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

This study has been completed.
Sponsor:
Collaborators:
Orphan Europe
Information provided by:
Mayo Clinic
ClinicalTrials.gov Identifier:
NCT00283387
First received: January 26, 2006
Last updated: November 21, 2013
Last verified: November 2013
  Purpose

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.


Condition Intervention Phase
Hyperoxaluria
Drug: Betaine
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Efficacy of Betaine for Reduction of Urine Oxalate in Patients With Type 1 Primary Hyperoxaluria

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • Urinary Oxalate Excretion [ Time Frame: baseline, 2 months, 6 months ] [ Designated as safety issue: No ]

    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.



Enrollment: 15
Study Start Date: February 2007
Study Completion Date: September 2011
Primary Completion Date: September 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Betaine
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.
Drug: Betaine
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.
Other Name: Cystadane
Drug: Placebo
Subjects received oral lactose placebo, in two doses daily, for 2 months.
Other Name: Lactose
Placebo Comparator: Placebo
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.
Drug: Betaine
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.
Other Name: Cystadane
Drug: Placebo
Subjects received oral lactose placebo, in two doses daily, for 2 months.
Other Name: Lactose

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.

  Eligibility

Ages Eligible for Study:   6 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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)
  2. Alanine-glyoxylate aminotransferase (AGXT) genotype known
  3. Hyperoxaluria not fully corrected by 3 months of continuous Vitamin B6 (VB6) at doses of 8 mg/kg/d or more
  4. Males or females, 6-70 years of age, inclusive
  5. Preserved renal function, as defined by measured glomerular filtration rate (GFR) > 30 ml/min/1.73 m^2
  6. 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.
  7. Written informed consent for participation in this study.

Exclusion Criteria:

  1. Patients who are fully VB6 responsive (i.e., G170R homozygotes).
  2. Prior recipients of liver transplantation performed for correction of AGT deficiency.
  3. Pregnancy or breastfeeding
  4. Unwillingness of patient and/or partner to use contraception during treatment.
  5. Malignant disease (other than non-melanoma skin cancer) in the previous two years.
  6. Markedly reduced renal function (Stage IV Chronic Kidney Disease or measured or estimated GFR < 30 ml/min/1.73 m^2)
  7. Allergy to betaine or related compounds
  8. History of papilledema or increased intracranial pressure.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00283387

Locations
United States, Minnesota
Mayo Clinic Hyperoxaluria Center
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Mayo Clinic
Orphan Europe
Investigators
Principal Investigator: Carla G Monico, M.D. Mayo Clinic Hyperoxaluria Center, Rochester MN
  More Information

Additional Information:
Publications:
Archer HE, Dormer AE, Scowen EF, and Watts RWE. Primary hyperoxaluria. Lancet: 320-322, 1957.
Danpure CJ and Rumsby G. Enzymology and molecular genetics of primary hyperoxaluria type 1. Consequences for clinical management. In: Calcium Oxalate in Biological Systems, edited by Khan SR. Boca Raton, FL: CRC Press, 1995, p. 189-205.
Berlow S, Bachman RP, Berry GT, Donnell GN, Grix A, Levitsky LL, Hoganson G, Levy HL. Betaine therapy in homocystinemia. Brain Dysfunct 2:10-24, 1989.

Responsible Party: Dr. Carla G. Monico, Mayo Clinic
ClinicalTrials.gov Identifier: NCT00283387     History of Changes
Other Study ID Numbers: 2147-05, 5R01DK073354-04
Study First Received: January 26, 2006
Results First Received: November 1, 2012
Last Updated: November 21, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Mayo Clinic:
Primary Hyperoxaluria

Additional relevant MeSH terms:
Hyperoxaluria, Primary
Carbohydrate Metabolism, Inborn Errors
Genetic Diseases, Inborn
Hyperoxaluria
Kidney Diseases
Metabolic Diseases
Metabolism, Inborn Errors
Urologic Diseases
Betaine
Antimetabolites
Gastrointestinal Agents
Hypolipidemic Agents
Lipid Regulating Agents
Lipotropic Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014