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

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00283387
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH), Orphan Europe (Other)
• Enrollment: 15
• Location: 1
• Arms: 2
• Duration (Months): 55
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Hyperoxaluria	Drug: Betaine; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Efficacy of Betaine for Reduction of Urine Oxalate in Patients With Type 1 Primary Hyperoxaluria
• Study Start Date: Feb 1, 2007
• Actual Primary Completion Date: Sep 1, 2011
• Actual Study Completion Date: Sep 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
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 Names: Cystadane ; Drug: Placebo; Subjects received oral lactose placebo, in two doses daily, for 2 months.; Other Names: 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 Names: Cystadane ; Drug: Placebo; Subjects received oral lactose placebo, in two doses daily, for 2 months.; Other Names: Lactose

Outcome Measures

Primary Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Hyperoxaluria Center	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Carla G Monico, M.D., Mayo Clinic Hyperoxaluria Center, Rochester MN

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

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

Publications

• 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.
• 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.
• ARCHER HE, DORMER AE, SCOWEN EF, WATTS RW. Primary hyperoxaluria. Lancet. 1957 Aug 17;273(6990):320-2.
• 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.
• 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.
• Bourot S, Sire O, Trautwetter A, Touzé 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.
• Cochat P, Deloraine A, Rotily M, Olive F, Liponski I, Deries N. Epidemiology of primary hyperoxaluria type 1. Société de Néphrologie and the Société de Néphrologie Pédiatrique. Nephrol Dial Transplant. 1995;10 Suppl 8:3-7.
• 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.
• 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.
• 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. Epub 2001 Aug 21.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Micromedex Healthcare Series (http://wwwmicromed.mayo.edu).
• 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.
• 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.
• Rantanen I, Nicander I, Jutila K, Ollmar S, Tenovuo J, Söderling 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.
• 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. Epub 2003 May 30.
• 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.
• Smolin LA, Benevenga NJ, Berlow S. The use of betaine for the treatment of homocystinuria. J Pediatr. 1981 Sep;99(3):467-72.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

• ClinicalTrials.gov Identifier: NCT00283387
• Other Study ID Numbers: 2147-05; 5R01DK073354-04
• First Posted: Jan 27, 2006
• Last Update Posted: Dec 16, 2013
• Last Verified: Nov 1, 2013

• Keywords provided by , ,: Primary Hyperoxaluria
• Additional relevant MeSH terms: Hyperoxaluria, Primary; Betaine

Study Results

Participant Flow

Recruitment Details	Subjects were recruited from Mayo Clinic, Rochester between October 2006 and September 2008.
Pre-assignment Detail	Fifteen subjects were enrolled, but 2 subjects withdrew prior to group assignment.

Arm/Group Title	Betaine First, Then Placebo	Placebo First, Then Betaine
Arm/Group Description	Subjects received oral betaine 10 gm (subjects >10 yrs old) or 6 gm (subjects <10 yrs old) divided in two doses daily, for 2 months, followed by a 2 month washout period. Subjects then received oral lactose placebo divided in two doses daily, for 2 months.	Subjects received oral lactose placebo divided in two doses daily, for 2 months, followed by a 2 month washout period. Subjects then received oral betaine 10 gm (subjects >10 yrs old) or 6 gm (subjects <10 yrs old), divided in two doses daily, for 2 months.
Period Title: First Intervention
STARTED	6	7
COMPLETED	5	5
NOT COMPLETED	1	2
Period Title: First Intervention
STARTED	5	5
COMPLETED	5	5
NOT COMPLETED	0	0
Period Title: First Intervention
STARTED	5	5
COMPLETED	5	5
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Entire Study Population
Arm/Group Description	Includes groups randomized to receive placebo first and betaine first.
Overall Participants	13
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	20.1
Sex: Female, Male (Count of Participants)
Female	7 53.8%
Male	6 46.2%
Region of Enrollment (participants) [Number]
United States	13 100%
Glomerular Filtration Rate (GFR) (ml/min/1.73 m^2) [Mean (Full Range) ]
Mean (Full Range) [ml/min/1.73 m^2]	79
Number of Subjects on Concomitant Medications (participants) [Number]
Vitamin B6	9 69.2%
Neutral Phosphate	7 53.8%
Citrate	3 23.1%

Outcome Measures

1. Primary Outcome

Title	Urinary Oxalate Excretion
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Betaine	Placebo
Arm/Group Description	Subjects received oral betaine 10 gm (subjects >10 yrs old) or 6 gm (subjects <10 yrs old), divided in two doses daily, for 2 months.	Subjects received oral lactose placebo divided in two doses daily, for 2 months.
Measure Participants	10	10
Mean (Standard Deviation) [umol/mg]	1.43 (0.97)	1.04 (0.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Betaine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	Subjects will be followed for adverse events for the 6 months while on study.
Adverse Event Reporting Description	Subjects unable to tolerate the initial dose due to gastrointestinal symptoms will be offered a dose reduction of 3 - 5 g/day. Monitoring for symptoms and signs of cerebral edema will be 1) weekly telephone calls from the study coordinator with a list of questions re: increased intracranial pressure and 2) full eye exam before and after treatment.
Arm/Group Title	Betaine		Placebo
Arm/Group Description	Subjects received oral betaine 10 gm (subjects >10 yrs old) or 6 gm (subjects <10 yrs old), divided in two doses daily, for 2 months.		Subjects received oral lactose placebo divided in two doses daily, for 2 months.
All Cause Mortality
	Betaine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Betaine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Betaine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/13 (84.6%)		8/13 (61.5%)
Gastrointestinal disorders
Dyspepsia	10/13 (76.9%)	10	7/13 (53.8%)	7
Diarrhea/loose stools	6/13 (46.2%)	6	6/13 (46.2%)	6
Constipation	2/13 (15.4%)	2	1/13 (7.7%)	1
General disorders
Headache	4/13 (30.8%)	4	1/13 (7.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.