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Tolvaptan-Octreotide LAR Combination in ADPKD (TOOL)

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ClinicalTrials.gov Identifier: NCT03541447
Recruitment Status : Not yet recruiting
First Posted : May 30, 2018
Last Update Posted : August 31, 2018
Sponsor:
Collaborator:
Otsuka Pharmaceutical Italy S.r.l.
Information provided by (Responsible Party):
Mario Negri Institute for Pharmacological Research

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).


Condition or disease Intervention/treatment Phase
Autosomal Dominant Polycystic Kidney Disease Drug: Tolvaptan Drug: Octreotide LAR Other: Placebo Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Estimated Study Start Date : September 2018
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : September 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Tolvaptan plus Octreotide LAR / Tolvaptan plus Placebo
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)
Drug: Tolvaptan
Starting morning and afternoon doses of 45 and 15 mg, respectively, to be up titrated every two days to 60 and 30 mg and then to 90 and 30 mg, according to tolerability.
Other Name: Jinarc

Drug: Octreotide LAR
A single dose of two 20 mg i.m. injections.
Other Name: Sandostatin LAR

Other: Placebo
A single dose of two 20 mg i.m. injections.
Other Name: NaCl 0.9%

Experimental: Tolvaptan plus placebo/Tolvaptan plus Octreotide LAR
Patients will receive a first 4-week treatment period with Tolvaptan up to 120 mg/die, according to tolerability, and a single dose of placebo (two i.m. injections of 0.9% NaCl solution). 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 Octreotide LAR (two 20 mg i.m. injections).
Drug: Tolvaptan
Starting morning and afternoon doses of 45 and 15 mg, respectively, to be up titrated every two days to 60 and 30 mg and then to 90 and 30 mg, according to tolerability.
Other Name: Jinarc

Drug: Octreotide LAR
A single dose of two 20 mg i.m. injections.
Other Name: Sandostatin LAR

Other: Placebo
A single dose of two 20 mg i.m. injections.
Other Name: NaCl 0.9%




Primary Outcome Measures :
  1. Glomerular Filtration Rate (GFR) [ Time Frame: Changes from 4 weeks before randomization at baseline, 1,4,8,9,12 and 16 weeks after the randomization. ]
    GFR will be assessed by the Iohexol Plasma Clearance Technique


Secondary Outcome Measures :
  1. Total Kidney Volume (TKV) [ Time Frame: Changes from baseline at 4,8,12 and 16 weeks after the randomization. ]
    TKV will be assessed by Magnetic Resonance Imaging (MRI)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

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): NCT03541447


Contacts
Contact: Piero Ruggenenti, MD 003903545351 piero.ruggenenti@marionegri.it
Contact: Norberto Perico, MD 0039035453531 norberto.perico@marionegri.it

Locations
Italy
CRC per le Malattie Rare Aldo e Cele Daccò Not yet recruiting
Ranica, Bergamo, Italy, 24020
Contact: Piero Ruggenenti, MD    003903545351    piero.ruggenenti@marionegri.it   
Contact: Norberto Perico, MD    003903545351    norberto.perico@marionegri.it   
Sponsors and Collaborators
Mario Negri Institute for Pharmacological Research
Otsuka Pharmaceutical Italy S.r.l.
Investigators
Study Chair: Giuseppe Remuzzi, MD CRC per le Malattie Rare Aldo e Cele Daccò

Responsible Party: Mario Negri Institute for Pharmacological Research
ClinicalTrials.gov Identifier: NCT03541447     History of Changes
Other Study ID Numbers: TOOL
2017-004701-40 ( EudraCT Number )
First Posted: May 30, 2018    Key Record Dates
Last Update Posted: August 31, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Mario Negri Institute for Pharmacological Research:
ADPKD, Tolvaptan, Octrotide LAR

Additional relevant MeSH terms:
Kidney Diseases
Polycystic Kidney Diseases
Polycystic Kidney, Autosomal Dominant
Urologic Diseases
Kidney Diseases, Cystic
Abnormalities, Multiple
Congenital Abnormalities
Genetic Diseases, Inborn
Octreotide
Tolvaptan
Gastrointestinal Agents
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Antidiuretic Hormone Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Natriuretic Agents
Physiological Effects of Drugs