XAMNANTIOXAP2010

IDIBELL

AV. GRAN VIA DE L’HOSPITALET 199, L’HOSPITALET DE LLOBREGAT, Spain, 08908

UICEC, Bellvitge University Hospital, Neurometabolic Diseases Laboratory, +34 932607500, phereu@bellvitgehospital.cat

UICEC, Bellvitge University Hospital, Neurometabolic Diseases Laboratory, +34 932607500, phereu@bellvitgehospital.cat

No

No

No

Final

11 Feb 2017

Yes

22 Jul 2013

Yes

22 Jul 2013

Yes

The main objective of the trial is the validation and identification of markers and evaluation of the biological effects on these markers as well as the tolerance and safety of a combination of antioxidants (NAC, lipoic acid and vitamin E), in patients with adrenomyeloneuropathy (AMN) . This is the study of a combination of drugs in a new therapeutic indication.

A physical examination and measurement of vital signs of the subjects has been done at each visit. Also biochemical and hematological tests will be requested at each visit including: blood count, ionogram, kidney function, liver function, proteins, lipid profile and urine analysis.

23 Sep 2011

No

No

Spain: 13

13

13

0

0

0

0

0

0

13

0

0

Baseline

Not applicable

NAC + Lipoic Acid + Vitamin E

Capsule, hard, Capsule, soft

Oral use

All AMN subjects initially received a lower dose A: NAC (800 mg), LA (300 mg), and vit E (150 IU) orally daily for 2 months.

Dose A-2 months

Not applicable

NAC + Lipoic Acid + Vitamin E

Capsule, hard, Capsule, soft

Oral use

All AMN subjects initially received a lower dose A: NAC (800 mg), LA (300 mg), and vit E (150 IU) orally daily for 2 months.

Dose B-3 months

Not applicable

NAC + Lipoic Acid + Vitamin E

Capsule, hard, Capsule, soft

Oral use

Subjects showing no normalization of oxidative damage biomarkers with Dose A, after 2 months of washout the dosage was increased to dose B for 3 months: NAC (2400 mg), LA (600 mg), and vit E (300 IU) daily.

Dose B-12 months

Not applicable

NAC + Lipoic Acid + Vitamin E

Capsule, hard, Capsule, soft

Oral use

NAC (2400 mg), LA (600 mg), and vit E (300 IU) daily during 12 months

Dose A-12 months

Not applicable

NAC + Lipoic Acid + Vitamin E

Capsule, hard, Capsule, soft

Oral use

All AMN subjects initially received a lower dose A: NAC (800 mg), LA (300 mg), and vit E (150 IU) orally daily for 12 months.

Baseline

AMN M0

AMN Dose A 2-months

AMN Dose B-3 months

AMN Dose B-12 months

AMN Dose A-12 months

8-Oxo-dG (7,8-dihydro-8-oxo-2-deoxyguanosine) was tested in the urine by HPLC according to the methodology described by Haghdoost et al. (Int J Radiat Oncol Biol Phys 2001;50:405–410). The reference values were calculated according to the sample distribution of 25 healthy individuals. The point that defines a superior moderate outlier in the sample of controls was taken as the reference limit (Q75 + 1.5 × IQR, Q75 = 75% percentile, IQR = interquartile range). 25 healthy subjects were used to determine the control biomarker values.

Primary

8-Oxo-dG was measured in urine at baseline, after 2 months with dose A (13 subjects) and after 3 months with dose B in subjects who do not normalize oxidative biomarkers (12 subjects)

Data were examined for normality by the Shapiro–Wilk test. Significant differences were determined using a 1-tailed Student’s T test if the data were normally distributed or a 1-tailed Wilcoxon rank sum test otherwise.

AMN Dose A 2-months v AMN M0

26

Pre-specified

1-sided

Standard error of the mean

Data were examined for normality by the Shapiro–Wilk test. Significant differences were determined using a 1-tailed Student’s T test if the data were normally distributed or a 1-tailed Wilcoxon rank sum test otherwise.

AMN Dose B-3 months v AMN M0

25

Pre-specified

1-sided

Standard error of the mean

GSA (glutamic semialdehyde) is a metal-catalyzed oxidation product. GSA was tested in the plasma by GC/MS according to the methodology described by Fourcade et al. (Hum Mol Genet 2008;17:1762–1773). The reference values were calculated according to the sample distribution of 12 healthy individuals. The point that defines a superior moderate outlier in the sample of controls was taken as the reference limit (Q75 + 1.5 × IQR, Q75 = 75% percentile, IQR = interquartile range). 25 healthy subjects were used to determine the control biomarker values.

Primary

GSA was measured in plasma at baseline, after 2 months with dose A (13 subjects) and after 3 months with dose B in subjects who do not normalize oxidative biomarkers (12 subjects)

Data were examined for normality by the Shapiro–Wilk test. Significant differences were determined using a 1-tailed Student’s T test if the data were normally distributed or a 1-tailed Wilcoxon rank sum test otherwise.

AMN Dose B-3 months v AMN M0

25

Pre-specified

1-sided

Data were examined for normality by the Shapiro–Wilk test. Significant differences were determined using a 1-tailed Student’s T test if the data were normally distributed or a 1-tailed Wilcoxon rank sum test otherwise.

AMN Dose B-3 months v AMN M0

25

Pre-specified

1-sided

Standard error of the mean

AASA (aminoadipic semialdehyde) is a metal-catalyzed oxidation product. AASA was tested in the plasma by GC/MS according to the methodology described by Fourcade et al. (Hum Mol Genet 2008;17:1762–1773). The reference values were calculated according to the sample distribution of 12 healthy individuals. The point that defines a superior moderate outlier in the sample of controls was taken as the reference limit (Q75 + 1.5 × IQR, Q75 = 75% percentile, IQR = interquartile range). 25 healthy subjects were used to determine the control biomarker values.

Primary

AASA was measured in plasma at baseline, after 2 months with dose A (13 subjects) and after 3 months with dose B in subjects who do not normalize oxidative biomarkers (12 subjects)

Data were examined for normality by the Shapiro–Wilk test. Significant differences were determined using a 1-tailed Student’s T test if the data were normally distributed or a 1-tailed Wilcoxon rank sum test otherwise.

AMN Dose A 2-months v AMN M0

26

Pre-specified

1-sided

Data were examined for normality by the Shapiro–Wilk test. Significant differences were determined using a 1-tailed Student’s T test if the data were normally distributed or a 1-tailed Wilcoxon rank sum test otherwise.

AMN Dose B-3 months v AMN M0

25

Pre-specified

1-sided

CML (Nepsilon-(carboxymethyl) - lysine)) is a mixed glycoxidation/lipoxidation product. CML was tested in the plasma by GC/MS according to the methodology described by Fourcade et al. (Hum Mol Genet 2008;17:1762–1773). The reference values were calculated according to the sample distribution of 12 healthy individuals. The point that defines a superior moderate outlier in the sample of controls was taken as the reference limit (Q75 + 1.5 × IQR, Q75 = 75% percentile, IQR = interquartile range). 25 healthy subjects were used to determine the control biomarker values.

Primary

CML was measured in plasma at baseline, after 2 months with dose A (13 subjects) and after 3 months with dose B in subjects who do not normalize oxidative biomarkers (12 subjects)

Data were examined for normality by the Shapiro–Wilk test. Significant differences were determined using a 1-tailed Student’s T test if the data were normally distributed or a 1-tailed Wilcoxon rank sum test otherwise.

AMN Dose A 2-months v AMN M0

26

Pre-specified

1-sided

Standard error of the mean

Data were examined for normality by the Shapiro–Wilk test. Significant differences were determined using a 1-tailed Student’s T test if the data were normally distributed or a 1-tailed Wilcoxon rank sum test otherwise.

AMN Dose B-3 months v AMN M0

25

Pre-specified

1-sided

Standard error of the mean

CEL (Nepsilon-(carboxyethyl)-lysine) is a mixed glycoxidation/lipoxidation product. CEL was tested in the plasma by GC/MS according to the methodology described by Fourcade et al. (Hum Mol Genet 2008;17:1762–1773). The reference values were calculated according to the sample distribution of 12 healthy individuals. The point that defines a superior moderate outlier in the sample of controls was taken as the reference limit (Q75 + 1.5 × IQR, Q75 = 75% percentile, IQR = interquartile range). 25 healthy subjects were used to determine the control biomarker values.

Primary

CEL was measured in plasma at baseline, after 2 months with dose A (13 subjects) and after 3 months with dose B in subjects who do not normalize oxidative biomarkers (12 subjects)

Data were examined for normality by the Shapiro–Wilk test. Significant differences were determined using a 1-tailed Student’s T test if the data were normally distributed or a 1-tailed Wilcoxon rank sum test otherwise.

AMN Dose A 2-months v AMN M0

26

Post-hoc

1-sided

Standard error of the mean

Data were examined for normality by the Shapiro–Wilk test. Significant differences were determined using a 1-tailed Student’s T test if the data were normally distributed or a 1-tailed Wilcoxon rank sum test otherwise.

AMN Dose B-3 months v AMN M0

25

Pre-specified

1-sided

Standard error of the mean

MDAL (Nepsilonmalondialdehyde-lysine) is a lipid peroxidation-derived product. MDAL was tested in the plasma by GC/MS according to the methodology described by Fourcade et al. (Hum Mol Genet 2008;17:1762–1773). The reference values were calculated according to the sample distribution of 12 healthy individuals. The point that defines a superior moderate outlier in the sample of controls was taken as the reference limit (Q75 + 1.5 × IQR, Q75 = 75% percentile, IQR = interquartile range). 25 healthy subjects were used to determine the control biomarker values.

Primary

MDAL was measured in plasma at baseline, after 2 months with dose A (13 subjects) and after 3 months with dose B in subjects who do not normalize oxidative biomarkers (12 subjects)

Data were examined for normality by the Shapiro–Wilk test. Significant differences were determined using a 1-tailed Student’s T test if the data were normally distributed or a 1-tailed Wilcoxon rank sum test otherwise.

AMN Dose A 2-months v AMN M0

26

Post-hoc

1-sided

Standard error of the mean

Data were examined for normality by the Shapiro–Wilk test. Significant differences were determined using a 1-tailed Student’s T test if the data were normally distributed or a 1-tailed Wilcoxon rank sum test otherwise.

AMN Dose B-3 months v AMN M0

25

Pre-specified

1-sided

Standard error of the mean

6 Minute Walk Test (6MWT): this test is used as a physical performance‐based measure of global responses of all systems to submaximal exercise. It measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. The individual is allowed to self‐pace and rest as needed as he traverses back and forth along a marked walkway.

Secondary

6MWT was measured at baseline, and after 12 months with dose B (11 subjects)

Data were examined for normality by the Shapiro–Wilk test. Significant differences were determined using a 1-tailed Student’s T test if the data were normally distributed or a 1-tailed Wilcoxon rank sum test otherwise.

AMN M0 v AMN Dose B-12 months

23

Pre-specified

1-sided

Neopterin is a sensitive marker of immune system activation for neurodegenerative disorders such as Parkinson’s disease, which was not previously reported in AMN.

Secondary

Neopterin was measured in cerebrospinal fluid at baseline, and after 12 months with dose B (6 subjects)

Data were examined for normality by the Shapiro–Wilk test. Significant differences were determined using a 1-tailed Student’s T test if the data were normally distributed or a 1-tailed Wilcoxon rank sum test otherwise.

AMN M0 v AMN Dose B-12 months

15

Pre-specified

1-sided

The evaluation, registration and analysis of the security parameters were carried out at each visit, from the initial visit to the end of the study.

0

AMN-Dose A

AMN-Dose B