Efficacy of Betaine for Reduction of Urine Oxalate in Patients With Type 1 Primary Hyperoxaluria
Condition: Hyperoxaluria
MeSH terms: Hyperoxaluria, Primary
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Betaine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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.; Subjects received oral lactose placebo, in two doses daily, for 2 months.
Other intervention name(s): Cystadane; Lactose
Intervention MeSH terms: Betaine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Primary Hyperoxaluria