Autosomal Dominant Polycystic Kidney DiseasePhase 2TOOLNCT03541447
Tolvaptan-Octreotide LAR Combination in ADPKD
A Phase 2 study testing Tolvaptan and Octreotide LAR in people with Autosomal Dominant Polycystic Kidney Disease, run by Mario Negri Institute for Pharmacological Research at 1 site in Italy.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Autosomal Dominant Polycystic Kidney Disease
- What is being tested?
- Tolvaptan and Octreotide LAR
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 20 participants
- Where
- 1 siteItaly
- Study dates
- 12 Dec 2018to 23 Dec 2021
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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;
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- 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.
Trial locations and contacts
1 site in 1 country.
About this study
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
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).
- Being tested
- Tolvaptan, Octreotide LAR, Placebo
- Keywords
- ADPKD, Tolvaptan, Octrotide LAR
- Medical subject headings
- Polycystic Kidney, Autosomal Dominant
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TolvaptanDrug
Also called Jinarc
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.
Octreotide LARDrug
Also called Sandostatin LAR
A single dose of two 20 mg i.m. injections.
PlaceboOther
Also called NaCl 0.9%
A single dose of two 20 mg i.m. injections.
| Study group | Role | What they receive |
|---|---|---|
| Tolvaptan plus Octreotide LAR / Tolvaptan plus Placebo | Experimental | 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) Receives: Drug: Tolvaptan; Drug: Octreotide LAR; Other: Placebo |
| Tolvaptan plus placebo/Tolvaptan plus Octreotide LAR | Experimental | 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). Receives: Drug: Tolvaptan; Drug: Octreotide LAR; Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Glomerular Filtration Rate (GFR)
GFR will be assessed by the Iohexol Plasma Clearance Technique
Measured: Changes from 4 weeks before randomization at baseline, 1,4,8,9,12 and 16 weeks after the randomization.
Secondary outcomes (1)
Total Kidney Volume (TKV)
TKV will be assessed by Magnetic Resonance Imaging (MRI)
Measured: Changes from baseline at 4,8,12 and 16 weeks after the randomization.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 May 2018
- Study start12 Dec 2018
- Primary completion23 Dec 2021
- Study completion23 Dec 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Autosomal Dominant Polycystic Kidney DiseaseStudies of the same condition, open and under way.
- More trials run by Mario Negri Institute for Pharmacological ResearchThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Collaborators
- Otsuka Pharmaceutical Italy S.r.l.
- Responsible party
- Sponsor
- Investigators
- Giuseppe Remuzzi, MD, Study chair, CRC per le Malattie Rare Aldo e Cele Daccò
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03541447
- Sponsor's protocol ID
- TOOL
- Other IDs
- 2017-004701-40, 2017
- Acronym
- TOOL
- Status last verified
- Nov 2022
- First submitted
- 17 May 2018
- Last updated
- 3 Nov 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
St Pierre K, Cashmore BA, Bolignano D, Zoccali C, Ruospo M, Craig JC, Strippoli GF, Mallett AJ, Green SC, Tunnicliffe DJ. Interventions for preventing the progression of autosomal dominant polycystic kidney disease. Cochrane Database Syst Rev. 2024 Oct 2;10(10):CD010294. doi: 10.1002/14651858.CD010294.pub3.
PubMed 39356039Trillini M, Caroli A, Perico N, Remuzzi A, Brambilla P, Villa G, Perna A, Peracchi T, Rubis N, Martinetti D, Caruso M, Leone VF, Cugini D, Carrara F, Remuzzi G, Ruggenenti P; TOOL Study Group. Effects of Octreotide-Long-Acting Release Added-on Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease: Pilot, Randomized, Placebo-Controlled, Cross-Over Trial. Clin J Am Soc Nephrol. 2023 Feb 1;18(2):223-233. doi: 10.2215/CJN.0000000000000049.
PubMed 36754009
Study at a glance
From the registry record, last updated by the sponsor on 3 Nov 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03541447
- Acronym / sponsor ID
- TOOL / TOOL
- Keywords
- ADPKD, Tolvaptan, Octrotide LAR
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- Mario Negri Institute for Pharmacological ResearchUniversity, hospital or other
- Collaborators
- Otsuka Pharmaceutical Italy S.r.l.
- Study start
- 12 Dec 2018 (actual)
- Primary completion
- 23 Dec 2021 (actual)
- Study completion
- 23 Dec 2021 (actual)
- First posted
- 30 May 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Tolvaptan plus Octreotide LAR / Tolvaptan plus Placebo | Experimental | Drug: Tolvaptan, Drug: Octreotide LAR, Other: PlaceboPatients 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) |
| Tolvaptan plus placebo/Tolvaptan plus Octreotide LAR | Experimental | Drug: Tolvaptan, Drug: Octreotide LAR, Other: PlaceboPatients 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). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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;
Key exclusion criteria (16 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TolvaptanAlso: JinarcStarting 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. | Drug | Tolvaptan plus Octreotide LAR / Tolvaptan plus Placebo, Tolvaptan plus placebo/Tolvaptan plus Octreotide LAR |
| Octreotide LARAlso: Sandostatin LARA single dose of two 20 mg i.m. injections. | Drug | Tolvaptan plus Octreotide LAR / Tolvaptan plus Placebo, Tolvaptan plus placebo/Tolvaptan plus Octreotide LAR |
| PlaceboAlso: NaCl 0.9%A single dose of two 20 mg i.m. injections. | Other | Tolvaptan plus Octreotide LAR / Tolvaptan plus Placebo, Tolvaptan plus placebo/Tolvaptan plus Octreotide LAR |
Primary outcome
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
1 secondary outcome
Total Kidney Volume (TKV)
Time frame: Changes from baseline at 4,8,12 and 16 weeks after the randomization.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Nov 2022.
- Derived from this study: PubMed 39356039St Pierre K, Cashmore BA, Bolignano D, Zoccali C, Ruospo M, Craig JC, Strippoli GF, Mallett AJ, Green SC, Tunnicliffe DJ. Interventions for preventing the progression of autosomal dominant polycystic kidney disease. Cochrane Database Syst Rev. 2024 Oct 2;10(10):CD010294. doi: 10.1002/14651858.CD010294.pub3.
- Derived from this study: PubMed 36754009Trillini M, Caroli A, Perico N, Remuzzi A, Brambilla P, Villa G, Perna A, Peracchi T, Rubis N, Martinetti D, Caruso M, Leone VF, Cugini D, Carrara F, Remuzzi G, Ruggenenti P; TOOL Study Group. Effects of Octreotide-Long-Acting Release Added-on Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease: Pilot, Randomized, Placebo-Controlled, Cross-Over Trial. Clin J Am Soc Nephrol. 2023 Feb 1;18(2):223-233. doi: 10.2215/CJN.0000000000000049.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Giuseppe Remuzzi, MD study chair
CRC per le Malattie Rare Aldo e Cele Daccò
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Tolvaptan and Octreotide LAR in people with Autosomal Dominant Polycystic Kidney Disease, run by Mario Negri Institute for Pharmacological Research at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 3 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03541447, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Nov 2022; AzTrials last refreshed its copy on 4 Nov 2026.