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Efficacy of Betaine for Reduction of Urine Oxalate in Patients With Type 1 Primary Hyperoxaluria

Primary Purpose

Hyperoxaluria

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Betaine
Placebo
Sponsored by
Mayo Clinic
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hyperoxaluria focused on measuring Primary Hyperoxaluria

Eligibility Criteria

6 Years - 70 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: A definitive diagnosis of Type 1 Primary Hyperoxaluria (PHI) as confirmed by hepatic angiotensinogen (AGT) deficiency, biochemical criteria (marked hyperoxaluria and hyperglycolic aciduria) or mutation analysis (having a known PHI mutation) Alanine-glyoxylate aminotransferase (AGXT) genotype known Hyperoxaluria not fully corrected by 3 months of continuous Vitamin B6 (VB6) at doses of 8 mg/kg/d or more Males or females, 6-70 years of age, inclusive Preserved renal function, as defined by measured glomerular filtration rate (GFR) > 30 ml/min/1.73 m^2 Sexually active female patients of childbearing potential must practice adequate contraception during the treatment period and for 6 months after discontinuation of therapy. A pregnancy test obtained at entry prior to the initiation of treatment must be negative. Female patients must not be breast-feeding. Sexually active male patients must practice acceptable methods of contraception during the treatment period and for 6 months after discontinuation of therapy. Written informed consent for participation in this study. Exclusion Criteria: Patients who are fully VB6 responsive (i.e., G170R homozygotes). Prior recipients of liver transplantation performed for correction of AGT deficiency. Pregnancy or breastfeeding Unwillingness of patient and/or partner to use contraception during treatment. Malignant disease (other than non-melanoma skin cancer) in the previous two years. Markedly reduced renal function (Stage IV Chronic Kidney Disease or measured or estimated GFR < 30 ml/min/1.73 m^2) Allergy to betaine or related compounds History of papilledema or increased intracranial pressure.

Sites / Locations

  • Mayo Clinic Hyperoxaluria Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Betaine

Placebo

Arm Description

Subjects were randomly assigned oral betaine 12 grams/day in subjects younger than 10 years of age, and 20 grams/day in subjects 10 years of age and older, in two divided doses. This was followed by a 2 month washout period. Subjects then received the alternative study medication, oral lactose placebo, in two doses daily, for 2 months.

Subjects were randomly assigned to receive oral lactose placebo, in two doses daily, for 2 months. This was followed by a 2 month washout period. Subjects then received the alternative study medication, oral betaine 12 grams/day in subjects younger than 10 years of age, and 20 grams/day in subjects 10 years of age and older, in two divided doses, for 2 months.

Outcomes

Primary Outcome Measures

Urinary Oxalate Excretion
The patients were randomly assigned oral betaine or placebo for 2 months, followed by a 2 month washout. Each patient then received the alternate study medication for 2 months. Urinary Oxalate Excretion was measured by oxalate oxidase. Two 24 hour urine collections were obtained at baseline, and during the eighth week of each study period.

Secondary Outcome Measures

Full Information

First Posted
January 26, 2006
Last Updated
November 21, 2013
Sponsor
Mayo Clinic
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Orphan Europe
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1. Study Identification

Unique Protocol Identification Number
NCT00283387
Brief Title
Efficacy of Betaine for Reduction of Urine Oxalate in Patients With Type 1 Primary Hyperoxaluria
Official Title
Efficacy of Betaine for Reduction of Urine Oxalate in Patients With Type 1 Primary Hyperoxaluria
Study Type
Interventional

2. Study Status

Record Verification Date
November 2013
Overall Recruitment Status
Completed
Study Start Date
February 2007 (undefined)
Primary Completion Date
September 2011 (Actual)
Study Completion Date
September 2011 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
Mayo Clinic
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Orphan Europe

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The aim of this study is to assess the efficacy and safety of betaine in reducing urine oxalate excretion of Type 1 Primary Hyperoxaluria (PHI) patients. Hypothesis: Betaine will effectively reduce urine oxalate excretion in Primary Hyperoxaluria Type I patients.
Detailed Description
Our prior genotyping results have shown an association between the G170R allele and the clinical response to VB6. Patients homozygous for this change show a complete response and heterozygous patients a partial response. Since VB6 is a safe and completely effective treatment for patients homozygous for G170R, we will not study betaine in this group. Instead, 20 participants older than 6 years of age who are G170R compound heterozygous, non-G170R missense or truncating sequence change homozygous or heterozygous, will be selected for enrollment. Participants in whom VB6 provides a partial reduction in urine oxalate excretion (compound heterozygotes for the G170R mutation) will be maintained on a stable dose of VB6 (8 mg/kg/d) for two months before and throughout betaine treatment. Those who have demonstrated no response to VB6 will receive betaine alone. Participants will be randomized to receive either betaine or placebo for the first 2 month arm of the study. Following 2 months of treatment and 2 months of washout, each participant will cross over to the other arm of the study. The other arm will consist of the participant being on 2 months of treatment of whatever they were not taking in the first arm (betaine vs. placebo). Neither the study staff nor the participant will know whether the participant is taking betaine for the first or second arm of the study, or the placebo for the first or second arm of the study. Only the pharmacy will know this. Prior to the study, a complete history and physical examination, and baseline laboratory studies pertinent to the routine care of primary hyperoxaluria patients will be performed (Complete Blood Count (CBC) with differential, chemistry group, electrolytes, plasma oxalate and creatinine clearance, urinary supersaturation). All women capable of reproduction will receive a pregnancy test prior to enrollment. Participant will complete two 24-hour urine collections for calcium oxalate super-saturation (includes 24-hour urine oxalate excretion) at baseline, inclusive of creatinine determination for assessment of completeness. They will then begin Cystadane anhydrous solution (12 grams/day in subjects younger than 10 years of age, and 20 grams/day in subjects 10 years of age and older, in two divided doses). These doses of betaine have been shown to effectively treat pediatric patients with VB6-resistant homocystinuria and reverse Nonalcoholic Steatohepatitis (NASH) in adult patients, so we expect they will achieve sufficient intra-hepatocyte levels to have an effect in PHI. A sample of each 24-hour urine will be stored frozen (-80ºC) to allow determination of indicators of oxidant stress, should urinary oxalate fall. If effective, betaine could represent a new and safe treatment option for a subset of PHI patients, particularly those with either partially VB6 responsive or VB6 refractory hyperoxaluria, or those with adverse effects such as peripheral neuropathy from large doses of VB6. We do not anticipate any adverse medication effects specific to primary hyperoxaluria. However, as an extra safeguard for children with PHI, ten subjects older than 15 years of age will be tested first and if the agent is well tolerated in PHI patients, pediatric subjects older than 6 years of age will then be recruited for participation.

6. Conditions and Keywords

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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
15 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Betaine
Arm Type
Experimental
Arm Description
Subjects were randomly assigned oral betaine 12 grams/day in subjects younger than 10 years of age, and 20 grams/day in subjects 10 years of age and older, in two divided doses. This was followed by a 2 month washout period. Subjects then received the alternative study medication, oral lactose placebo, in two doses daily, for 2 months.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Subjects were randomly assigned to receive oral lactose placebo, in two doses daily, for 2 months. This was followed by a 2 month washout period. Subjects then received the alternative study medication, oral betaine 12 grams/day in subjects younger than 10 years of age, and 20 grams/day in subjects 10 years of age and older, in two divided doses, for 2 months.
Intervention Type
Drug
Intervention Name(s)
Betaine
Other Intervention Name(s)
Cystadane
Intervention Description
Subjects were randomly assigned oral betaine 12 grams/day in subjects younger than 10 years of age, and 20 grams/day in subjects 10 years of age and older, in two divided doses, for 2 months.
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Lactose
Intervention Description
Subjects received oral lactose placebo, in two doses daily, for 2 months.
Primary Outcome Measure Information:
Title
Urinary Oxalate Excretion
Description
The patients were randomly assigned oral betaine or placebo for 2 months, followed by a 2 month washout. Each patient then received the alternate study medication for 2 months. Urinary Oxalate Excretion was measured by oxalate oxidase. Two 24 hour urine collections were obtained at baseline, and during the eighth week of each study period.
Time Frame
baseline, 2 months, 6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: A definitive diagnosis of Type 1 Primary Hyperoxaluria (PHI) as confirmed by hepatic angiotensinogen (AGT) deficiency, biochemical criteria (marked hyperoxaluria and hyperglycolic aciduria) or mutation analysis (having a known PHI mutation) Alanine-glyoxylate aminotransferase (AGXT) genotype known Hyperoxaluria not fully corrected by 3 months of continuous Vitamin B6 (VB6) at doses of 8 mg/kg/d or more Males or females, 6-70 years of age, inclusive Preserved renal function, as defined by measured glomerular filtration rate (GFR) > 30 ml/min/1.73 m^2 Sexually active female patients of childbearing potential must practice adequate contraception during the treatment period and for 6 months after discontinuation of therapy. A pregnancy test obtained at entry prior to the initiation of treatment must be negative. Female patients must not be breast-feeding. Sexually active male patients must practice acceptable methods of contraception during the treatment period and for 6 months after discontinuation of therapy. Written informed consent for participation in this study. Exclusion Criteria: Patients who are fully VB6 responsive (i.e., G170R homozygotes). Prior recipients of liver transplantation performed for correction of AGT deficiency. Pregnancy or breastfeeding Unwillingness of patient and/or partner to use contraception during treatment. Malignant disease (other than non-melanoma skin cancer) in the previous two years. Markedly reduced renal function (Stage IV Chronic Kidney Disease or measured or estimated GFR < 30 ml/min/1.73 m^2) Allergy to betaine or related compounds History of papilledema or increased intracranial pressure.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Carla G Monico, M.D.
Organizational Affiliation
Mayo Clinic Hyperoxaluria Center, Rochester MN
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mayo Clinic Hyperoxaluria Center
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States

12. IPD Sharing Statement

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Links:
URL
http://www.mayoclinic.org/hyperoxaluria/
Description
Mayo Clinic Hyperoxaluria Center (disease web page)
URL
http://www.ohf.org
Description
Oxalosis and Hyperoxaluria Foundation

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Efficacy of Betaine for Reduction of Urine Oxalate in Patients With Type 1 Primary Hyperoxaluria

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