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

NCT00283387 | Completed Phase 2 Results

• 2 other identifiers: 2147-055R01DK073354-04
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

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.

Conditions

Hyperoxaluria

Keywords

Primary Hyperoxaluria

Outcome Measures

Primary Outcomes (1)

• 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.

  baseline, 2 months, 6 months

Study Arms (2)

Betaine

EXPERIMENTAL

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; Drug: Placebo

Placebo

PLACEBO COMPARATOR

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; Drug: Placebo

Interventions

Betaine DRUG

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.

Also known as: Cystadane

Betaine; Placebo

Placebo DRUG

Subjects received oral lactose placebo, in two doses daily, for 2 months.

Also known as: Lactose

Betaine; Placebo

Eligibility Criteria

• Age: 6 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Mayo Clinic: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator
• Orphan Europe: collaborator

Study Sites (1)

Mayo Clinic Hyperoxaluria Center

Rochester, Minnesota, 55905, United States

Location

Related Publications (32)

• Abdelmalek MF, Angulo P, Jorgensen RA, Sylvestre PB, Lindor KD. Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study. Am J Gastroenterol. 2001 Sep;96(9):2711-7. doi: 10.1111/j.1572-0241.2001.04129.x.

  PMID: 11569700 BACKGROUND

• Adamzik M, Schmermund A, Reed JE, Adamzik S, Behrenbeck T, Sheedy PF 2nd. Comparison of two different software systems for electron-beam CT-derived quantification of coronary calcification. Invest Radiol. 1999 Dec;34(12):767-73. doi: 10.1097/00004424-199912000-00006.

  PMID: 10587873 BACKGROUND

• ARCHER HE, DORMER AE, SCOWEN EF, WATTS RW. Primary hyperoxaluria. Lancet. 1957 Aug 17;273(6990):320-2. doi: 10.1016/s0140-6736(57)92210-9. No abstract available.

  PMID: 13464052 BACKGROUND

• Barak AJ, Beckenhauer HC, Badakhsh S, Tuma DJ. The effect of betaine in reversing alcoholic steatosis. Alcohol Clin Exp Res. 1997 Sep;21(6):1100-2.

  PMID: 9309323 BACKGROUND

• Bourot S, Sire O, Trautwetter A, Touze T, Wu LF, Blanco C, Bernard T. Glycine betaine-assisted protein folding in a lysA mutant of Escherichia coli. J Biol Chem. 2000 Jan 14;275(2):1050-6. doi: 10.1074/jbc.275.2.1050.

  PMID: 10625645 BACKGROUND

• Cochat P, Deloraine A, Rotily M, Olive F, Liponski I, Deries N. Epidemiology of primary hyperoxaluria type 1. Societe de Nephrologie and the Societe de Nephrologie Pediatrique. Nephrol Dial Transplant. 1995;10 Suppl 8:3-7. doi: 10.1093/ndt/10.supp8.3.

  PMID: 8592622 BACKGROUND

• 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.

  BACKGROUND

• Diamant S, Eliahu N, Rosenthal D, Goloubinoff P. Chemical chaperones regulate molecular chaperones in vitro and in cells under combined salt and heat stresses. J Biol Chem. 2001 Oct 26;276(43):39586-91. doi: 10.1074/jbc.M103081200. Epub 2001 Aug 21.

  PMID: 11517217 BACKGROUND

• Diamant S, Rosenthal D, Azem A, Eliahu N, Ben-Zvi AP, Goloubinoff P. Dicarboxylic amino acids and glycine-betaine regulate chaperone-mediated protein-disaggregation under stress. Mol Microbiol. 2003 Jul;49(2):401-10. doi: 10.1046/j.1365-2958.2003.03553.x.

  PMID: 12828638 BACKGROUND

• Levine DZ, Nash LA, Chan T, Dubrovskis AH. Proximal bicarbonate reabsorption during Ringer and albumin infusions in the rat. J Clin Invest. 1976 Jun;57(6):1490-7. doi: 10.1172/JCI108419.

  PMID: 932191 BACKGROUND

• Lumb MJ, Birdsey GM, Danpure CJ. Correction of an enzyme trafficking defect in hereditary kidney stone disease in vitro. Biochem J. 2003 Aug 15;374(Pt 1):79-87. doi: 10.1042/BJ20030371.

  PMID: 12737622 BACKGROUND

• Lumb MJ, Danpure CJ. Functional synergism between the most common polymorphism in human alanine:glyoxylate aminotransferase and four of the most common disease-causing mutations. J Biol Chem. 2000 Nov 17;275(46):36415-22. doi: 10.1074/jbc.M006693200.

  PMID: 10960483 BACKGROUND

• Monico CG, Rossetti S, Olson JB, Milliner DS. Pyridoxine effect in type I primary hyperoxaluria is associated with the most common mutant allele. Kidney Int. 2005 May;67(5):1704-9. doi: 10.1111/j.1523-1755.2005.00267.x.

  PMID: 15840016 BACKGROUND

• Purdue PE, Takada Y, Danpure CJ. Identification of mutations associated with peroxisome-to-mitochondrion mistargeting of alanine/glyoxylate aminotransferase in primary hyperoxaluria type 1. J Cell Biol. 1990 Dec;111(6 Pt 1):2341-51. doi: 10.1083/jcb.111.6.2341.

  PMID: 1703535 BACKGROUND

• Rantanen I, Nicander I, Jutila K, Ollmar S, Tenovuo J, Soderling E. Betaine reduces the irritating effect of sodium lauryl sulfate on human oral mucosa in vivo. Acta Odontol Scand. 2002 Oct;60(5):306-10. doi: 10.1080/00016350260248292.

  PMID: 12418722 BACKGROUND

• Santana A, Salido E, Torres A, Shapiro LJ. Primary hyperoxaluria type 1 in the Canary Islands: a conformational disease due to I244T mutation in the P11L-containing alanine:glyoxylate aminotransferase. Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7277-82. doi: 10.1073/pnas.1131968100. Epub 2003 May 30.

  PMID: 12777626 BACKGROUND

• Schwahn BC, Hafner D, Hohlfeld T, Balkenhol N, Laryea MD, Wendel U. Pharmacokinetics of oral betaine in healthy subjects and patients with homocystinuria. Br J Clin Pharmacol. 2003 Jan;55(1):6-13. doi: 10.1046/j.1365-2125.2003.01717.x.

  PMID: 12534635 BACKGROUND

• Voziyan PA, Fisher MT. Polyols induce ATP-independent folding of GroEL-bound bacterial glutamine synthetase. Arch Biochem Biophys. 2002 Jan 15;397(2):293-7. doi: 10.1006/abbi.2001.2620.

  PMID: 11795885 BACKGROUND

• Micromedex Healthcare Series (http://wwwmicromed.mayo.edu).

  BACKGROUND

• 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.

  BACKGROUND

• Smolin LA, Benevenga NJ, Berlow S. The use of betaine for the treatment of homocystinuria. J Pediatr. 1981 Sep;99(3):467-72. doi: 10.1016/s0022-3476(81)80352-6. No abstract available.

  PMID: 7264811 BACKGROUND

• Holme E, Kjellman B, Ronge E. Betaine for treatment of homocystinuria caused by methylenetetrahydrofolate reductase deficiency. Arch Dis Child. 1989 Jul;64(7):1061-4. doi: 10.1136/adc.64.7.1061.

  PMID: 2629632 BACKGROUND

• Wilcken DE, Wilcken B, Dudman NP, Tyrrell PA. Homocystinuria--the effects of betaine in the treatment of patients not responsive to pyridoxine. N Engl J Med. 1983 Aug 25;309(8):448-53. doi: 10.1056/NEJM198308253090802.

  PMID: 6877313 BACKGROUND

• Dudman NP, Guo XW, Gordon RB, Dawson PA, Wilcken DE. Human homocysteine catabolism: three major pathways and their relevance to development of arterial occlusive disease. J Nutr. 1996 Apr;126(4 Suppl):1295S-300S. doi: 10.1093/jn/126.suppl_4.1295S.

  PMID: 8642474 BACKGROUND

• McGregor DO, Dellow WJ, Robson RA, Lever M, George PM, Chambers ST. Betaine supplementation decreases post-methionine hyperhomocysteinemia in chronic renal failure. Kidney Int. 2002 Mar;61(3):1040-6. doi: 10.1046/j.1523-1755.2002.00199.x.

  PMID: 11849459 BACKGROUND

• van Guldener C, Janssen MJ, de Meer K, Donker AJ, Stehouwer CD. Effect of folic acid and betaine on fasting and postmethionine-loading plasma homocysteine and methionine levels in chronic haemodialysis patients. J Intern Med. 1999 Feb;245(2):175-83. doi: 10.1046/j.1365-2796.1999.00430.x.

  PMID: 10081520 BACKGROUND

• van Guldener C, Lambert J, ter Wee PM, Donker AJ, Stehouwer CD. Carotid artery stiffness in patients with end-stage renal disease: no effect of long-term homocysteine-lowering therapy. Clin Nephrol. 2000 Jan;53(1):33-41.

  PMID: 10661480 BACKGROUND

• Matthews A, Johnson TN, Rostami-Hodjegan A, Chakrapani A, Wraith JE, Moat SJ, Bonham JR, Tucker GT. An indirect response model of homocysteine suppression by betaine: optimising the dosage regimen of betaine in homocystinuria. Br J Clin Pharmacol. 2002 Aug;54(2):140-6. doi: 10.1046/j.1365-2125.2002.01620.x.

  PMID: 12207633 BACKGROUND

• Surtees R, Bowron A, Leonard J. Cerebrospinal fluid and plasma total homocysteine and related metabolites in children with cystathionine beta-synthase deficiency: the effect of treatment. Pediatr Res. 1997 Nov;42(5):577-82. doi: 10.1203/00006450-199711000-00004.

  PMID: 9357926 BACKGROUND

• Wendel U, Bremer HJ. Betaine in the treatment of homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency. Eur J Pediatr. 1984 Jun;142(2):147-50. doi: 10.1007/BF00445602.

  PMID: 6381059 BACKGROUND

• Devlin AM, Hajipour L, Gholkar A, Fernandes H, Ramesh V, Morris AA. Cerebral edema associated with betaine treatment in classical homocystinuria. J Pediatr. 2004 Apr;144(4):545-8. doi: 10.1016/j.jpeds.2003.12.041.

  PMID: 15069409 BACKGROUND

• Yaghmai R, Kashani AH, Geraghty MT, Okoh J, Pomper M, Tangerman A, Wagner C, Stabler SP, Allen RH, Mudd SH, Braverman N. Progressive cerebral edema associated with high methionine levels and betaine therapy in a patient with cystathionine beta-synthase (CBS) deficiency. Am J Med Genet. 2002 Feb 15;108(1):57-63. doi: 10.1002/ajmg.10186.

  PMID: 11857551 BACKGROUND

Related Links

• Mayo Clinic Hyperoxaluria Center home page
• Mayo Clinic Hyperoxaluria Center (disease web page)
• Oxalosis and Hyperoxaluria Foundation

MeSH Terms

Conditions

Hyperoxaluria; Hyperoxaluria, Primary

Interventions

Betaine; Lactose

Condition Hierarchy (Ancestors)

Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Trimethyl Ammonium Compounds; Quaternary Ammonium Compounds; Amines; Organic Chemicals; Onium Compounds; Disaccharides; Oligosaccharides; Polysaccharides; Carbohydrates; Sugars

Results Point of Contact

• Title: Dr. Dawn S. Milliner
• Organization: Mayo Clinic

milliner.dawn@mayo.edu

507-284-7431

Study Officials

• Carla G Monico, M.D.

  Mayo Clinic Hyperoxaluria Center, Rochester MN

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: January 26, 2006
• First Posted: January 27, 2006
• Study Start: February 1, 2007
• Primary Completion: September 1, 2011
• Study Completion: September 1, 2011
• Last Updated: December 16, 2013
• Results First Posted: January 1, 2013

Record last verified: 2013-11

Locations

US (1)