Metformin vs Tolvaptan for Treatment of Autosomal Dominant Polycystic Kidney Disease

• Status: Not yet recruiting
• Trial end date: 2022-01-30
• Target enrollment: 0
• Participant gender: All

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).

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Azienda Ospedaliero-Universitaria Consorziale; Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari
• Treatments: Metformin; Tolvaptan

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.