ADPKD Clinical Trial
Official 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).
Objective of the study is to assess if a two-year course of 1500 mg oral metformin is
effective and safe in treatment of ADPKD, as compared to the actual gold-standard therapy,
tolvaptan (Jinarc®) This is a phase 3a, independent, multi-centre, parallel arms, randomized
controlled trial comparing efficacy and safety of metformin and tolvaptan in ADPKD.
This trial will enroll approximately 150 tolvaptan and metformin naïve subjects affected by
Type I-truncating ADPKD, as these subjects have grater probability of progression.
The trial contemplates a 2 weeks screening period (included in a 9 months total recruitment
period) during which 3 visits have to be collected (the 1st and the 2nd in three days, and
the 3rd after biochemical analyses performed during the first two visits have been reviewed).
The subject's eligibility for the trial will be confirmed by the mean of eGFR calculated from
the 2 pre-treatment, central-lab, serum creatinine assessments. Longer screening periods (up
to 4 additional weeks) are acceptable for subjects needing stabilization after changing or
discontinuing other treatments, especially anti-hypertensives and diuretics.
Once eligibility is assessed, patients will undergo non-contrast enhanced CT-scan of kidneys
(if not performed within six months prior to randomization).
Randomization visit will occur on Day -29. During this visit patients will be randomized (in
a ratio 1:1 tolvaptan:metformin) to each arm of treatment and will start an IMP titration
period (3 weeks from -28 to -8). Subjects not tolerating the minimum IMP dose will be
considered "Titration failures" and will complete End of Treatment (EoTx) visit assessments
and will be followed up after 7 days by phone call to assess any ongoing AEs. Subjects
tolerating the minimum IMP dose enter the unblind run-in period (1 week from Day -7 to -1).
During the "Run-in" phase, subjects will continue on a stable IMP dose to confirm
tolerability over a longer period. At the end of the run-in period (Day -1), subjects not
tolerating the minimum IMP dose will be considered "Run-in failures" and will complete EoTx
visit assessments and will be followed up after 7 days by phone call to assess any ongoing
AEs. Subjects completing the run-in will start the open-label 24 months treatment period,
during which visits will be collected three-monthly. At the end of the 24th month, and in
case of early treatment cessation, follow-up period (3 weeks from +8 to +21) will start,
during which 2 visits have to be collected. No IMP will be administered during this period.
This trial will enroll approximately 150 tolvaptan and metformin naïve subjects and will be
conducted in about 11 Italian Hospital Nephrology Departments The investigators plan to
recruit a total of 150 patients which are currently within the reach of the network
coordinated by the proponent and composed by 11 Nephrology Centres. This network treats a
total of 1500 (already genetically studied) patients of which the investigators expect (based
on standard response rates recognized in the population) acceptance to participate in the
study to a value of approximately 40% of patients that will be then allocated to the
experimental and control intervention.
The selected sample is adequate to evaluate a significant reduction in the slope of eGFR at 2
years by 10%, which is a clinically relevant piece of information at the current state of
knowledge, as well as a complete assessment of the benefits-harms trade-off of the two
interventions.
The trial has a 36 months overall duration, that include a 9 months recruitment period; has a
2 weeks duration, it is included in the 9 months recruitment period. The treatment period has
a 25 months duration. Each month lasts 28 days. It includes the 3 weeks titration period and
the 1 week run-in period.
The post-treatment follow-up: lasts 21 days. The total Study Duration is of about 3 years.
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