SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study

• Sponsor: MedDay Pharmaceuticals SA (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02967679
• Collaborator: (none)
• Enrollment: 15
• Location: 1
• Arm: 1
• Actual Duration (Months): 27.4
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The single-center, open-label Phase II study has the objective of assess the effect of MD1003 on motor and sensory conduction in patients suffering from demyelinating polyneuropathies in 15 subjects.

Condition or Disease	Intervention/Treatment	Phase
Chronic Inflammatory Demyelinating Polyneuropathy; Peripheral Neuropathy; Charcot-Marie-Tooth Disease; Charcot-Marie-Tooth Disease Type 1A; Charcot-Marie-Tooth Disease, Type 1B; Anti-MAG Neuropathy	Drug: MD1003	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: SERENDEM Study: MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
• Actual Study Start Date: Dec 5, 2016
• Actual Primary Completion Date: Mar 18, 2019
• Actual Study Completion Date: Mar 18, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MD1003 MD1003 100mg capsules, 1 capsule tid for 48 weeks	Drug: MD1003; Other Names: High Dose Biotin

Outcome Measures

Primary Outcome Measures

1. Motor Nerve Conduction Velocity (m/Sec) [48 weeks]

   Absolute change from baseline at Week 48.

2. Distal Latency (Msec) [48 weeks]

   Absolute change from baseline at Week 48.

3. F Wave Latency (Msec) [48 weeks]

   Absolute change from baseline at Week 48.

4. Length of Motor Nerve Potential [48 weeks]

   Absolute change from baseline at W48.

Secondary Outcome Measures

1. ONLS (Overall Neuropathy Limitations Scale) [48 weeks]

   The ONLS focuses on upper and lower limb functions, and consists of a checklist for interviewing patients. It is scored from 0 to 5 on the upper limb section and from 0 to 7 on the lower limb section. A score of 0 indicates no limitations (the ceiling of the scale) and a score of 5 or 7 indicates no purposeful movement. Absolute change from baseline at week 48.

2. Change From Baseline at Week 48 for Timed 10-meter Walk Test [48 weeks]

   Absolute change from baseline at week 48. The patient is instructed to walk at normal pace for 10 meters. Start and stop of performance time coincides with the toes of the leading foot crossing the 2-m mark and the 8-m mark, respectively. From these data, the speed may be calculated by dividing the middle 6 m by the time (in seconds).

3. Absolute Change From Baseline at Week 48 for Medical Research Council (MRC) Subscore (Total Muscle) and Total Score [48 weeks]

   MRC score assessed in 19 muscles. The muscle scale grades muscle power on a scale of 0 to 5 in relation to the maximum expected for that muscle. The patient's effort is graded on a scale of 0-5: Grade 5: Muscle contracts normally against full resistance. Grade 4: Muscle strength is reduced but muscle contraction can still move joint against resistance. Grade 3: Muscle strength is further reduced such that the joint can be moved only against gravity with the examiner's resistance completely removed. As an example, the elbow can be moved from full extension to full flexion starting with the arm hanging down at the side. Grade 2: Muscle can move only if the resistance of gravity is removed. As an example, the elbow can be fully flexed only if the arm is maintained in a horizontal plane. Grade 1: Only a trace or flicker of movement is seen or felt in the muscle or fasciculations are observed in the muscle. Grade 0: No movement is observed.

4. INCAT Sensory Sum Score (ISS) [48 weeks]

   This sensory scale comprises pin prick and vibration sense plus a two point discrimination value in the arms and legs, and ranges from 0 ("normal sensation") to 20 ("most severe sensory deficit"). Absolute change from baseline at week 48.

5. 6-minute Walk Test [48 weeks]

   The 6MWT is a practical simple test that requires a 30 m (100-ft) hallway. This test measures the distance that a patient can quickly walk on a flat, hard surface in a period of 6 minutes. Absolute change from baseline at week 48.

6. Posturography Score [48 weeks]

   Computerized dynamic posturography (CDP) is a non-invasive specialized clinical assessment technique used to quantify the central nervous system adaptive mechanisms (sensory, motor and central) involved in the control of posture and balance, both in normal and abnormal conditions. Absolute change of speed in spontaneous speed condition from baseline at week 48.

7. Excitability Testing: Supernormality (%) [48 weeks]

   Nerve excitability testing is a non-invasive approach in investigating the pathophysiology of peripheral nerve disorders, which determines the electrical properties of the nerve membrane at the site of stimulation. Absolute change from baseline at week 48. After a nerve fiber is depolarized, a sequence of excitability changes, called the 'recovery cycle', occurs before the membrane potential returns to its resting stage. This cycle includes phases in which the nerve excitability is decreased ('refractory period' or increased ('supernormal period'). During the 10-30 ms following the end of the refractory period, the axon increases its excitability and the nerve fiber is more easily excited (the supernormal period). Depolarization of the node of Ranvier excites the adjacent internodes, which then charge with electric current as capacitors. Supernormality depends on many factors and its interpretation is therefore not univoqual. Data were provided for information only.

8. Strength-duration Time Constant (ms) [48 weeks]

   This secondary outcome measure is an electrophysiological testing endpoint. Absolute change from baseline at week 48. Strength-duration Time Constant (ms) is a measurement of excitability, defined as the duration of the stimulus that has twice the strength of the rheobase current (see below). The lower the rheobase is, the higher is the Strenght duration time constant. Accordingly, higer values of SDTC are associated with better outcome.

9. Rheobase (mA) [48 weeks]

   This secondary outcome measure is an electrophysiological testing endpoint. Absolute change from baseline at week 48. Rheobase is the minimal strength of an electrical stimulus of infinitely long duration that is able to cause excitation. Low values are associated with better outcome (the nerve becomes more excitable).

10. Refractoriness (%) [48 weeks]

    This secondary outcome measure is an electrophysiological testing endpoint. Absolute change from baseline to week 48. After a nerve fiber is depolarized, a sequence of excitability changes, called the 'recovery cycle', occurs before the membrane potential returns to its resting stage. This cycle includes phases in which the nerve excitability is decreased ('refractory period' or increased ('supernormal period'). Refractoriness depends on many factors and its interpretation is therefore not univoqual. Data were provided for information only.

11. Minimum Absolute Refractory Period (ms). [48 weeks]

    This secondary outcome measure is an electrophysiological testing endpoint. Absolute change from baseline at week 48. After a nerve fiber is depolarized, a sequence of excitability changes, called the 'recovery cycle', occurs before the membrane potential returns to its resting stage. This cycle includes phases in which the nerve excitability is decreased ('refractory period' or increased ('supernormal period'). Refractoriness depends on many factors and its interpretation is therefore not univoqual. Data were provided for information only.

12. Maximum Absolute Refractory Period (ms). [Week 48]

    This secondary outcome measure is an electrophysiological testing endpoint. Absolute change from baseline at week 48. After a nerve fiber is depolarized, a sequence of excitability changes, called the 'recovery cycle', occurs before the membrane potential returns to its resting stage. This cycle includes phases in which the nerve excitability is decreased ('refractory period' or increased ('supernormal period'). Refractoriness depends on many factors and its interpretation is therefore not univoqual. Data were provided for information only.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male and female aged between 20 and 85 years.

• Patients fulfilling one of the following diagnosis:

• Five patients with chronic inflammatory demyelinating polyneuropathy on both clinical and neurophysiological grounds.

• Five patients with proven genetic diagnosis of CMT1a or CMT1b

• Five patients with anti-MAG polyneuropathy.

• Electrophysiological parameters worsening for the past 3 years

• Available EMG record, performed during the past 6 months to assess variability of NCV parameters

• Signed and dated written informed consent to participate in the study in accordance with local regulations

• Likely to be able to participate in all scheduled evaluation and complete all required study procedures,

• In the opinion of the investigator, the patient will be compliant and have a high probability of completing the study.

• Both male and female subjects who are not either surgically sterile (tubal ligation/obstruction or removal of ovaries or uterus) or post-menopausal (no spontaneous menstrual periods for at least one year confirmed by a negative hormone panel) must commit to using TWO highly effective method of birth control for the duration of the study and for two months after the treatment termination.

Exclusion Criteria:

• Any general chronic handicapping disease other than peripheral neuropathy

• Impossibility to perform the 10 meters walking test

• Impossibility to assess electrophysiological parameters

• Patients with uncontrolled hepatic disorder, renal or cardiovascular disease, or cancer,

• Patients with hypersensitivity to MD1003 excipients (lactose)

• Laboratory tests out of normal range according to the reference laboratory values. Deviations may be accepted if considered by the investigator as not clinically significant with regards to the study continuation,

• Patients with history or presence of alcohol abuse or drug addiction,

• Patients likely to be non-compliant to the study procedures or for whom a long-term follow-up seems to be difficult to achieve.

• Any new medication for neuropathy initiated less than 3 months prior to inclusion. For CIDP patients, relapse in the past 3 months before inclusion.

• Not easily contactable by the investigator in case of emergency or not capable to call the investigator

• Subjects without effective contraception

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hôpital Henri Mondor, Créteil, France	Creteil		France	94010

Sponsors and Collaborators

• MedDay Pharmaceuticals SA

Investigators

• Principal Investigator: Alain CREANGE, MD, Hôpital Henri Mondor, Créteil, France
• Study Director: Frederic Sedel, MD, Medday Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Feb 10, 2017
• Statistical Analysis Plan - Nov 4, 2019

More Information

Additional Information:

• Sponsor

Publications

None provided.

• Responsible Party: MedDay Pharmaceuticals SA
• ClinicalTrials.gov Identifier: NCT02967679
• Other Study ID Numbers: MD1003CT2015-01 SERENDEM
• First Posted: Nov 18, 2016
• Last Update Posted: Nov 2, 2020
• Last Verified: Oct 1, 2020

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by MedDay Pharmaceuticals SA: Neuropathy; Demyelinating polyradiculoneuropathy
• Additional relevant MeSH terms: Tooth Diseases; Peripheral Nervous System Diseases; Polyneuropathies; Charcot-Marie-Tooth Disease; Nerve Compression Syndromes; Hereditary Sensory and Motor Neuropathy; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Biotin

Study Results

Participant Flow

Arm/Group Title	MD1003
Arm/Group Description	MD1003 100mg capsules, 1 capsule tid for 48 weeks
Period Title: Overall Study
STARTED	15
COMPLETED	14
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	MD1003
Arm/Group Description	MD1003 100mg capsules, 1 capsule tid for 48 weeks
Overall Participants	15
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.36 (14.07)
Sex: Female, Male (Count of Participants)
Female	8 53.3%
Male	7 46.7%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (participants) [Number]
France	15 100%
Disease type (participants) [Number]
CIDP patients	5 33.3%
CMT1a or CMT1b patients	5 33.3%
anti-MAG polyneuropathy	5 33.3%

Outcome Measures

1. Primary Outcome

Title	Motor Nerve Conduction Velocity (m/Sec)
Description	Absolute change from baseline at Week 48.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MD1003
Arm/Group Description	MD1003 100mg capsules, 1 capsule tid for 48 weeks
Measure Participants	15
Mean (Standard Deviation) [m/s]	1.67 (11.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MD1003
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7615
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.67
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 11.45
	Estimation Comments

2. Primary Outcome

Title	Distal Latency (Msec)
Description	Absolute change from baseline at Week 48.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MD1003
Arm/Group Description	MD1003 100mg capsules, 1 capsule tid for 48 weeks
Measure Participants	15
Mean (Standard Deviation) [ms]	0.20 (8.89)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MD1003
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5995
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.20
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 8.89
	Estimation Comments

3. Primary Outcome

Title	F Wave Latency (Msec)
Description	Absolute change from baseline at Week 48.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MD1003
Arm/Group Description	MD1003 100mg capsules, 1 capsule tid for 48 weeks
Measure Participants	9
Mean (Standard Deviation) [ms]	4.8 (8.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MD1003
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1641
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	4.8
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 8.40
	Estimation Comments

4. Primary Outcome

Title	Length of Motor Nerve Potential
Description	Absolute change from baseline at W48.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MD1003
Arm/Group Description	MD1003 100mg capsules, 1 capsule tid for 48 weeks
Measure Participants	15
Mean (Standard Deviation) [ms]	8.5 (16.50)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MD1003
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0353
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	8.5
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 16.5
	Estimation Comments

5. Secondary Outcome

Title	ONLS (Overall Neuropathy Limitations Scale)
Description	The ONLS focuses on upper and lower limb functions, and consists of a checklist for interviewing patients. It is scored from 0 to 5 on the upper limb section and from 0 to 7 on the lower limb section. A score of 0 indicates no limitations (the ceiling of the scale) and a score of 5 or 7 indicates no purposeful movement. Absolute change from baseline at week 48.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MD1003
Arm/Group Description	MD1003 100mg capsules, 1 capsule tid for 48 weeks
Measure Participants	15
Mean (Standard Deviation) [score on a scale]	-0.5 (1.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MD1003
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2642
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 1.4
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline at Week 48 for Timed 10-meter Walk Test
Description	Absolute change from baseline at week 48. The patient is instructed to walk at normal pace for 10 meters. Start and stop of performance time coincides with the toes of the leading foot crossing the 2-m mark and the 8-m mark, respectively. From these data, the speed may be calculated by dividing the middle 6 m by the time (in seconds).
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MD1003
Arm/Group Description	MD1003 100mg capsules, 1 capsule tid for 48 weeks
Measure Participants	15
Mean (Standard Deviation) [second]	-0.6 (1.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MD1003
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1777
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 1.2
	Estimation Comments

7. Secondary Outcome

Title	Absolute Change From Baseline at Week 48 for Medical Research Council (MRC) Subscore (Total Muscle) and Total Score
Description	MRC score assessed in 19 muscles. The muscle scale grades muscle power on a scale of 0 to 5 in relation to the maximum expected for that muscle. The patient's effort is graded on a scale of 0-5: Grade 5: Muscle contracts normally against full resistance. Grade 4: Muscle strength is reduced but muscle contraction can still move joint against resistance. Grade 3: Muscle strength is further reduced such that the joint can be moved only against gravity with the examiner's resistance completely removed. As an example, the elbow can be moved from full extension to full flexion starting with the arm hanging down at the side. Grade 2: Muscle can move only if the resistance of gravity is removed. As an example, the elbow can be fully flexed only if the arm is maintained in a horizontal plane. Grade 1: Only a trace or flicker of movement is seen or felt in the muscle or fasciculations are observed in the muscle. Grade 0: No movement is observed.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MD1003
Arm/Group Description	MD1003 100mg capsules, 1 capsule tid for 48 weeks
Measure Participants	15
Mean (Standard Deviation) [score on a scale]	4.5 (8.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MD1003
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0371
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	4.5
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 8.2
	Estimation Comments

8. Secondary Outcome

Title	INCAT Sensory Sum Score (ISS)
Description	This sensory scale comprises pin prick and vibration sense plus a two point discrimination value in the arms and legs, and ranges from 0 ("normal sensation") to 20 ("most severe sensory deficit"). Absolute change from baseline at week 48.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MD1003
Arm/Group Description	MD1003 100mg capsules, 1 capsule tid for 48 weeks
Measure Participants	15
Mean (Standard Deviation) [score on a scale]	-2.2 (2.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MD1003
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0142
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.2
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 2.9
	Estimation Comments

9. Secondary Outcome

Title	6-minute Walk Test
Description	The 6MWT is a practical simple test that requires a 30 m (100-ft) hallway. This test measures the distance that a patient can quickly walk on a flat, hard surface in a period of 6 minutes. Absolute change from baseline at week 48.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MD1003
Arm/Group Description	MD1003 100mg capsules, 1 capsule tid for 48 weeks
Measure Participants	15
Mean (Standard Deviation) [m]	61.1 (48.9)

10. Secondary Outcome

Title	Posturography Score
Description	Computerized dynamic posturography (CDP) is a non-invasive specialized clinical assessment technique used to quantify the central nervous system adaptive mechanisms (sensory, motor and central) involved in the control of posture and balance, both in normal and abnormal conditions. Absolute change of speed in spontaneous speed condition from baseline at week 48.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MD1003
Arm/Group Description	MD1003 100mg capsules, 1 capsule tid for 48 weeks
Measure Participants	13
Mean (Standard Deviation) [m/s]	0.111 (0.201)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MD1003
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1055
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.111
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.201
	Estimation Comments

11. Secondary Outcome

Title	Excitability Testing: Supernormality (%)
Description	Nerve excitability testing is a non-invasive approach in investigating the pathophysiology of peripheral nerve disorders, which determines the electrical properties of the nerve membrane at the site of stimulation. Absolute change from baseline at week 48. After a nerve fiber is depolarized, a sequence of excitability changes, called the 'recovery cycle', occurs before the membrane potential returns to its resting stage. This cycle includes phases in which the nerve excitability is decreased ('refractory period' or increased ('supernormal period'). During the 10-30 ms following the end of the refractory period, the axon increases its excitability and the nerve fiber is more easily excited (the supernormal period). Depolarization of the node of Ranvier excites the adjacent internodes, which then charge with electric current as capacitors. Supernormality depends on many factors and its interpretation is therefore not univoqual. Data were provided for information only.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MD1003
Arm/Group Description	MD1003 100mg capsules, 1 capsule tid for 48 weeks
Measure Participants	15
Mean (Standard Deviation) [percentage of supernormality]	9.84 (28.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MD1003
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2130
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	9.84
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 28.16
	Estimation Comments

12. Secondary Outcome

Title	Strength-duration Time Constant (ms)
Description	This secondary outcome measure is an electrophysiological testing endpoint. Absolute change from baseline at week 48. Strength-duration Time Constant (ms) is a measurement of excitability, defined as the duration of the stimulus that has twice the strength of the rheobase current (see below). The lower the rheobase is, the higher is the Strenght duration time constant. Accordingly, higer values of SDTC are associated with better outcome.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MD1003
Arm/Group Description	MD1003 100mg capsules, 1 capsule tid for 48 weeks
Measure Participants	15
Mean (Standard Deviation) [ms]	0.068 (0.112)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MD1003
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0393
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.068
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.112
	Estimation Comments

13. Secondary Outcome

Title	Rheobase (mA)
Description	This secondary outcome measure is an electrophysiological testing endpoint. Absolute change from baseline at week 48. Rheobase is the minimal strength of an electrical stimulus of infinitely long duration that is able to cause excitation. Low values are associated with better outcome (the nerve becomes more excitable).
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MD1003
Arm/Group Description	MD1003 100mg capsules, 1 capsule tid for 48 weeks
Measure Participants	15
Mean (Standard Deviation) [mA]	-5.905 (6.283)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MD1003
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-5.905
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 6.283
	Estimation Comments

14. Secondary Outcome

Title	Refractoriness (%)
Description	This secondary outcome measure is an electrophysiological testing endpoint. Absolute change from baseline to week 48. After a nerve fiber is depolarized, a sequence of excitability changes, called the 'recovery cycle', occurs before the membrane potential returns to its resting stage. This cycle includes phases in which the nerve excitability is decreased ('refractory period' or increased ('supernormal period'). Refractoriness depends on many factors and its interpretation is therefore not univoqual. Data were provided for information only.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MD1003
Arm/Group Description	MD1003 100mg capsules, 1 capsule tid for 48 weeks
Measure Participants	15
Mean (Standard Deviation) [percentage of refractoriness]	-4.28 (32.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MD1003
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3303
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-4.28
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 32.21
	Estimation Comments

15. Secondary Outcome

Title	Minimum Absolute Refractory Period (ms).
Description	This secondary outcome measure is an electrophysiological testing endpoint. Absolute change from baseline at week 48. After a nerve fiber is depolarized, a sequence of excitability changes, called the 'recovery cycle', occurs before the membrane potential returns to its resting stage. This cycle includes phases in which the nerve excitability is decreased ('refractory period' or increased ('supernormal period'). Refractoriness depends on many factors and its interpretation is therefore not univoqual. Data were provided for information only.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MD1003
Arm/Group Description	MD1003 100mg capsules, 1 capsule tid for 48 weeks
Measure Participants	15
Mean (Standard Deviation) [ms]	0.000 (0.092)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MD1003
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9229
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.000
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.092
	Estimation Comments

16. Secondary Outcome

Title	Maximum Absolute Refractory Period (ms).
Description	This secondary outcome measure is an electrophysiological testing endpoint. Absolute change from baseline at week 48. After a nerve fiber is depolarized, a sequence of excitability changes, called the 'recovery cycle', occurs before the membrane potential returns to its resting stage. This cycle includes phases in which the nerve excitability is decreased ('refractory period' or increased ('supernormal period'). Refractoriness depends on many factors and its interpretation is therefore not univoqual. Data were provided for information only.
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MD1003
Arm/Group Description	MD1003 100mg capsules, 1 capsule tid for 48 weeks
Measure Participants	15
Mean (Standard Deviation) [ms]	-0.277 (0.871)

Adverse Events

Time Frame	52 weeks
Arm/Group Title	MD1003
Arm/Group Description	MD1003 100mg capsules, 1 capsule tid for 48 weeks
All Cause Mortality
	MD1003
	Affected / at Risk (%)	# Events
Total	0/15 (0%)
Serious Adverse Events
	MD1003
	Affected / at Risk (%)	# Events
Total	2/15 (13.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Clear cell renal cell carcinoma	1/15 (6.7%)	1
Nervous system disorders
Autoimmune encephalopathy	1/15 (6.7%)	1
Other (Not Including Serious) Adverse Events
	MD1003
	Affected / at Risk (%)	# Events
Total	14/15 (93.3%)
Gastrointestinal disorders
Gastric disorder	1/15 (6.7%)	1
Diarrhoea	1/15 (6.7%)	1
Nausea	1/15 (6.7%)	1
Vomiting	1/15 (6.7%)	1
General disorders
Fatigue	3/15 (20%)	3
Oedema peripheral	1/15 (6.7%)	1
Infections and infestations
Urinary tract infection	1/15 (6.7%)	1
Injury, poisoning and procedural complications
Ankle fracture	1/15 (6.7%)	1
Burn oesophageal	1/15 (6.7%)	1
Foot fracture	1/15 (6.7%)	1
Investigations
Laboratory test interference	2/15 (13.3%)	2
Haemoglobin decreased	1/15 (6.7%)	1
Musculoskeletal and connective tissue disorders
arthralgia	3/15 (20%)	4
Muscle spasms	1/15 (6.7%)	1
Musculoskeletal stiffness	1/15 (6.7%)	1
Pain in extremity	1/15 (6.7%)	1
Nervous system disorders
Insomnia	3/15 (20%)	3
balance disorder	1/15 (6.7%)	1
Memory impairment	1/15 (6.7%)	1
Muscle contractions involuntary	1/15 (6.7%)	1
Neuralgia	1/15 (6.7%)	2
Restless legs syndrome	1/15 (6.7%)	1
Sciatica	1/15 (6.7%)	1
Psychiatric disorders
Depression	1/15 (6.7%)	1
Respiratory, thoracic and mediastinal disorders
Sleep apnoea syndrome	1/15 (6.7%)	1
Skin and subcutaneous tissue disorders
Pruritus	2/15 (13.3%)	2
Alopecia	1/15 (6.7%)	1
Rash papular	1/15 (6.7%)	1
Surgical and medical procedures
Breast reconstruction	1/15 (6.7%)	1
Vascular disorders
Hypertension	1/15 (6.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.