HyperoxaluriaPhase 1/2NCT02038543
Hydroxyproline Influence on Oxalate Metabolism
A Phase 1/2 study testing Hydroxyproline and Leucine in people with Hyperoxaluria, run by Mayo Clinic at 1 site in United States.
Trial summary
Primary hyperoxaluria is an inborn error of metabolism that results in marked overproduction of oxalate by the liver. The excess oxalate causes kidney failure and can cause severe systemic disease due to oxalate deposition in multiple body tissues. Read more about this study
- Who is it for?
- Ages 15 to 65 years
- Conditions the study is for
- Hyperoxaluria
- What is being tested?
- Hydroxyproline and Leucine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 22 participants
- Where
- 1 siteUnited States
- Study dates
- Sep 2013to Jan 2017
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 15 to 65 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Confirmed diagnosis of primary hyperoxaluria (PH)
- Estimated Glomerular Filtration Rate (eGFR) (by serum creatinine) > 50ml/min/1.73m^2 - Patients with a diagnosis of PH I, PH II, PH III, or Non I/Non II/Non III PH (PH types will be confirmed by DNA)
Who cannot join
- eGFR < 50 ml/min/1.73m^2
- History of liver or kidney transplant
- Primary hyperoxaluria patients who have responded to pyridoxine therapy with reduction of urine oxalate excretion to < 0.45 mmol/1.73m^2/day
- Pregnancy
Trial locations and contacts
1 site in 1 country.
United States1 site
Mayo Clinic Hyperoxaluria Center
Rochester, Minnesota, 55905
About this study
Official title: Influence of Hydroxyproline Plasma Concentration on Its Metabolism to Oxalate
Primary hyperoxaluria is an inborn error of metabolism that results in marked overproduction of oxalate by the liver. The excess oxalate causes kidney failure and can cause severe systemic disease due to oxalate deposition in multiple body tissues.
Metabolic pathways that lead to oxalate are poorly understood, but recent evidence suggests that hydroxyproline may play a role. Sources of hydroxyproline include the diet and bone turnover. If hydroxyproline can be confirmed as a significant factor in primary hyperoxaluria, diet modification might be of value in reducing the severity of disease.
This protocol, in which hydroxyproline labelled with a cold isotope is infused intravenously in patients with primary hyperoxaluria, will allow the researchers to measure the amount of oxalate produced from hydroxyproline. The contribution of hydroxyproline metabolism to the amount of oxalate excreted in urine in will be able to be determined for patients with each of the known types of primary hyperoxaluria.
Read the detailed description
The purpose of this study is to determine the contribution of hydroxyproline metabolism to urinary oxalate and glycolate excretion in patients with primary hyperoxaluria.
Oxalic acid (COOH)2 is an end product of metabolism that is synthesized mainly in the liver. The researchers have estimated that 10 - 20 mg is synthesized in the body of healthy adults each day. The main precursor of oxalate is glyoxylate (CHO•COOH). The bulk of the glyoxylate formed is normally transaminated to glycine (NH2•CH2•COOH) by alanine: glyoxylate aminotransferase (AGT) or reduced to glycolate (CHOH•COOH) by glyoxylate reductase (GR). Less than 10% of the glyoxylate is oxidized to oxalate by lactate dehydrogenase (LDH). In individuals with the disease, primary hyperoxaluria, AGT, GR, or hydroxy-oxoglutarate aldolase (HOGA) enzyme is deficient and the amount of oxalate synthesized by the liver increases to 80 - 300 mg per day. The increased oxalate excreted in urine can cause damage to kidney tissue. Calcium oxalate stones may form in the kidney or calcium oxalate crystals may deposit in renal tubules and the renal parenchyma (nephrocalcinosis). An increased rate of oxalate synthesis could also contribute to idiopathic calcium oxalate stone disease. Understanding the pathways of endogenous oxalate synthesis and identifying strategies that decrease oxalate production could be beneficial for individuals with these diseases.
Hydroxyproline is the primary source of glyoxylate identified in the body. Daily collagen turnover of bone results in the formation of 300 - 450 mg of hydroxyproline, which cannot be re-utilized by the body and is broken down. This metabolism yields 180 - 250 mg of glyoxylate. Further hydroxyproline is obtained from the diet, primarily from meat and gelatin-containing products. The bulk of the glyoxylate formed is converted to glycine by the liver enzyme AGT, some to glycolate and a small amount to oxalate. The proportion of these metabolites is not known with any certainty. In this study, a quantitative estimate of the metabolites formed will provide estimates of the contribution of hydroxyproline turnover to daily oxalate production.
- Conditions
- Hyperoxaluria
- Being tested
- Hydroxyproline and Leucine
- Keywords
- Hyperoxaluria, Oxalate, Primary Hyperoxaluria
- Medical subject headings
- Hyperoxaluria, Hyperoxaluria, Primary
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Hydroxyproline and LeucineDrug
Also called 13C5-hydroxyproline, 2H3-leucine
Subjects will be infused with 13C5-hydroxyproline and 2H3-leucine for 6 hrs in the CRTU. The metabolic flux of 2H3-leucine has been well characterized, and is used as a control when studying the metabolism of trace infusions of labeled amino acids 3. Blood samples will be obtained every 30 min to determine the enrichment of plasma with 13C5-hydroxyproline and 2H3-leucine. Urine collections will be obtained hourly. The fluxes of whole body hydroxyproline and leucine will be calculated
| Study group | Role | What they receive |
|---|---|---|
| Primary hyperoxaluria patients | Experimental | Subjects will be infused with 13C5-hydroxyproline and 2H3-leucine for 6 hrs in the Clinical Research and Trials Unit (CRTU). The metabolic flux of 2H3-leucine has been well characterized, and is used as a control when studying the metabolism of trace infusions of labeled amino acids 3. Blood samples will be obtained every 30 min to determine the enrichment of plasma with 13C5-hydroxyproline and 2H3-leucine. Urine collections will be obtained hourly. The fluxes of whole body hydroxyproline and leucine will be calculated Receives: Drug: Hydroxyproline and Leucine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mean Percent Conversion of Hydroxyproline (Hyp) to Urinary Oxalate (UOx)
The overall contribution of hydroxyproline catabolism to urinary oxalate (UOx) and glycolate (UGlc) excretion is determined by the excess mole percent enrichment of urine with 13C2-oxalate and glycolate corrected for the fraction of labelled [15N,13C5]-Hyp that is circulating in the plasma.
Measured: Participants will be followed for the duration of study infusion and observation, an average of 24 hours.
Secondary outcomes (1)
Mean Percent Conversion of Hydroxyproline (Hyp) to Urinary Glycolate (UGIc)
The overall contribution of Hyp catabolism to urinary oxalate (UOx) and glycolate (UGlc) excretion is determined by the excess mole percent enrichment of urine with 13C2-oxalate and glycolate corrected for the fraction of labelled [15N,13C5]-Hyp that is circulating in the plasma.
Measured: Participants will be followed for the duration of the study infusion and observations, an average of 24 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Jan 2014 (estimated)
- Study startSep 2013
- Primary completionSep 2016
- Study completionJan 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for HyperoxaluriaStudies of the same condition, open and under way.
- More trials run by Mayo ClinicThe 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 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 22 participants (actual)
Sponsor and investigators
- Lead sponsor
- Mayo Clinic
- Sponsor type
- University, hospital or other
- Collaborators
- National Institutes of Health (NIH), Rare Diseases Clinical Research Network, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Responsible party
- Principal investigator, John Lieske, Mayo Clinic
- Investigators
- John C Lieske, MD, Principal investigator, Mayo Clinic
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02038543
- Sponsor's protocol ID
- 13-000150
- Other IDs
- U54DK083908
- Status last verified
- Jun 2017
- First submitted
- 19 Dec 2013
- Last updated
- 2 Jul 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 2 Jul 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Influence of Hydroxyproline Plasma Concentration on Its Metabolism to Oxalate
- ClinicalTrials.gov ID
- NCT02038543
- Acronym / sponsor ID
- 13-000150
- Conditions
- Hyperoxaluria
- Keywords
- Hyperoxaluria, Oxalate, Primary Hyperoxaluria
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 22 participants (actual)
- Lead sponsor
- Mayo ClinicUniversity, hospital or other
- Collaborators
- National Institutes of Health (NIH), Rare Diseases Clinical Research Network, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Study start
- Sep 2013
- Primary completion
- Sep 2016 (actual)
- Study completion
- Jan 2017 (actual)
- First posted
- 16 Jan 2014 (estimated)
- Results
- Posted 2 Jul 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Primary hyperoxaluria is an inborn error of metabolism that results in marked overproduction of oxalate by the liver. The excess oxalate causes kidney failure and can cause severe systemic disease due to oxalate deposition in multiple body tissues.
Metabolic pathways that lead to oxalate are poorly understood, but recent evidence suggests that hydroxyproline may play a role. Sources of hydroxyproline include the diet and bone turnover. If hydroxyproline can be confirmed as a significant factor in primary hyperoxaluria, diet modification might be of value in reducing the severity of disease.
This protocol, in which hydroxyproline labelled with a cold isotope is infused intravenously in patients with primary hyperoxaluria, will allow the researchers to measure the amount of oxalate produced from hydroxyproline. The contribution of hydroxyproline metabolism to the amount of oxalate excreted in urine in will be able to be determined for patients with each of the known types of primary hyperoxaluria.
Detailed description
The purpose of this study is to determine the contribution of hydroxyproline metabolism to urinary oxalate and glycolate excretion in patients with primary hyperoxaluria.
Oxalic acid (COOH)2 is an end product of metabolism that is synthesized mainly in the liver. The researchers have estimated that 10 - 20 mg is synthesized in the body of healthy adults each day. The main precursor of oxalate is glyoxylate (CHO•COOH). The bulk of the glyoxylate formed is normally transaminated to glycine (NH2•CH2•COOH) by alanine: glyoxylate aminotransferase (AGT) or reduced to glycolate (CHOH•COOH) by glyoxylate reductase (GR). Less than 10% of the glyoxylate is oxidized to oxalate by lactate dehydrogenase (LDH). In individuals with the disease, primary hyperoxaluria, AGT, GR, or hydroxy-oxoglutarate aldolase (HOGA) enzyme is deficient and the amount of oxalate synthesized by the liver increases to 80 - 300 mg per day. The increased oxalate excreted in urine can cause damage to kidney tissue. Calcium oxalate stones may form in the kidney or calcium oxalate crystals may deposit in renal tubules and the renal parenchyma (nephrocalcinosis). An increased rate of oxalate synthesis could also contribute to idiopathic calcium oxalate stone disease. Understanding the pathways of endogenous oxalate synthesis and identifying strategies that decrease oxalate production could be beneficial for individuals with these diseases.
Hydroxyproline is the primary source of glyoxylate identified in the body. Daily collagen turnover of bone results in the formation of 300 - 450 mg of hydroxyproline, which cannot be re-utilized by the body and is broken down. This metabolism yields 180 - 250 mg of glyoxylate. Further hydroxyproline is obtained from the diet, primarily from meat and gelatin-containing products. The bulk of the glyoxylate formed is converted to glycine by the liver enzyme AGT, some to glycolate and a small amount to oxalate. The proportion of these metabolites is not known with any certainty. In this study, a quantitative estimate of the metabolites formed will provide estimates of the contribution of hydroxyproline turnover to daily oxalate production.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Primary hyperoxaluria patients | Experimental | Drug: Hydroxyproline and LeucineSubjects will be infused with 13C5-hydroxyproline and 2H3-leucine for 6 hrs in the Clinical Research and Trials Unit (CRTU). The metabolic flux of 2H3-leucine has been well characterized, and is used as a control when studying the metabolism of trace infusions of labeled amino acids 3. Blood samples will be obtained every 30 min to determine the enrichment of plasma with 13C5-hydroxyproline and 2H3-leucine. Urine collections will be obtained hourly. The fluxes of whole body hydroxyproline and leucine will be calculated |
Who may qualify
- Ages
- 15 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (2 listed)
- Confirmed diagnosis of primary hyperoxaluria (PH)
- Estimated Glomerular Filtration Rate (eGFR) (by serum creatinine) > 50ml/min/1.73m^2 - Patients with a diagnosis of PH I, PH II, PH III, or Non I/Non II/Non III PH (PH types will be confirmed by DNA)
Key exclusion criteria (4 listed)
- eGFR < 50 ml/min/1.73m^2
- History of liver or kidney transplant
- Primary hyperoxaluria patients who have responded to pyridoxine therapy with reduction of urine oxalate excretion to < 0.45 mmol/1.73m^2/day
- Pregnancy
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 |
|---|---|---|
| Hydroxyproline and LeucineAlso: 13C5-hydroxyproline, 2H3-leucineSubjects will be infused with 13C5-hydroxyproline and 2H3-leucine for 6 hrs in the CRTU. The metabolic flux of 2H3-leucine has been well characterized, and is used as a control when studying the metabolism of trace infusions of labeled amino acids 3. Blood samples will be obtained every 30 min to determine the enrichment of plasma with 13C5-hydroxyproline and 2H3-leucine. Urine collections will be obtained hourly. The fluxes of whole body hydroxyproline and leucine will be calculated | Drug | Primary hyperoxaluria patients |
Primary outcome
Mean Percent Conversion of Hydroxyproline (Hyp) to Urinary Oxalate (UOx)
Time frame: Participants will be followed for the duration of study infusion and observation, an average of 24 hours.
The overall contribution of hydroxyproline catabolism to urinary oxalate (UOx) and glycolate (UGlc) excretion is determined by the excess mole percent enrichment of urine with 13C2-oxalate and glycolate corrected for the fraction of labelled [15N,13C5]-Hyp that is circulating in the plasma.
1 secondary outcome
Mean Percent Conversion of Hydroxyproline (Hyp) to Urinary Glycolate (UGIc)
Time frame: Participants will be followed for the duration of the study infusion and observations, an average of 24 hours
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Jul 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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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.
John C Lieske, MD principal investigator
Mayo Clinic
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Hydroxyproline and Leucine in people with Hyperoxaluria, run by Mayo Clinic at 1 site in United States.
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 2 inclusion and 4 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 2 Jul 2017. 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 United States. 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 combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
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?
Yes. Results are posted in the registry (first posted 2 Jul 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Mean Percent Conversion of Hydroxyproline (Hyp) to Urinary Oxalate (UOx) (time frame: Participants will be followed for the duration of study infusion and observation, an average of 24 hours.). 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 2 Jul 2017.