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Tolvaptan-Octreotide LAR Combination in ADPKD (TOOL)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03541447
Recruitment Status : Completed
First Posted : May 30, 2018
Last Update Posted : March 11, 2022
Sponsor:
Collaborator:
Otsuka Pharmaceutical Italy S.r.l.
Information provided by (Responsible Party):
Mario Negri Institute for Pharmacological Research

Tracking Information
First Submitted Date  ICMJE May 17, 2018
First Posted Date  ICMJE May 30, 2018
Last Update Posted Date March 11, 2022
Actual Study Start Date  ICMJE December 12, 2018
Actual Primary Completion Date December 23, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 17, 2018)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 17, 2018)
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)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Tolvaptan-Octreotide LAR Combination in ADPKD
Official Title  ICMJE 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).

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Autosomal Dominant Polycystic Kidney Disease
Intervention  ICMJE
  • 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%
Study Arms  ICMJE
  • 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)
    Interventions:
    • Drug: Tolvaptan
    • Drug: Octreotide LAR
    • Other: Placebo
  • 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).
    Interventions:
    • Drug: Tolvaptan
    • Drug: Octreotide LAR
    • Other: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 17, 2018)
20
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE December 23, 2021
Actual Primary Completion Date December 23, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03541447
Other Study ID Numbers  ICMJE TOOL
2017-004701-40 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party Mario Negri Institute for Pharmacological Research
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Mario Negri Institute for Pharmacological Research
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Otsuka Pharmaceutical Italy S.r.l.
Investigators  ICMJE
Study Chair: Giuseppe Remuzzi, MD CRC per le Malattie Rare Aldo e Cele Daccò
PRS Account Mario Negri Institute for Pharmacological Research
Verification Date March 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP