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.
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.
At the beginning of the study you will have blood drawn and be asked to complete two 24-hour urine collections. You will be randomized into one of two groups. Group 1 will take Betaine twice per day. Group 2 will take a placebo twice per day.
After two months, you will have blood drawn and be asked to complete two 24-hour urine collections. In addition, you will have an eye examination. You will then stop taking Betaine/placebo for two months. Then you will be placed in the opposite group. Group 1 will take placebo twice per day, and Group 2 will take Betaine twice per day.
After two months after switching groups, you will have blood drawn and be asked to complete two 24-hour urine collections. In addition, you will have an eye examination.
If it is inconvenient for you to return to Mayo Clinic for the required study tests, arrangements will be made to collect the samples at your home medical facility and mail them to Mayo. During the time you are taking the Betaine/placebo, the study coordinator will call every week to see how you are doing, ask if you have missed any doses or noticed any side effects.
You will be in the study for 8 months.
Last updated: 01/02/2013
NCT ID: NCT00283387
IRB Number:2147-05
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