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Tolvaptan-Octreotide LAR Combination in ADPKD (TOOL)

Primary Purpose

Autosomal Dominant Polycystic Kidney Disease

Status

Completed

Phase

Phase 2

Locations

Italy

Study Type

Interventional

Intervention

Tolvaptan

Octreotide LAR

Placebo

About this trial

This is an interventional treatment trial for Autosomal Dominant Polycystic Kidney Disease focused on measuring ADPKD, Tolvaptan, Octrotide LAR

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Adult (>18-yr-old) men and women, with a clinical and ultrasonographic diagnosis of ADPKD;
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;
Creatinine clearance > 80 ml/min/1.73m2 measured one to two weeks apart during the pre-screening period;
GFR ≥ 80 ml/min/1.73m2 (by iohexol plasma clearance technique) at screening and baseline evaluations;
TKV ranging between 1000 and 2000 ml at screening (by ultrasound imaging) and at baseline (by MRI) evaluations;
Female participants must be of non-childbearing potential or must agree to abstinence or use a highly effective form of contraception;
Written informed consent.

Exclusion Criteria:

Patients with concomitant systemic, renal parenchymal or urinary tract disease;
Diabetes;
Overt proteinuria (urinary protein excretion rate >1 g/24 hours);
Abnormal urinalysis suggestive of concomitant, clinically significant glomerular disease, urinary tract lithiasis, infection or obstruction, biliary tract lithiasis or obstruction;
Hemorrhagic or complicated cysts which might acutely affect kidney function and volumes;
QT-related ECG abnormalities;
Cancer and major systemic diseases that could prevent completion of the planned follow-up or interfere with data collection or interpretation;
Hypersensitivity to the IMP active substance or to any of the excipients or to benzazepine or benzazepine derivatives;
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);
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
Patients with anuria, volume depletion and hypernatraemia
Patients who cannot perceive or respond to thirst
Ferro-magnetic prosthesis, aneurysm clips, severe claustrophobia or any other contraindication to MRI evaluation;
Psychiatric disorders and any condition that could prevent full comprehension of the purposes and risks of the study;
Pregnant or lactating;
Participation in another interventional clinical trial within the 4 weeks prior to screening.

Sites / Locations

CRC per le Malattie Rare Aldo e Cele Daccò

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Tolvaptan plus Octreotide LAR / Tolvaptan plus Placebo

Tolvaptan plus placebo/Tolvaptan plus Octreotide LAR

Arm 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)

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).

Outcomes

Primary Outcome Measures

Glomerular Filtration Rate (GFR)

GFR will be assessed by the Iohexol Plasma Clearance Technique

Secondary Outcome Measures

Total Kidney Volume (TKV)

TKV will be assessed by Magnetic Resonance Imaging (MRI)

Full Information

NCT ID

NCT03541447

First Posted

May 17, 2018

Last Updated

November 2, 2022

Sponsor

Mario Negri Institute for Pharmacological Research

Collaborators

Otsuka Pharmaceutical Italy S.r.l.

1. Study Identification

Unique Protocol Identification Number

NCT03541447

Brief Title

Tolvaptan-Octreotide LAR Combination in ADPKD

Acronym

TOOL

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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2022

Overall Recruitment Status

Completed

Study Start Date

December 12, 2018 (Actual)

Primary Completion Date

December 23, 2021 (Actual)

Study Completion Date

December 23, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Mario Negri Institute for Pharmacological Research

Collaborators

Otsuka Pharmaceutical Italy S.r.l.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Autosomal Dominant Polycystic Kidney Disease

Keywords

ADPKD, Tolvaptan, Octrotide LAR

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Crossover Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

20 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Tolvaptan plus Octreotide LAR / Tolvaptan plus Placebo

Arm Type

Experimental

Arm Description

Arm Title

Tolvaptan plus placebo/Tolvaptan plus Octreotide LAR

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Tolvaptan

Other Intervention Name(s)

Jinarc

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Octreotide LAR

Other Intervention Name(s)

Sandostatin LAR

Intervention Description

A single dose of two 20 mg i.m. injections.

Intervention Type

Other

Intervention Name(s)

Placebo

Other Intervention Name(s)

NaCl 0.9%

Intervention Description

A single dose of two 20 mg i.m. injections.

Primary Outcome Measure Information:

Title

Glomerular Filtration Rate (GFR)

Description

GFR will be assessed by the Iohexol Plasma Clearance Technique

Time Frame

Changes from 4 weeks before randomization at baseline, 1,4,8,9,12 and 16 weeks after the randomization.

Secondary Outcome Measure Information:

Title

Total Kidney Volume (TKV)

Description

TKV will be assessed by Magnetic Resonance Imaging (MRI)

Time Frame

Changes from baseline at 4,8,12 and 16 weeks after the randomization.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Adult (>18-yr-old) men and women, with a clinical and ultrasonographic diagnosis of ADPKD; 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; Creatinine clearance > 80 ml/min/1.73m2 measured one to two weeks apart during the pre-screening period; GFR ≥ 80 ml/min/1.73m2 (by iohexol plasma clearance technique) at screening and baseline evaluations; TKV ranging between 1000 and 2000 ml at screening (by ultrasound imaging) and at baseline (by MRI) evaluations; Female participants must be of non-childbearing potential or must agree to abstinence or use a highly effective form of contraception; Written informed consent. Exclusion Criteria: Patients with concomitant systemic, renal parenchymal or urinary tract disease; Diabetes; Overt proteinuria (urinary protein excretion rate >1 g/24 hours); Abnormal urinalysis suggestive of concomitant, clinically significant glomerular disease, urinary tract lithiasis, infection or obstruction, biliary tract lithiasis or obstruction; Hemorrhagic or complicated cysts which might acutely affect kidney function and volumes; QT-related ECG abnormalities; Cancer and major systemic diseases that could prevent completion of the planned follow-up or interfere with data collection or interpretation; Hypersensitivity to the IMP active substance or to any of the excipients or to benzazepine or benzazepine derivatives; 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); 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 Patients with anuria, volume depletion and hypernatraemia Patients who cannot perceive or respond to thirst Ferro-magnetic prosthesis, aneurysm clips, severe claustrophobia or any other contraindication to MRI evaluation; Psychiatric disorders and any condition that could prevent full comprehension of the purposes and risks of the study; Pregnant or lactating; Participation in another interventional clinical trial within the 4 weeks prior to screening.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Giuseppe Remuzzi, MD

Organizational Affiliation

CRC per le Malattie Rare Aldo e Cele Daccò

Official's Role

Study Chair

Facility Information:

Facility Name

CRC per le Malattie Rare Aldo e Cele Daccò

City

Ranica

State/Province

Bergamo

ZIP/Postal Code

24020

Country

Italy

12. IPD Sharing Statement

Plan to Share IPD

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Tolvaptan-Octreotide LAR Combination in ADPKD

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