Trial Outcomes & Findings for Oxidative Stress Markers In Inherited Homocystinuria And The Impact Of Taurine (NCT NCT01192828)

Results Overview

TBARS were measured in plasma via colorimetric absorbance. TBARS are a marker of oxidative stress. They are formed as a by-product of lipid (fat) oxidation. TBARS predominantly reflect the level of malondialdehyde (MDA) a substance that is formed from the breakdown of polyunsaturated fatty acids.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

15 participants

Primary outcome timeframe

Baseline and after 4 days of therapy.

Results posted on

2018-07-09

Participant Flow

Subjects were screened and recruited from three sites in the United States.

After enrollment a washout period for medications was required. At first study visit, assignment to arm occurred. One individual, while consented, did not participate at first study visit due to acute illness, was never rescheduled, and was removed. Number of subjects who started arm and completed study was thus 14.

Participant milestones

Participant milestones
Measure	Taurine Intervention For safety reason, the first two subjects studies received low dose taurine therapy: 25 mg/kg body weight twice a day (maximum dose 1.5 grams). The next subjects received target high dose therapy: 75 mg/kg body weight twice a day (maximum dose of 5 grams).
Overall Study STARTED	14
Overall Study COMPLETED	14
Overall Study NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Total number of participant enrolled in study was 15. One subject who enrolled per phone had to postpone study visit due to acute illness. This individual failed to reschedule for study visit and was eventually removed from the study. Number of subjects who completed study and analyzed is therefore 14.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Taurine Intervention n=14 Participants Treatment with taurine for 4 1/2 days, two doses per day
Age, Customized Age Distribution by Meaningful Groups · Prepubertal (8-12 years)	4 Participants n=5 Participants • Total number of participant enrolled in study was 15. One subject who enrolled per phone had to postpone study visit due to acute illness. This individual failed to reschedule for study visit and was eventually removed from the study. Number of subjects who completed study and analyzed is therefore 14.
Age, Customized Age Distribution by Meaningful Groups · Teenagers (12-<20 years)	4 Participants n=5 Participants • Total number of participant enrolled in study was 15. One subject who enrolled per phone had to postpone study visit due to acute illness. This individual failed to reschedule for study visit and was eventually removed from the study. Number of subjects who completed study and analyzed is therefore 14.
Age, Customized Age Distribution by Meaningful Groups · Young Adults (20-<30 years)	4 Participants n=5 Participants • Total number of participant enrolled in study was 15. One subject who enrolled per phone had to postpone study visit due to acute illness. This individual failed to reschedule for study visit and was eventually removed from the study. Number of subjects who completed study and analyzed is therefore 14.
Age, Customized Age Distribution by Meaningful Groups · Older Adults (30-50 years)	2 Participants n=5 Participants • Total number of participant enrolled in study was 15. One subject who enrolled per phone had to postpone study visit due to acute illness. This individual failed to reschedule for study visit and was eventually removed from the study. Number of subjects who completed study and analyzed is therefore 14.
Sex: Female, Male Female	6 Participants n=5 Participants
Sex: Female, Male Male	8 Participants n=5 Participants
Race/Ethnicity, Customized Categories · Native American	0 Participants n=5 Participants
Race/Ethnicity, Customized Categories · Asian	0 Participants n=5 Participants
Race/Ethnicity, Customized Categories · Black	2 Participants n=5 Participants
Race/Ethnicity, Customized Categories · White	9 Participants n=5 Participants
Race/Ethnicity, Customized Categories · Hispanic	3 Participants n=5 Participants
Race/Ethnicity, Customized Categories · Other	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and after 4 days of therapy.

Population: Analyzable data from all individuals with CBSDH who received the target dose of taurine were used for the calculations. The two individuals treated with low dose taurine were excluded from he analysis.

TBARS were measured in plasma via colorimetric absorbance. TBARS are a marker of oxidative stress. They are formed as a by-product of lipid (fat) oxidation. TBARS predominantly reflect the level of malondialdehyde (MDA) a substance that is formed from the breakdown of polyunsaturated fatty acids.

Outcome measures

Outcome measures
Measure	Taurine Intervention Group n=12 Participants For safety reason, the first two subjects studies received low dose taurine therapy: 25 mg/kg body weight twice a day (maximum dose 1.5 grams). There after all received target dose therapy: 75 mg/kg body weight twice a day (maximum dose of 5 grams).
Difference in Thiobarbituric Acid Reactive Substances (TBARS) in Individuals With Cystathionine Beta Synthase Deficient Homocystinuria (CBSDH) Pre and Post Taurine Treatment. Pre Treatment	3.47 nmol/ml Standard Error 0.18
Difference in Thiobarbituric Acid Reactive Substances (TBARS) in Individuals With Cystathionine Beta Synthase Deficient Homocystinuria (CBSDH) Pre and Post Taurine Treatment. Post treatment	3.16 nmol/ml Standard Error 0.27

PRIMARY outcome

Timeframe: Baseline and after 4 days of treatment.

Population: Analyzable data from all individuals with CBSDH who received the target dose of taurine were used for the calculations. The two individuals treated with low dose taurine were excluded from the analysis.

TNF-alpha was measured in plasma via Luminex high sensitivity assay. TNF-alpha is a signaling protein, or cytokine that promotes an inflammatory response.

Outcome measures

Outcome measures
Measure	Taurine Intervention Group n=12 Participants For safety reason, the first two subjects studies received low dose taurine therapy: 25 mg/kg body weight twice a day (maximum dose 1.5 grams). There after all received target dose therapy: 75 mg/kg body weight twice a day (maximum dose of 5 grams).
Difference in Tumor Necrosis Factor Alpha (TNF-alpha) in Individuals With CBSDH Pre and Post Taurine Treatment. Pre treatment	5.95 pg/ml Standard Error 0.39
Difference in Tumor Necrosis Factor Alpha (TNF-alpha) in Individuals With CBSDH Pre and Post Taurine Treatment. Post treatment	6.07 pg/ml Standard Error 0.49

SECONDARY outcome

Timeframe: Baseline and after 4.5 days of taurine treatment

Population: Analyzable data from all individuals with CBSDH who received the target dose of taurine were used for the calculations. The two individuals treated with low dose taurine were excluded from the analysis.

Endothelial function was measured by doppler brachial artery flow-mediated dilation (FMD) studies.

Outcome measures

Outcome measures
Measure	Taurine Intervention Group n=12 Participants For safety reason, the first two subjects studies received low dose taurine therapy: 25 mg/kg body weight twice a day (maximum dose 1.5 grams). There after all received target dose therapy: 75 mg/kg body weight twice a day (maximum dose of 5 grams).
Difference in Endothelial Function (Blood Vessel Function) in Individuals With CBSDH Pre and Post Taurine Treatment Pre treatment	9.80 mm Standard Error 1.76
Difference in Endothelial Function (Blood Vessel Function) in Individuals With CBSDH Pre and Post Taurine Treatment Post treatment	11.57 mm Standard Error 1.21

SECONDARY outcome

Timeframe: Baseline and after 4.5 days of therapy.

Population: Analyzable data from all individuals with CBSDH having baseline homocysteine levels greater than 125 micromole/L who received the target dose of taurine were used for the calculations. The two individuals treated with low dose taurine were excluded from the analysis.

Endothelial function was measured by doppler brachial artery flow-mediated dilation (FMD) studies.

Outcome measures

Outcome measures
Measure	Taurine Intervention Group n=6 Participants For safety reason, the first two subjects studies received low dose taurine therapy: 25 mg/kg body weight twice a day (maximum dose 1.5 grams). There after all received target dose therapy: 75 mg/kg body weight twice a day (maximum dose of 5 grams).
Difference in Endothelial Function (Blood Vessel Function) in Individuals With CBSDH and Homocysteine Levels Greater Than 125 Micromole/L Pre and Post Taurine Treatment. Pre treatment	7.25 mm Standard Error 1.23
Difference in Endothelial Function (Blood Vessel Function) in Individuals With CBSDH and Homocysteine Levels Greater Than 125 Micromole/L Pre and Post Taurine Treatment. Post treatment	11.10 mm Standard Error 1.48

SECONDARY outcome

Timeframe: Baseline and after 4.5 days of therapy.

Population: Analyzable data from all individuals with CBSDH studied with baseline flow mediated dilation values of less than 10 mm and who received the target dose of taurine were used for the calculations. The two individuals treated with low dose taurine were excluded from the analysis.

Endothelial function was measured by doppler brachial artery flow-mediated dilation (FMD) studies.

Outcome measures

Outcome measures
Measure	Taurine Intervention Group n=8 Participants For safety reason, the first two subjects studies received low dose taurine therapy: 25 mg/kg body weight twice a day (maximum dose 1.5 grams). There after all received target dose therapy: 75 mg/kg body weight twice a day (maximum dose of 5 grams).
Difference in Endothelial Function (Blood Vessel Function) in Individuals With CBSDH and Pre Taurine Exposure FMD Values Less Than 10 mm Pre and Post Taurine Treatment. Pre Treatment	5.98 mm Standard Error 0.51
Difference in Endothelial Function (Blood Vessel Function) in Individuals With CBSDH and Pre Taurine Exposure FMD Values Less Than 10 mm Pre and Post Taurine Treatment. Post Treatment	9.86 mm Standard Error 1.28

SECONDARY outcome

Timeframe: Baseline

Population: Analysis was on all analyzable data from subjects with CBSDH who participated in the active study and data from control population as provided by DEXA report.

Bone mineral density was assessed via whole body dual energy X-ray absorptiometry (DEXA) with bone density corrected for age. The absolute DEXA value was not used for analysis, rather values below 2 standard deviations of normal were taken as evidence of osteoporosis.

Outcome measures

Outcome measures
Measure	Taurine Intervention Group n=14 Participants For safety reason, the first two subjects studies received low dose taurine therapy: 25 mg/kg body weight twice a day (maximum dose 1.5 grams). There after all received target dose therapy: 75 mg/kg body weight twice a day (maximum dose of 5 grams).
Percent of Individuals With Decreased Bone Mineral Density. Normal bone mineral denisty	14 Participants
Percent of Individuals With Decreased Bone Mineral Density. Abnormal bone mineral density	0 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline

Population: Analyzable data from all subjects with CBSDH who completed day one of active study and normal homocysteine values provided by assaying laboratory were used for the calculations.

TBARS were measured in plasma via colorimetric absorbance. Homocysteine was measured in serum by gas chromatography/mass spectrometry (GC/MS) in a Clinical Laboratory Improvements Amendments (CLIA) approved clinical laboratory. TBARS are a marker of oxidative stress. TBARS are formed as a by-product of lipid (fat) oxidation. TBARS predominantly reflect the level of malondialdehyde (MDA) a substance that is formed from the breakdown of polyunsaturated fatty acids.

Outcome measures

Outcome measures
Measure	Taurine Intervention Group n=14 Participants For safety reason, the first two subjects studies received low dose taurine therapy: 25 mg/kg body weight twice a day (maximum dose 1.5 grams). There after all received target dose therapy: 75 mg/kg body weight twice a day (maximum dose of 5 grams).
Thiobarbituric Acid Reactive Substances (TBARS) in Individuals With CBSDH Compare to Homocysteine Level. TBARS	0.00365 micromol/l Standard Error 0.00087
Thiobarbituric Acid Reactive Substances (TBARS) in Individuals With CBSDH Compare to Homocysteine Level. Homocysteine	161 micromol/l Standard Error 67.2

OTHER_PRE_SPECIFIED outcome

Timeframe: Taurine levels were obtained prior to taurine adminstration and at , t=0.5, t=1, t=2, t=3, t=4, t=6, t=8, t=12 and 96 hours.

Population: Analyzable data from all individuals with CBSDH who received the target dose of taurine were used for the calculations. The two individuals treated with low dose taurine were excluded from the analysis.

Taurine was measured in plasma via liquid chromatogram(LC)-MS/MS.

Outcome measures

Outcome measures
Measure	Taurine Intervention Group n=12 Participants For safety reason, the first two subjects studies received low dose taurine therapy: 25 mg/kg body weight twice a day (maximum dose 1.5 grams). There after all received target dose therapy: 75 mg/kg body weight twice a day (maximum dose of 5 grams).
Determination of Baseline Taurine Level, Peak Taurine Level on Day One, Trough Level on Day One and Trough Level on Day Four of Taurine Treatment. Baseline value	40.5 microM Standard Deviation 11.9
Determination of Baseline Taurine Level, Peak Taurine Level on Day One, Trough Level on Day One and Trough Level on Day Four of Taurine Treatment. Peak Value Day One	753.0 microM Standard Deviation 240.0
Determination of Baseline Taurine Level, Peak Taurine Level on Day One, Trough Level on Day One and Trough Level on Day Four of Taurine Treatment. Trough Value Day One 12h	50.0 microM Standard Deviation 14.0
Determination of Baseline Taurine Level, Peak Taurine Level on Day One, Trough Level on Day One and Trough Level on Day Four of Taurine Treatment. Trough Value Day Four	82.0 microM Standard Deviation 36.2

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and after 4 days of treatment.

Population: Analyzable data from all individuals with CBSDH who were treated with taurine, this being both low dose and targeted dose of medication.

Triglycerides were measured in a CLIA approved clinical laboratory.Triglycerides are a natural occurring fat. High levels over a long period of time can increase the chances for heart disease. Levels greater that 1000 mg/dl over a short period of time can increase chances of pancreatitis.

Outcome measures

Outcome measures
Measure	Taurine Intervention Group n=14 Participants For safety reason, the first two subjects studies received low dose taurine therapy: 25 mg/kg body weight twice a day (maximum dose 1.5 grams). There after all received target dose therapy: 75 mg/kg body weight twice a day (maximum dose of 5 grams).
Difference in Triglycerides in Individuals With CBSDH Receiving Both Low Dose and Target Dose Taurine Pre and Post Taurine Treatment (Safety Assessment) Pre Taurine	77.5 mg/dL Standard Error 19.0
Difference in Triglycerides in Individuals With CBSDH Receiving Both Low Dose and Target Dose Taurine Pre and Post Taurine Treatment (Safety Assessment) Post Taurine	116.7 mg/dL Standard Error 33.4

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and after 4 days of treatment.

Population: Analyzable data from all individuals with CBSDH who received the target dose of taurine were used for the calculations. The two individuals treated with low dose taurine were excluded from the analysis.

Triglycerides were measured in a CLIA approved clinical laboratory. Triglycerides are a natural occurring fat, High levels over a long period of time can increase the chances for heart disease. Levels greater that 1000 mg/dl over a short period of time can increase chances of pancreatitis.

Outcome measures

Outcome measures
Measure	Taurine Intervention Group n=12 Participants For safety reason, the first two subjects studies received low dose taurine therapy: 25 mg/kg body weight twice a day (maximum dose 1.5 grams). There after all received target dose therapy: 75 mg/kg body weight twice a day (maximum dose of 5 grams).
Difference in Triglycerides in Individuals With CBSDH Receiving Target Dose Taurine Pre and Post Taurine Treatment (Safety Assessment) Pre Treatment	61.6 mg/dL Standard Error 12.7
Difference in Triglycerides in Individuals With CBSDH Receiving Target Dose Taurine Pre and Post Taurine Treatment (Safety Assessment) Post Treatment	98.7 mg/dL Standard Error 29.7

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and after 4 days of treatment.

Population: Analyzable data from all individuals with CBSDH who were treated with taurine, this being both low dose and targeted dose of medication.

Outcome measures

Outcome measures
Measure	Taurine Intervention Group n=14 Participants For safety reason, the first two subjects studies received low dose taurine therapy: 25 mg/kg body weight twice a day (maximum dose 1.5 grams). There after all received target dose therapy: 75 mg/kg body weight twice a day (maximum dose of 5 grams).
Difference in Systolic Blood Pressure in Individuals With CBSDH Receiving Both Low Dose and Target Dose Taurine Pre and Post Taurine Treatment (Safety Assessment). Pre Taurine	116 mmHg Standard Deviation 12
Difference in Systolic Blood Pressure in Individuals With CBSDH Receiving Both Low Dose and Target Dose Taurine Pre and Post Taurine Treatment (Safety Assessment). Post Taurine	112 mmHg Standard Deviation 12

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and after 4 days of treatment.

Population: Analyzable data from all individuals with CBSDH who were treated with taurine, this being both low dose and targeted dose of medication.

Outcome measures

Outcome measures
Measure	Taurine Intervention Group n=14 Participants For safety reason, the first two subjects studies received low dose taurine therapy: 25 mg/kg body weight twice a day (maximum dose 1.5 grams). There after all received target dose therapy: 75 mg/kg body weight twice a day (maximum dose of 5 grams).
Difference in Diastolic Blood Pressure in Individuals With CBSDH Receiving Both Low Dose and Target Dose Taurine Pre and Post Taurine Treatment (Safety Assessment). Pre Taurine	70 mmHg Standard Deviation 10
Difference in Diastolic Blood Pressure in Individuals With CBSDH Receiving Both Low Dose and Target Dose Taurine Pre and Post Taurine Treatment (Safety Assessment). Post Taurine	68 mmHg Standard Deviation 8

Adverse Events

Taurine Intervention

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Taurine Intervention n=14 participants at risk Taurine Intervention
Gastrointestinal disorders Gastrointestinal symptoms	35.7% 5/14 • Number of events 6 • 19 days (During the 5 days taurine was administered plus two weeks after taurine administration.)
Nervous system disorders Headache	7.1% 1/14 • Number of events 1 • 19 days (During the 5 days taurine was administered plus two weeks after taurine administration.)

Additional Information

Dr. Johan Van Hove, Primary Investigator

University of Colorado Denver

Phone: 303-724-2338

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place