Trial Outcomes & Findings for Study of Metanx® in Subjects With Type 2 Diabetic Peripheral Neuropathy (DPN) (NCT NCT00726713)

NCT ID: NCT00726713

Last Updated: 2013-08-30

Results Overview

Vibration Perception Threshold (VPT) 25-45 volts at hallux on either leg as measured by VPT meter on the great toe of each foot. Mean VPT averaged across both toes.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 214 participants
• Primary outcome timeframe: VPT was measured a 0 (baseline), and 24 weeks
• Results posted on: 2013-08-30

Participant Flow

Of 373 patients screened, 214 entered the study , and 200 completed. The study was conducted at 6 participating U.S. sites

Inclusion criteria included individuals 25 and 80 years of age, documented diabetes Type 2, Peripheral polyneuropathy, adequate lower extremity vascular status, and subject competence. 17 exclusion criteria including an HbA1c >9, uncontrolled heart or lung disease, and vitamin B supplementation, contributed to the number of screening failures.

Participant milestones

Measure	Metanx Patients aged 25 to 80 years with type 2 diabetes and neuropathy, were given Metanx (L-methylfolate calcium 3 mg, methylcobalamin 2 mg, and pyridoxal-5'-phosphate 35 mg (LMF-MC-PLP)) one tablet twice a day.	Placebo Patients aged 25 to 80 years with type 2 diabetes and neuropathy, were given Placebo, one tablet twice a day
Overall Study STARTED	106	108
Overall Study COMPLETED	99	101
Overall Study NOT COMPLETED	7	7

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Study of Metanx® in Subjects With Type 2 Diabetic Peripheral Neuropathy (DPN)

Baseline characteristics by cohort

Measure	Metanx n=106 Participants Metanx one tablet twice a day	Placebo n=108 Participants Placebo one tablet twice a day	Total n=214 Participants Total of all reporting groups
Age Continuous	62.29 years STANDARD_DEVIATION 8.54 • n=5 Participants	62.95 years STANDARD_DEVIATION 9.17 • n=7 Participants	62.6 years STANDARD_DEVIATION 8.9 • n=5 Participants
Sex: Female, Male Female	33 Participants n=5 Participants	33 Participants n=7 Participants	66 Participants n=5 Participants
Sex: Female, Male Male	73 Participants n=5 Participants	75 Participants n=7 Participants	148 Participants n=5 Participants

PRIMARY outcome

Timeframe: VPT was measured a 0 (baseline), and 24 weeks

Vibration Perception Threshold (VPT) 25-45 volts at hallux on either leg as measured by VPT meter on the great toe of each foot. Mean VPT averaged across both toes.

Outcome measures

Measure	Metanx n=106 Participants Patients aged 25 to 80 years with type 2 diabetes and neuropathy, were given Metanx (L-methylfolate calcium 3 mg, methylcobalamin 2 mg, and pyridoxal-5'-phosphate 35 mg (LMF-MC-PLP)) one tablet twice a day.	Placebo n=108 Participants Patients aged 25 to 80 years with type 2 diabetes and neuropathy, were given Placebo, one tablet twice a day
Change From Baseline in Vibration Perception Threshold (VPT) at 24 Weeks Baseline	32.16 volts Standard Deviation 13.00	33.88 volts Standard Deviation 14.24
Change From Baseline in Vibration Perception Threshold (VPT) at 24 Weeks Change from Baseline Week 24	-1.96 volts Standard Deviation 13.08	-3.27 volts Standard Deviation 10.32

SECONDARY outcome

Timeframe: NTSS-6 scores were taken at 0 (Baseline), 16, and 24 weeks

This measure was taken to determine if Metanx® (compared to placebo) changes neuropathic symptoms as evaluated by the Neuropathy Total Symptom Score-6 (NTSS-6)

The Neuropathy Total Symptom Score-6 Scale (NTSS-6) is a validated scale that evaluates individual neuropathy sensory symptoms in patients with diabetes mellitus (DM) and diabetic peripheral neuropathy (DPN). This scale was a modified 6 item scale that consists of yes or no questions. Scores range between 0 and 21.96, a higher score indicates greater severity of symptoms. After adjusting for baseline measurements scores are reflected as negative numbers. Negative numbers indicate improvement in symptoms. ie. a change from baseline after 24 weeks of -2 would be a greater improvement than a change in baseline of -1 after 24 weeks.

Outcome measures

Measure	Metanx n=106 Participants Patients aged 25 to 80 years with type 2 diabetes and neuropathy, were given Metanx (L-methylfolate calcium 3 mg, methylcobalamin 2 mg, and pyridoxal-5'-phosphate 35 mg (LMF-MC-PLP)) one tablet twice a day.	Placebo n=108 Participants Patients aged 25 to 80 years with type 2 diabetes and neuropathy, were given Placebo, one tablet twice a day
Change From Baseline in Neuropathy Total Symptom Score-6 (NTSS-6) Baseline	3.73 units on a scale (0-6) Standard Deviation 1.79	3.45 units on a scale (0-6) Standard Deviation 2.05
Change From Baseline in Neuropathy Total Symptom Score-6 (NTSS-6) Change from Baseline Week 16	-0.09 units on a scale (0-6) Standard Deviation 1.42	-0.40 units on a scale (0-6) Standard Deviation 1.72
Change From Baseline in Neuropathy Total Symptom Score-6 (NTSS-6) Change from Baseline Week 24	-0.96 units on a scale (0-6) Standard Deviation 1.54	-0.53 units on a scale (0-6) Standard Deviation 1.69

SECONDARY outcome

Timeframe: NDS scores were taken at 0 (Baseline), 16, and 24 weeks

This outcome was taken to determine if Metanx® (compared to placebo) has an effect on clinical examination as determined by the Neuropathy Disability Score (NDS)

The Neuropathy Disability Score (NDS) evaluates the severity of individual symptoms of neuropathy. A simple visual numeric distress scale is used that ranges from 0 to 10. The most favorable score is 0, which indicates an absence of symptoms. The most severe symptoms possible would be recorded as a score of 10.

Outcome measures

Measure	Metanx n=106 Participants Patients aged 25 to 80 years with type 2 diabetes and neuropathy, were given Metanx (L-methylfolate calcium 3 mg, methylcobalamin 2 mg, and pyridoxal-5'-phosphate 35 mg (LMF-MC-PLP)) one tablet twice a day.	Placebo n=108 Participants Patients aged 25 to 80 years with type 2 diabetes and neuropathy, were given Placebo, one tablet twice a day
Change From Baseline in Neuropathy Disability Score (NDS)at Week 16 and 24 Baseline	7.51 units on a scale (0-10) Standard Deviation 2.36	7.47 units on a scale (0-10) Standard Deviation 2.17
Change From Baseline in Neuropathy Disability Score (NDS)at Week 16 and 24 Change from Baseline Week 16	-0.78 units on a scale (0-10) Standard Deviation 2.13	-0.18 units on a scale (0-10) Standard Deviation 2.24
Change From Baseline in Neuropathy Disability Score (NDS)at Week 16 and 24 Change from Baseline Week 24	-0.47 units on a scale (0-10) Standard Deviation 2.11	-0.36 units on a scale (0-10) Standard Deviation 2.14

SECONDARY outcome

Timeframe: Change from Baseline in Plasma Marker Levels at 0 (Baseline), 16, and 24 weeks

To determine if Metanx® (compared to placebo) affects a change in subject's total folate and total methyl malonic acid (MMA) at week 16 and 24

Outcome measures

Measure	Metanx n=106 Participants Patients aged 25 to 80 years with type 2 diabetes and neuropathy, were given Metanx (L-methylfolate calcium 3 mg, methylcobalamin 2 mg, and pyridoxal-5'-phosphate 35 mg (LMF-MC-PLP)) one tablet twice a day.	Placebo n=108 Participants Patients aged 25 to 80 years with type 2 diabetes and neuropathy, were given Placebo, one tablet twice a day
Change From Baseline in Plasma Marker Levels of Total Folate and Total Methyl Malonic Acid (MMA) at Week 16 and 24 Total Folate (nmol/L) at Baseline	42.19 nmol/L Standard Deviation 9.93	43.04 nmol/L Standard Deviation 9.30
Change From Baseline in Plasma Marker Levels of Total Folate and Total Methyl Malonic Acid (MMA) at Week 16 and 24 Total Folate, Change from BL Week 16	7.25 nmol/L Standard Deviation 10.52	-1.07 nmol/L Standard Deviation 8.27
Change From Baseline in Plasma Marker Levels of Total Folate and Total Methyl Malonic Acid (MMA) at Week 16 and 24 Total Folate, Change from BL Week 24	7.53 nmol/L Standard Deviation 10.42	-2.75 nmol/L Standard Deviation 8.26
Change From Baseline in Plasma Marker Levels of Total Folate and Total Methyl Malonic Acid (MMA) at Week 16 and 24 Total methyl malonic acid (MMA) (nmol/L) at BL	186.16 nmol/L Standard Deviation 120.11	195.72 nmol/L Standard Deviation 169.19
Change From Baseline in Plasma Marker Levels of Total Folate and Total Methyl Malonic Acid (MMA) at Week 16 and 24 Total MMA, Change from BL Week 16	-56.38 nmol/L Standard Deviation 102.72	13.89 nmol/L Standard Deviation 125.21
Change From Baseline in Plasma Marker Levels of Total Folate and Total Methyl Malonic Acid (MMA) at Week 16 and 24 Total MMA, Change from BL Week 24	-63.29 nmol/L Standard Deviation 107.00	-15.42 nmol/L Standard Deviation 59.90

SECONDARY outcome

Timeframe: SF-36 MCS and SF-36 PCS scores were measured at 0 (Baseline) and 24 weeks

To determine if Metanx® (compared to placebo) affects a subject's "quality of life" as determined by the SF-36 questionnaire

The Short Form- 36 Mental Component Summary (SF-36 MCS) and SF-36 Physical Component Summary (SF-36 PCS) both measure health related quality of life, the MCS quantifying mental health and the PCS quantifying physical function. They are both scored on 100 point scales with 0 representing the worst possible outcome and 100 representing the most optimal possible scoring

Outcome measures

Measure	Metanx n=106 Participants Patients aged 25 to 80 years with type 2 diabetes and neuropathy, were given Metanx (L-methylfolate calcium 3 mg, methylcobalamin 2 mg, and pyridoxal-5'-phosphate 35 mg (LMF-MC-PLP)) one tablet twice a day.	Placebo n=108 Participants Patients aged 25 to 80 years with type 2 diabetes and neuropathy, were given Placebo, one tablet twice a day
Change From Baseline in SF-36 MCS and SF-36 PCS at Week 24 SF-36 PCS, Baseline	40.74 units on a scale (0-100) Standard Deviation 10.30	39.03 units on a scale (0-100) Standard Deviation 9.81
Change From Baseline in SF-36 MCS and SF-36 PCS at Week 24 SF-36 PCS, Change from BL, Week 24	0.03 units on a scale (0-100) Standard Deviation 8.34	0.87 units on a scale (0-100) Standard Deviation 8.21
Change From Baseline in SF-36 MCS and SF-36 PCS at Week 24 SF-36 MCS, Baseline	50.96 units on a scale (0-100) Standard Deviation 9.87	52.66 units on a scale (0-100) Standard Deviation 8.39
Change From Baseline in SF-36 MCS and SF-36 PCS at Week 24 SF-36 MCS, Change from BL, Week 24	1.99 units on a scale (0-100) Standard Deviation 8.57	-0.29 units on a scale (0-100) Standard Deviation 8.48

SECONDARY outcome

Timeframe: VAS scores were taken at 0 (Baseline) and 24 weeks

To determine if Metanx® (compared to placebo) affects a subject's lower extremity pain level using a 10-point Visual Analog Scale at Baseline and 24-week evaluation visits.

The Visual Analog Scale (VAS) measures a patients sensation of pain. A 10-cm visual analog scale is used. A measurement on the 10 cm analog scale is used to quantify the level of pain indicated with 0 cm indicating "no pain" and 10 cm indicating the "worst pain imaginable".

Outcome measures

Measure	Metanx n=106 Participants Patients aged 25 to 80 years with type 2 diabetes and neuropathy, were given Metanx (L-methylfolate calcium 3 mg, methylcobalamin 2 mg, and pyridoxal-5'-phosphate 35 mg (LMF-MC-PLP)) one tablet twice a day.	Placebo n=108 Participants Patients aged 25 to 80 years with type 2 diabetes and neuropathy, were given Placebo, one tablet twice a day
Change From Baseline in 10-point Visual Analog Scale(VAS) at Week 24 VAS Baseline	3.26 units on a scale (0-10) Standard Deviation 2.77	3.25 units on a scale (0-10) Standard Deviation 2.76
Change From Baseline in 10-point Visual Analog Scale(VAS) at Week 24 VAS, Change from BL, Week 24	-0.27 units on a scale (0-10) Standard Deviation 2.28	-0.03 units on a scale (0-10) Standard Deviation 2.61

SECONDARY outcome

Timeframe: Analyte levels were taken at 0 (Baseline) and 24 weeks

(Exploratory) To determine if Metanx® affects a subject's plasma oxidative stress and inflammatory marker levels, including IL-6 and TNF-α

Outcome measures

Measure	Metanx n=106 Participants Patients aged 25 to 80 years with type 2 diabetes and neuropathy, were given Metanx (L-methylfolate calcium 3 mg, methylcobalamin 2 mg, and pyridoxal-5'-phosphate 35 mg (LMF-MC-PLP)) one tablet twice a day.	Placebo n=108 Participants Patients aged 25 to 80 years with type 2 diabetes and neuropathy, were given Placebo, one tablet twice a day
(Exploratory) Change From Baseline in Levels of IL-6 and TNF-α, at Week 24 IL-6 (pg/mL), Baseline	3.66 pg/mL Standard Deviation 2.91	3.68 pg/mL Standard Deviation 3.01
(Exploratory) Change From Baseline in Levels of IL-6 and TNF-α, at Week 24 IL-6, Change from BL, Week 24	-0.25 pg/mL Standard Deviation 2.60	0.07 pg/mL Standard Deviation 2.42
(Exploratory) Change From Baseline in Levels of IL-6 and TNF-α, at Week 24 TNF-a (pg/mL), Baseline	1.69 pg/mL Standard Deviation 1.25	2.01 pg/mL Standard Deviation 2.72
(Exploratory) Change From Baseline in Levels of IL-6 and TNF-α, at Week 24 TNF-a, Change from BL, Week 24	0.03 pg/mL Standard Deviation 0.76	-0.04 pg/mL Standard Deviation 0.54

SECONDARY outcome

Timeframe: HADS Scores scores were taken at 0 (Baseline) and 24 weeks

The Hospital Anxiety and Depression Scale (HADS) consists of a 14-item questionnaire that provides a measurement of depression. Each item is rated on a 4-point scale, giving a maximum scores of 21 for the most severe depression. Depression was evaluated using the Hospital Anxiety and Depression Scale (HADS) question inventory at Baseline, and 24-week evaluation visits

Outcome measures

Measure	Metanx n=106 Participants Patients aged 25 to 80 years with type 2 diabetes and neuropathy, were given Metanx (L-methylfolate calcium 3 mg, methylcobalamin 2 mg, and pyridoxal-5'-phosphate 35 mg (LMF-MC-PLP)) one tablet twice a day.	Placebo n=108 Participants Patients aged 25 to 80 years with type 2 diabetes and neuropathy, were given Placebo, one tablet twice a day
(Exploratory) Change From Baseline in the Hospital Anxiety and Depression Scale (HADS) Question Inventory at Week 24 HADS Depression, Baseline	4.16 units on a scale (0-21) Standard Deviation 3.24	4.42 units on a scale (0-21) Standard Deviation 3.12
(Exploratory) Change From Baseline in the Hospital Anxiety and Depression Scale (HADS) Question Inventory at Week 24 HADS Depression, Change from BL, Week 24	-1.03 units on a scale (0-21) Standard Deviation 2.53	-0.45 units on a scale (0-21) Standard Deviation 2.58

SECONDARY outcome

Timeframe: Change from Baseline in Plasma Marker Levels at 0 (Baseline), 16, and 24 weeks

To determine if Metanx® (compared to placebo) affects change in subjects total homocysteine levels

Outcome measures

Measure	Metanx n=106 Participants Patients aged 25 to 80 years with type 2 diabetes and neuropathy, were given Metanx (L-methylfolate calcium 3 mg, methylcobalamin 2 mg, and pyridoxal-5'-phosphate 35 mg (LMF-MC-PLP)) one tablet twice a day.	Placebo n=108 Participants Patients aged 25 to 80 years with type 2 diabetes and neuropathy, were given Placebo, one tablet twice a day
Change From Baseline in Total Homocysteine at Week 16 and 24 Total homocysteine (µmol/L) at Baseline	9.71 µmol/L Standard Deviation 4.29	9.47 µmol/L Standard Deviation 3.90
Change From Baseline in Total Homocysteine at Week 16 and 24 Total homocysteine, Change from BL Week 16	-2.70 µmol/L Standard Deviation 2.90	0.58 µmol/L Standard Deviation 2.58
Change From Baseline in Total Homocysteine at Week 16 and 24 Total homocysteine, Change from BL Week 24	-2.68 µmol/L Standard Deviation 2.98	0.48 µmol/L Standard Deviation 2.40

SECONDARY outcome

Timeframe: Analyte levels were taken at 0 (Baseline) and 24 weeks

(Exploratory) To determine if Metanx® affects a subject's plasma oxidative stress and inflammatory markers levels including hs-CRP

Outcome measures

Measure	Metanx n=106 Participants Patients aged 25 to 80 years with type 2 diabetes and neuropathy, were given Metanx (L-methylfolate calcium 3 mg, methylcobalamin 2 mg, and pyridoxal-5'-phosphate 35 mg (LMF-MC-PLP)) one tablet twice a day.	Placebo n=108 Participants Patients aged 25 to 80 years with type 2 diabetes and neuropathy, were given Placebo, one tablet twice a day
(Exploratory) Change From Baseline in Levels of Hs-CRP at Week 24 hs-CRP (mg/L), Baseline	6.46 mg/L Standard Deviation 5.98	7.44 mg/L Standard Deviation 7.23
(Exploratory) Change From Baseline in Levels of Hs-CRP at Week 24 hs-CRP, Change from BL, Week 24	-0.71 mg/L Standard Deviation 4.05	0.13 mg/L Standard Deviation 4.15

SECONDARY outcome

Timeframe: Analyte levels were taken at 0 (Baseline) and 24 weeks

(Exploratory) To determine if Metanx® affects a subject's plasma oxidative stress and inflammatory markers levels including Potential Antioxidant (PAO)

Outcome measures

Measure	Metanx n=106 Participants Patients aged 25 to 80 years with type 2 diabetes and neuropathy, were given Metanx (L-methylfolate calcium 3 mg, methylcobalamin 2 mg, and pyridoxal-5'-phosphate 35 mg (LMF-MC-PLP)) one tablet twice a day.	Placebo n=108 Participants Patients aged 25 to 80 years with type 2 diabetes and neuropathy, were given Placebo, one tablet twice a day
(Exploratory) Change From Baseline in Levels Potential Antioxidant (PAO) at Week 24 PAO (µmol/L), Baseline	1094.52 µmol/L Standard Deviation 230.83	1102.15 µmol/L Standard Deviation 250.54
(Exploratory) Change From Baseline in Levels Potential Antioxidant (PAO) at Week 24 PAO, Change from BL, Week 24	7.95 µmol/L Standard Deviation 190.36	5.29 µmol/L Standard Deviation 204.92

Adverse Events

Metanx

Serious events: 5 serious events

Other events: 25 other events

Deaths: 0 deaths

Placebo

Serious events: 8 serious events

Other events: 27 other events

Deaths: 0 deaths

Serious adverse events

Measure	Metanx n=106 participants at risk Metanx one tablet twice a day	Placebo n=108 participants at risk Placebo one tablet twice a day
Vascular disorders Transient Ischemic Attack	1.9% 2/106 • Number of events 2 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.	0.00% 0/108 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.
Surgical and medical procedures Knee arthroplasty	0.94% 1/106 • Number of events 1 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.	0.93% 1/108 • Number of events 1 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.
Surgical and medical procedures Ligament Operation	0.94% 1/106 • Number of events 1 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.	0.00% 0/108 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast Cancer	0.00% 0/106 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.	0.93% 1/108 • Number of events 1 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.
Surgical and medical procedures Coronary Artery Bypass	0.00% 0/106 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.	0.93% 1/108 • Number of events 1 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.
General disorders Death	0.00% 0/106 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.	1.9% 2/108 • Number of events 2 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.
Gastrointestinal disorders Pancreatitis	0.00% 0/106 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.	0.93% 1/108 • Number of events 1 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.
General disorders Chest Pain	0.00% 0/106 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.	0.93% 1/108 • Number of events 1 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.
Cardiac disorders Cardiac Failure, Congestive	0.94% 1/106 • Number of events 1 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.	0.00% 0/108 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.
Metabolism and nutrition disorders Dehydration	0.00% 0/106 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.	0.93% 1/108 • Number of events 1 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.

Other adverse events

Measure	Metanx n=106 participants at risk Metanx one tablet twice a day	Placebo n=108 participants at risk Placebo one tablet twice a day
Infections and infestations Infections and infestations	5.7% 6/106 • Number of events 6 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.	5.6% 6/108 • Number of events 6 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.
Injury, poisoning and procedural complications Injury, poisoning, and procedural complications	4.7% 5/106 • Number of events 5 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.	3.7% 4/108 • Number of events 4 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.
General disorders General disorders and administration site conditions	3.8% 4/106 • Number of events 4 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.	2.8% 3/108 • Number of events 3 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.
Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders	0.94% 1/106 • Number of events 1 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.	5.6% 6/108 • Number of events 6 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.
Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders	2.8% 3/106 • Number of events 3 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.	3.7% 4/108 • Number of events 4 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.
Surgical and medical procedures Surgical and medical procedures	2.8% 3/106 • Number of events 3 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.	0.93% 1/108 • Number of events 1 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.
Gastrointestinal disorders Gastrointestinal disorders	1.9% 2/106 • Number of events 2 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.	0.93% 1/108 • Number of events 1 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.
Metabolism and nutrition disorders Metabolism and nutrition disorders	0.94% 1/106 • Number of events 1 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.	1.9% 2/108 • Number of events 2 • Reported Adverse Events (AEs) included events starting on or after the baseline visit until 4 weeks after the last study visit on week 24. The total duration of AE monitoring was 196 days. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, even if the event is not considered to be related to study drug. Adverse Event reporting was provided only with specificity to the affected Organ System. Additional detail was not available at the time of reporting.

Additional Information

Page Young, Clinical Project Manager

Pamlab Inc.

Phone: 985-867-5788

Email: pyoung@pamlab.com

Results disclosure agreements

• Principal investigator is a sponsor employee Investigators agreed to delay publication of study results until after multi-center results were published or, a period of up to 20 months had elapsed after termination of the study, whichever shall occur first.
• Publication restrictions are in place

Restriction type: OTHER