Polycystic Kidney Diseases; Kidney Diseases, Cystic; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Ciliopathies; Genetic Diseases, Inborn

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Loreto Gesualdo

  AOUConsorziale Policlinico di Bari

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Loreto Gesualdo

CONTACT

+390805594040; loretoge60@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Head of Nephrology

Model Details: 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.

Study Record Dates

• First Submitted: November 29, 2018
• First Posted: December 5, 2018
• Study Start: January 30, 2019
• Primary Completion: September 30, 2021
• Study Completion: January 30, 2022
• Last Updated: December 7, 2018

Record last verified: 2018-12

Data Sharing

• IPD Sharing: Will not share

Locations

IT (2)