Hyperoxaluria
Conditions
Keywords
Primary Hyperoxaluria
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.
Interventions
DRUGBetaine
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.
DRUGPlacebo
Subjects received oral lactose placebo, in two doses daily, for 2 months.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Orphan Europe
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
6 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Urinary Oxalate Excretion | baseline, 2 months, 6 months | 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. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from Mayo Clinic, Rochester between October 2006 and September 2008.
Pre-assignment details
Fifteen subjects were enrolled, but 2 subjects withdrew prior to group assignment.
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes groups randomized to receive placebo first and betaine first. | 13 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention | Subject non-compliant | 1 | 1 |
| First Intervention | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Continuous | 20.1 years |
| Glomerular Filtration Rate (GFR) | 79 ml/min/1.73 m^2 |
| Number of Subjects on Concomitant Medications Citrate | 3 participants |
| Number of Subjects on Concomitant Medications Neutral Phosphate | 7 participants |
| Number of Subjects on Concomitant Medications Vitamin B6 | 9 participants |
| Region of Enrollment United States | 13 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 13 | 8 / 13 |
| serious Total, serious adverse events | 0 / 13 | 0 / 13 |
Outcome results
Primary
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.
Time frame: baseline, 2 months, 6 months
Population: Per protocol analysis: 10 of 15 enrolled PHI subjects completed the study: 2 withdrew before initiation, 2 were noncompliant, in 1 symptoms led to withdrawal.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Betaine | Urinary Oxalate Excretion | 1.43 umol/mg | Standard Deviation 0.97 |
| Placebo | Urinary Oxalate Excretion | 1.04 umol/mg | Standard Deviation 0.71 |
p-value: 0.007t-test, 2 sided