Tolvaptan-Octreotide LAR Combination in ADPKD

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Brief Title

Tolvaptan-Octreotide LAR Combination in ADPKD

Official Title

A Pilot, Phase II Study With a Prospective, Randomized, Cross-Over, Placebo-Controlled, Double-Blind Design to Assess the Short-Term Effects of Tolvaptan Plus Placebo vs Tolvaptan Plus Octreotide LAR Combination Therapy in ADPKD Patients With Normal Kidney Function or Hyperfiltration

Brief Summary

      Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a leading cause of End Stage Kidney
      Disease (ESKD) worldwide. Elevated levels of 3', 5' - cyclic AMP (cAMP) play a central role
      in the pathogenesis and progression of the disease. Vasopressin antagonists and somatostatin
      analogues, which indirectly reduce adenyl cyclase 6 activity, have been found to markedly
      reduce renal tubular cell proliferation and cyst growth in experimental models of ADPKD. In
      combination, the two treatments show a clear additive effect and may significantly reduce
      renal cystic and fibrotic volume as well as cAMP levels to wild type levels.

      The vasopressin antagonist Tolvaptan and the somatostatin analogue Octreotide share a similar
      renoprotective effect also in human disease.

      Both medications effectively slow total kidney and cystic volume (TKV and TCV, respectively)
      growth and glomerular filtration rate (GFR) decline in patients with ADPKD. The short-term
      effect of both medications appear to be larger when the GFR is normal or even higher than
      normal and kidney volumes are still relatively stable. On the basis of experimental data, it
      is conceivable that Tolvaptan and Octreotide LAR should have an additive effect also in human
      disease, during initial treatment as well as in the long-term. To address the working
      hypothesis of an additional short-term effect of Tolvaptan and Octreotide, we propose to run
      a pilot, explorative, randomized, placebo-controlled, clinical trial with a Cross-Over Design
      to compare the short-term effects of Tolvaptan monotherapy and Tolvaptan plus Octreotide LAR
      combination therapy on TKV as assessed by MRI, and on GFR as directly measured by the iohexol
      plasma clearance technique in ADPKD patients with normal (80 to 120 ml/min/1.73m2) kidney
      function or even kidney hyperfiltration (GFR ≥120 ml/min/1.73m2).
    


Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Glomerular Filtration Rate (GFR)

Secondary Outcome

 Total Kidney Volume (TKV)

Condition

Autosomal Dominant Polycystic Kidney Disease

Intervention

Tolvaptan

Study Arms / Comparison Groups

 Tolvaptan plus Octreotide LAR / Tolvaptan plus Placebo
Description:  Patients will receive a first 4-week treatment period with Tolvaptan up to 120 mg/die, according to tolerability, and a single dose of Octreotide LAR (two 20 mg i.m. injections). Then, after a period of wash-out, each patient will cross over to the other treatment arm for a second 4-week treatment period with Tolvaptan plus a single dose of placebo (two i.m. injections of 0.9% NaCl solution)

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

20

Start Date

December 12, 2018

Completion Date

September 2022

Primary Completion Date

September 2022

Eligibility Criteria

        Inclusion Criteria:

          1. Adult (>18-yr-old) men and women, with a clinical and ultrasonographic diagnosis of
             ADPKD;

          2. Serum creatinine < 1.0 mg/dl (for man) and < 1.2 mg/dl (for woman) and changes in
             serum creatinine (and creatinine clearance when available) <30% over the last six
             months;

          3. Creatinine clearance > 80 ml/min/1.73m2 measured one to two weeks apart during the
             pre-screening period;

          4. GFR ≥ 80 ml/min/1.73m2 (by iohexol plasma clearance technique) at screening and
             baseline evaluations;

          5. TKV ranging between 1000 and 2000 ml at screening (by ultrasound imaging) and at
             baseline (by MRI) evaluations;

          6. Female participants must be of non-childbearing potential or must agree to abstinence
             or use a highly effective form of contraception;

          7. Written informed consent.

        Exclusion Criteria:

          1. Patients with concomitant systemic, renal parenchymal or urinary tract disease;

          2. Diabetes;

          3. Overt proteinuria (urinary protein excretion rate >1 g/24 hours);

          4. Abnormal urinalysis suggestive of concomitant, clinically significant glomerular
             disease, urinary tract lithiasis, infection or obstruction, biliary tract lithiasis or
             obstruction;

          5. Hemorrhagic or complicated cysts which might acutely affect kidney function and
             volumes;

          6. QT-related ECG abnormalities;

          7. Cancer and major systemic diseases that could prevent completion of the planned
             follow-up or interfere with data collection or interpretation;

          8. Hypersensitivity to the IMP active substance or to any of the excipients or to
             benzazepine or benzazepine derivatives;

          9. Concomitant treatment with drugs that may affect glomerular hemodynamics during the
             three months before the beginning of the study (including ACE inhibitors, angiotensin
             receptor blockers, aldosterone antagonists and non-steroideal anti-inflammatory
             medications);

         10. Elevated liver enzymes and/or signs or symptoms of liver injury prior to initiation of
             treatment that meet the requirements for permanent discontinuation of tolvaptan

         11. Patients with anuria, volume depletion and hypernatraemia

         12. Patients who cannot perceive or respond to thirst

         13. Ferro-magnetic prosthesis, aneurysm clips, severe claustrophobia or any other
             contraindication to MRI evaluation;

         14. Psychiatric disorders and any condition that could prevent full comprehension of the
             purposes and risks of the study;

         15. Pregnant or lactating;

         16. Participation in another interventional clinical trial within the 4 weeks prior to
             screening.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Giuseppe Remuzzi, MD, , 

Location Countries

Italy

Location Countries

Italy

Administrative Informations


NCT ID

NCT03541447

Organization ID

TOOL

Secondary IDs

2017-004701-40

Responsible Party

Sponsor

Study Sponsor

Mario Negri Institute for Pharmacological Research

Collaborators

 Otsuka Pharmaceutical Italy S.r.l.

Study Sponsor

Giuseppe Remuzzi, MD, Study Chair, CRC per le Malattie Rare Aldo e Cele Daccò


Verification Date

October 2021