NephrolithiasisPhase 2LIMONENCT01217372
Nephrolithiasis Prevention by Lemon Juice
A Phase 2 study testing Lemon supplementation in people with Nephrolithiasis, run by Mario Negri Institute for Pharmacological Research at 1 site in Italy.
Trial summary
Calcium oxalate nephrolithiasis is a relatively common disease. The prevalence in the general population may range from 10 to 12 percent, and 0.4 to 1 percent of new cases are reported every year according to different series. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Nephrolithiasis
- What is being tested?
- Lemon supplementation
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 203 participants
- Where
- 1 siteItaly
- Study dates
- Jan 2009to 16 Feb 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 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- male and female >18 years
- history of recurrent nephrolithiasis, with one o more calcium oxalate or mixed (calcium oxalate and phosphate, calcium oxalate and uric acid) stone formation over the last 5 years
- at least one kidney stone at baseline documented by renal echography and/or X-ray evaluation.
- written informed consent
Who cannot join
- Obstructive uropathy, chronic urosepsis, renal failure (serum creatinine >1.8 mg/dl), renal tubular acidosis, primary hyperparathyroidism, primary hyperoxaluria, pure uric acid and cystine stones, medullary sponge kidney
- lithotripsy treatment within the last 6 months
- active peptic ulcer disease, gastric esophagus reflux
- concomitant clinical conditions that might affect completion of the study or jeopardize data interpretation
- pharmacological therapy for stone disease over the last month
- impossibility to assess the number of kidney stones
- inability to provide an informed consent
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Prospective, Randomized, Open Blind Endpoint (Probe) Trial to Assess the Possibility to Prevent Stone Recurrence by Lemon Juice Supplementation in Patients With Recurrent Calcium Oxalate Nephrolithiasis (LIMONE Study)
Calcium oxalate nephrolithiasis is a relatively common disease. The prevalence in the general population may range from 10 to 12 percent, and 0.4 to 1 percent of new cases are reported every year according to different series. Without specific pharmacological therapy, the recurrence rate in patient with established diagnosis of nephrolithiasis is extremely high and may range from 15 to 20 percent per year, with a cumulative incidence at five years ranging from 27 to 50 percent.Although genetic factors play an important role in the development of nephrolithiasis, environmental factors such as diet also appear to affect stone formation. Potassium citrate is also effective in preventing stone recurrence in patients with calcium oxalate nephrolithiasis. Low tolerability, however, may remarkably limit the use of these medication. Citrus fruits are a natural rich source of citrate and diet supplementation with juice of citrus fruits may represent a valuable alternative option to supply citrate without exposing the patients to the adverse effects of citrate containing medications. Among the most commonly consumed citrus fruits, lemons contain the greatest concentrations of citric acid (49,2 g/Kg);a half cup of pure lemon juice can provide a daily amount of citrate comparable to that of a standard daily dose of alkali citrate medications.
A few studies tried to evaluate the effects of lemon juice supplementation in patients with calcium oxalate nephrolithiasis, but the findings were flawed by the retrospective, observational design of the study or by the too small sample size that limited the power of statistical analyses and the reliability of the results. This study will be primarily aimed at evaluating whether lemon juice added to standard diet recommendations compared to diet recommendations alone may reduce the risk of new stone formation in patients with recurrent idiopathic calcium oxalate nephrolithiasis. Secondarily, the study will evaluate the effects of lemon juice supplementation on complications of nephrolithiasis such as urinary tract infections, colic symptoms, and hospitalizations for stone disruption or removal, as well as the effects on urinary factors (such as urinary citrate, oxalate, calcium excretion or pH) that may favor or limit stone formations and the relationships between these effects and the risk of stone recurrence.
Read the detailed description
BACKGROUND Calcium oxalate nephrolithiasis is a relatively common disease. The prevalence in the general population may range from 10 to 12 percent, and 0.4 to 1 percent of new cases are reported every year according to different series. Without specific pharmacological therapy, the recurrence rate in patient with established diagnosis of nephrolithiasis is extremely high and may range from 15 to 20 percent per year, with a cumulative incidence at five years ranging from 27 to 50 percent.
Although genetic factors play an important role in the development of nephrolithiasis, environmental factors such as diet also appear to affect stone formation. Diet based on restricted intake of animal proteins and salt, combined with a normal calcium intake, may reduce the risk of stone formation. However, the efficacy in preventing stone recurrences is limited, in particular in repeated stone formers.
Potassium citrate is also effective in preventing stone recurrence in patients with calcium oxalate nephrolithiasis. Low tolerability, however, may remarkably limit the use of these medication.
Citrus fruits are a natural rich source of citrate and diet supplementation with juice of citrus fruits may represent a valuable alternative option to supply citrate without exposing the patients to the adverse effects of citrate containing medications.
Among the most commonly consumed citrus fruits, lemons contain the greatest concentrations of citric acid (49,2 g/Kg), nearly 5 times the concentrations in the orange. A half cup of pure lemon juice can provide a daily amount of citrate comparable to that of a standard daily dose of alkali citrate medications. The citrate supplied with the juice that escapes metabolic degradation in vivo is excreted unchanged in the urine where may prevent the tendency of calcium oxalate salts to precipitate. Lemon juice supplementation may also have the additional advantage of reducing urinary calcium excretion without affecting oxalate excretion, while orange juice does not affect urinary calcium and may increase urinary oxalate.
A few studies tried to evaluate the effects of lemon juice supplementation in patients with calcium oxalate nephrolithiasis, but the findings were flawed by the retrospective, observational design of the study or by the too small sample size that limited the power of statistical analyses and the reliability of the results. Thus, the protective effect of lemon juice supplementation against recurrence of stones in patients with calcium oxalate nephrolithiasis is worth investigating in adequately powered and designed trials.
AIM The study will be primarily aimed at evaluating whether lemon juice added to standard diet recommendations compared to diet recommendations alone may reduce the risk of new stone formation in patients with recurrent idiopathic calcium oxalate nephrolithiasis. Secondarily, the study will evaluate the effects of lemon juice supplementation on complications of nephrolithiasis such as urinary tract infections, colic symptoms, and hospitalizations for stone disruption or removal, as well as the effects on urinary factors (such as urinary citrate, oxalate, calcium excretion or pH) that may favor or limit stone formations and the relationships between these effects and the risk of stone recurrence.
DESIGN
According to urinary citrate excretion at baseline evaluation patients satisfying the selection criteria will be stratified into two strata:
Stratum 1: Hypocitraturia (urinary citrate excretion >320 mg/24 h) Stratum 2: Normocitraturia (urinary citrate excretion <320 mg/24 h) Within each stratum, patients will be randomized on a 1:1 basis to two-year treatment with lemon juice supplemented to standard recommended diet or to standard diet alone. All patients in the hypocitraturic stratum will also be prescribed potassium citrate 2g twice daily. Due to the Prospective, Randomized, Open, Blind Endpoint (PROBE) design of the study, patients and physicians in charge of patient care and monitoring will be aware of patient treatment, while all the Investigators involved in data handling and analyses will be blinded to patient treatment allocation.
101 patients per group will have to be included. Thus, a total of 202 patients will have to be randomized.
- Conditions
- Nephrolithiasis
- Being tested
- Lemon supplementation
- Keywords
- Recurrent idiopathic calcium oxalate nephrolithiasis.
- Medical subject headings
- Nephrolithiasis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Lemon supplementationDietary supplement
60 ml of lemon juice twice daily (an amount expected to provide 6 grams or 92 mEq of citric acid per day)
| Study group | Role | What they receive |
|---|---|---|
| Lemon supplementation YES | Experimental | 60 ml of lemon juice twice daily (an amount expected to provide 6 grams or 92 mEq of citric acid per day) Receives: Dietary Supplement: Lemon supplementation |
| Lemon supplementation NO | No intervention | No lemon supplementation |
What is being measured
The primary outcome is the main question the study is designed to answer.
Spontaneous passage of stone or gravel.
Measured: At 6 month.
Appearance of new stones.
Measured: At 6 month.
More than 30 percent increase in pre-existing stone size
Measured: At 6 month.
Spontaneous passage of stone or gravel.
Measured: At 12 month.
Spontaneous passage of stone or gravel.
Measured: At 24 month.
Appearance of new stones.
Measured: At 12 month.
Appearance of new stones.
Measured: At 24 month.
More than 30 percent increase in pre-existing stone size
Measured: At 12 month.
More than 30 percent increase in pre-existing stone size
Measured: At 24 month.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Oct 2010 (estimated)
- Study startJan 2009
- Primary completion16 Feb 2021
- Study completion16 Feb 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for NephrolithiasisStudies of the same condition, open and under way.
- 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
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 203 participants (actual)
Sponsor and investigators
- Lead sponsor
- Mario Negri Institute for Pharmacological Research
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01217372
- Sponsor's protocol ID
- LIMONE
- Acronym
- LIMONE
- Status last verified
- Mar 2021
- First submitted
- 30 Sep 2010
- Last updated
- 1 Apr 2021
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 1 Apr 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Prospective, Randomized, Open Blind Endpoint (Probe) Trial to Assess the Possibility to Prevent Stone Recurrence by Lemon Juice Supplementation in Patients With Recurrent Calcium Oxalate Nephrolithiasis (LIMONE Study)
- ClinicalTrials.gov ID
- NCT01217372
- Acronym / sponsor ID
- LIMONE / LIMONE
- Conditions
- Nephrolithiasis
- Keywords
- Recurrent idiopathic calcium oxalate nephrolithiasis.
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 203 participants (actual)
- Lead sponsor
- Mario Negri Institute for Pharmacological ResearchUniversity, hospital or other
- Study start
- Jan 2009 (actual)
- Primary completion
- 16 Feb 2021 (actual)
- Study completion
- 16 Feb 2021 (actual)
- First posted
- 8 Oct 2010 (estimated)
- 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.
Calcium oxalate nephrolithiasis is a relatively common disease. The prevalence in the general population may range from 10 to 12 percent, and 0.4 to 1 percent of new cases are reported every year according to different series. Without specific pharmacological therapy, the recurrence rate in patient with established diagnosis of nephrolithiasis is extremely high and may range from 15 to 20 percent per year, with a cumulative incidence at five years ranging from 27 to 50 percent.Although genetic factors play an important role in the development of nephrolithiasis, environmental factors such as diet also appear to affect stone formation. Potassium citrate is also effective in preventing stone recurrence in patients with calcium oxalate nephrolithiasis. Low tolerability, however, may remarkably limit the use of these medication. Citrus fruits are a natural rich source of citrate and diet supplementation with juice of citrus fruits may represent a valuable alternative option to supply citrate without exposing the patients to the adverse effects of citrate containing medications. Among the most commonly consumed citrus fruits, lemons contain the greatest concentrations of citric acid (49,2 g/Kg);a half cup of pure lemon juice can provide a daily amount of citrate comparable to that of a standard daily dose of alkali citrate medications.
A few studies tried to evaluate the effects of lemon juice supplementation in patients with calcium oxalate nephrolithiasis, but the findings were flawed by the retrospective, observational design of the study or by the too small sample size that limited the power of statistical analyses and the reliability of the results. This study will be primarily aimed at evaluating whether lemon juice added to standard diet recommendations compared to diet recommendations alone may reduce the risk of new stone formation in patients with recurrent idiopathic calcium oxalate nephrolithiasis. Secondarily, the study will evaluate the effects of lemon juice supplementation on complications of nephrolithiasis such as urinary tract infections, colic symptoms, and hospitalizations for stone disruption or removal, as well as the effects on urinary factors (such as urinary citrate, oxalate, calcium excretion or pH) that may favor or limit stone formations and the relationships between these effects and the risk of stone recurrence.
Detailed description
BACKGROUND Calcium oxalate nephrolithiasis is a relatively common disease. The prevalence in the general population may range from 10 to 12 percent, and 0.4 to 1 percent of new cases are reported every year according to different series. Without specific pharmacological therapy, the recurrence rate in patient with established diagnosis of nephrolithiasis is extremely high and may range from 15 to 20 percent per year, with a cumulative incidence at five years ranging from 27 to 50 percent.
Although genetic factors play an important role in the development of nephrolithiasis, environmental factors such as diet also appear to affect stone formation. Diet based on restricted intake of animal proteins and salt, combined with a normal calcium intake, may reduce the risk of stone formation. However, the efficacy in preventing stone recurrences is limited, in particular in repeated stone formers.
Potassium citrate is also effective in preventing stone recurrence in patients with calcium oxalate nephrolithiasis. Low tolerability, however, may remarkably limit the use of these medication.
Citrus fruits are a natural rich source of citrate and diet supplementation with juice of citrus fruits may represent a valuable alternative option to supply citrate without exposing the patients to the adverse effects of citrate containing medications.
Among the most commonly consumed citrus fruits, lemons contain the greatest concentrations of citric acid (49,2 g/Kg), nearly 5 times the concentrations in the orange. A half cup of pure lemon juice can provide a daily amount of citrate comparable to that of a standard daily dose of alkali citrate medications. The citrate supplied with the juice that escapes metabolic degradation in vivo is excreted unchanged in the urine where may prevent the tendency of calcium oxalate salts to precipitate. Lemon juice supplementation may also have the additional advantage of reducing urinary calcium excretion without affecting oxalate excretion, while orange juice does not affect urinary calcium and may increase urinary oxalate.
A few studies tried to evaluate the effects of lemon juice supplementation in patients with calcium oxalate nephrolithiasis, but the findings were flawed by the retrospective, observational design of the study or by the too small sample size that limited the power of statistical analyses and the reliability of the results. Thus, the protective effect of lemon juice supplementation against recurrence of stones in patients with calcium oxalate nephrolithiasis is worth investigating in adequately powered and designed trials.
AIM The study will be primarily aimed at evaluating whether lemon juice added to standard diet recommendations compared to diet recommendations alone may reduce the risk of new stone formation in patients with recurrent idiopathic calcium oxalate nephrolithiasis. Secondarily, the study will evaluate the effects of lemon juice supplementation on complications of nephrolithiasis such as urinary tract infections, colic symptoms, and hospitalizations for stone disruption or removal, as well as the effects on urinary factors (such as urinary citrate, oxalate, calcium excretion or pH) that may favor or limit stone formations and the relationships between these effects and the risk of stone recurrence.
DESIGN
According to urinary citrate excretion at baseline evaluation patients satisfying the selection criteria will be stratified into two strata:
Stratum 1: Hypocitraturia (urinary citrate excretion >320 mg/24 h) Stratum 2: Normocitraturia (urinary citrate excretion <320 mg/24 h) Within each stratum, patients will be randomized on a 1:1 basis to two-year treatment with lemon juice supplemented to standard recommended diet or to standard diet alone. All patients in the hypocitraturic stratum will also be prescribed potassium citrate 2g twice daily. Due to the Prospective, Randomized, Open, Blind Endpoint (PROBE) design of the study, patients and physicians in charge of patient care and monitoring will be aware of patient treatment, while all the Investigators involved in data handling and analyses will be blinded to patient treatment allocation.
101 patients per group will have to be included. Thus, a total of 202 patients will have to be randomized.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Lemon supplementation YES | Experimental | Dietary Supplement: Lemon supplementation60 ml of lemon juice twice daily (an amount expected to provide 6 grams or 92 mEq of citric acid per day) |
| Lemon supplementation NO | No intervention | –No lemon supplementation |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- male and female >18 years
- history of recurrent nephrolithiasis, with one o more calcium oxalate or mixed (calcium oxalate and phosphate, calcium oxalate and uric acid) stone formation over the last 5 years
- at least one kidney stone at baseline documented by renal echography and/or X-ray evaluation.
- written informed consent
Key exclusion criteria (7 listed)
- Obstructive uropathy, chronic urosepsis, renal failure (serum creatinine >1.8 mg/dl), renal tubular acidosis, primary hyperparathyroidism, primary hyperoxaluria, pure uric acid and cystine stones, medullary sponge kidney
- lithotripsy treatment within the last 6 months
- active peptic ulcer disease, gastric esophagus reflux
- concomitant clinical conditions that might affect completion of the study or jeopardize data interpretation
- pharmacological therapy for stone disease over the last month
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 |
|---|---|---|
| Lemon supplementation60 ml of lemon juice twice daily (an amount expected to provide 6 grams or 92 mEq of citric acid per day) | Dietary supplement | Lemon supplementation YES |
Primary outcome
Spontaneous passage of stone or gravel.
Time frame: At 6 month.
Appearance of new stones.
Time frame: At 6 month.
More than 30 percent increase in pre-existing stone size
Time frame: At 6 month.
Spontaneous passage of stone or gravel.
Time frame: At 12 month.
Spontaneous passage of stone or gravel.
Time frame: At 24 month.
Appearance of new stones.
Time frame: At 12 month.
Appearance of new stones.
Time frame: At 24 month.
More than 30 percent increase in pre-existing stone size
Time frame: At 12 month.
More than 30 percent increase in pre-existing stone size
Time frame: At 24 month.
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 1 Apr 2021.
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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.
The record lists no contact. Use the official record to reach the sponsor.
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 Lemon supplementation in people with Nephrolithiasis, 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 4 inclusion and 7 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 1 Apr 2021. 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?
Spontaneous passage of stone or gravel. (time frame: At 6 month.). The study lists 9 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 1 Apr 2021.