Background
Methods
Patients
Selection of doses
Randomisation, masking and blinding
Procedures
Safety and tolerability
Pharmacokinetics
Electrophysiology
Efficacy
-
i) Functional measures:
-
6-Minute Walk Test (6MWT) [32] to assess gait velocity by the distance walked during six minutes (in metres).
-
9-Hole Peg Test (9HPT) to assess finger dexterity by the time required to put nine pegs in nine holes (in seconds, non-dominant hand considered).
-
Quantified Muscular Testing (QMT) [33] to assess muscle strength by Ankle Dorsiflexion (in Newton metres, mean of left and right side considered) and Hand Grip (in kilogrammes, non-dominant hand considered).
-
-
ii) Electrophysiological parameters:
-
Amplitude of Compound Muscle Action Potential (CMAP, in millivolt), Motor Conduction Velocity (MCV, in metres per second) and Distal Motor Latency (DML, in millisecond) measured from the mean motor responses of the median and ulnar nerves (non-dominant side considered).
-
Amplitude of Sensory Nerve Action Potential (SNAP, in microvolt) and Sensitive Conduction Velocity (SCV, in metres per second) measured from the mean sensory responses of the median and ulnar nerves (non-dominant side considered). The nerve sensory measures have to be interpreted with caution because of a particularly high content of missing values in SCV and of 0 values in SNAP, the latter reflecting measures below the detection threshold.
Myelin state of non-degenerated axons is generally assessed by MCV, DML and SCV while CMAP and SNAP inform on the degree of axonal loss, but it must be stressed that the variability attached to these measures is high. -
-
iii) Self-assessment-based measurements:
-
Visual Analog Scales (VAS) for pain, fatigue and global state were assessed by the patient;
-
Clinical Global Impression (CGI) for global improvement, illness severity and therapeutic effect was assessed by the physician.
-
Additional exploratory outcomes
-
Intra-epidermal axon density in cutaneous biopsy of the lateral malleolus.
-
mRNA expression of PMP22 in cutaneous biopsy of the lateral malleolus.
-
Plasma concentrations of a series of bio-chemical biomarkers.
Between-sites standardisation
Statistical analysis
Analysis population
Baseline analysis
Safety and tolerability analysis
Efficacy analysis
General procedures
Results
Placebo
(
n
= 19)
|
PXT3003 LD
(
n
= 21)
|
PXT3003 ID
(
n
= 21)
|
PXT3003 HD
(
n
= 19)
| |
---|---|---|---|---|
Mild/Moderate
| 3 (16%)/16 (84%) | 4 (19%)/17(81%) | 5 (24%)/16 (76%) | 3 (16%)/16 (84%) |
Women/Men
| 11 (58%)/8 (42%) | 14 (67%)/7 (33%) | 13 (62%)/8 (38%) | 10 (53%)/9 (47%) |
Age (years)
| 43.2 (12.2) | 47.9 (14.9) | 44.3 (12.7) | 44.6 (11.2) |
Body Mass Index
| 25.0 (3.9) | 24.5 (4.0) | 23.5 (3.5) | 23.6 (4.6) |
Disease Duration (years)
| 7.1 (5.5) | 10.2 (13.1) | 6.6 (4.5) | 8.9 (5.5) |
CMTNS
| 14.3 (3.8) | 14.2 (4.1) | 13.0 (4.0) | 13.8 (3.4) |
ONLS
| 3.1 (1.1) | 3.3 (1.0) | 3.5 (0.9) | 3.6 (0.8) |
6MWT (m)
| 468.2 (99.9) | 473.1 (70.9) | 450.7 (71.1) | 429.3 (83.7) |
9HPT (s)
| 17.2 (2.5) | 16.1 (3.9) | 18.4 (4.7) | 20.8 (7.8) |
Ankle Dorsiflexion (Nm)
| 7.8 (6.6) | 9.1 (5.0) | 8.3 (5.6) | 8.2 (6.1) |
Grip (kg)
| 22.6 (10.7) | 21.6 (6.1) | 23.1 (9.2) | 20.6 (10.4) |
CMAP (milliV)
| 3.7 (2.0) | 4.0 (1.8) | 3.7 (2.1) | 3.4 (2.3) |
MCV (m/s)
| 21.5 (3.6) | 22.7 (4.7) | 20.8 (4.8) | 20.5 (5.3) |
DML (ms)
| 8.6 (2.2) | 7.9 (2.1) | 8.2 (1.8) | 8.2 (1.9) |
SNAP (microV)
| 2.6 (3.2) | 2.3 (3.0) | 2.6 (3.8) | 2.2 (2.7) |
SCV (m/s)
| 31.1 (14.8) | 29.4 (8.2) | 31.3 (9.4) | 29.9 (7.7) |
Safety and tolerability
PXT3003
|
Placebo
|
Total
| ||||||||
---|---|---|---|---|---|---|---|---|---|---|
High dose
|
Intermediate dose
|
Low dose
| ||||||||
(
n
= 19)
|
(
n
= 21)
|
(
n
= 21)
|
(
n
= 19)
|
(
n
= 80)
| ||||||
n
|
(%)
|
n
|
(%)
|
n
|
(%)
|
n
|
(%)
|
n
|
(%)
| |
Any adverse event
| 6 | 31.6 | 7 | 33.3 | 5 | 23.8 | 9 | 47.4 | 27 | 33.8 |
Gastrointestinal disorders
| 4 | 21.1 | 1 | 4.8 | 1 | 4.8 | 6 | 31.6 | 12 | 15.0 |
Nausea
| 2 | 10.5 | 1 | 4.8 | 0 | 0.0 | 3 | 15.8 | 6 | 7.5 |
Abdominal pain
| 2 | 10.5 | 0 | 0.0 | 0 | 0.0 | 1 | 5.3 | 3 | 3.8 |
Diarrhoea
| 1 | 5.3 | 0 | 0.0 | 0 | 0.0 | 1 | 5.3 | 2 | 2.5 |
Nervous system disorders
| 3 | 15.8 | 2 | 9.5 | 2 | 9.5 | 2 | 10.5 | 9 | 11.3 |
Dizziness
| 1 | 5.3 | 0 | 0.0 | 2 | 9.5 | 2 | 10.5 | 5 | 6.3 |
Headache
| 0 | 0.0 | 2 | 9.5 | 0 | 0.0 | 0 | 0.0 | 2 | 2.5 |
Somnolence
| 2 | 10.5 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 2 | 2.5 |
General disorders and administration site conditions
| 0 | 0.0 | 1 | 4.8 | 1 | 4.8 | 3 | 15.8 | 5 | 6.3 |
Fatigue
| 0 | 0.0 | 1 | 4.8 | 1 | 4.8 | 1 | 5.3 | 3 | 3.8 |
Musculoskeletal and connective tissue disorders
| 1 | 5.3 | 1 | 4.8 | 1 | 4.8 | 1 | 5.3 | 4 | 5.0 |
Muscle spasms
| 1 | 5.3 | 1 | 4.8 | 0 | 0.0 | 0 | 0.0 | 2 | 2.5 |
Renal and urinary disorders
| 1 | 5.3 | 0 | 0.0 | 0 | 0.0 | 1 | 5.3 | 2 | 2.5 |
Efficacy
Mean % of improvement
|
PXT3003 LD
versus
Placebo
|
PXT3003 ID
versus
Placebo
|
PXT3003 HD
versus
Placebo
|
Dose-effect
| ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Placebo
(
n
= 19)
|
PXT3003 LD
(
n
= 21)
|
PXT3003 ID
(
n
= 21)
|
PXT3003 HD
(
n
= 19)
|
Estimate
|
P
-value
|
Estimate
|
P
-value
|
Estimate
|
P
-value
|
Correlation
|
P
-value
| |
CMTNS
| 2.6 (17.5) | 0.5 (23.2) | −3.1 (16.0) |
7.7 (18.4)
| −2.6 (−11.9;7.6) | 0.67 | −3.1 (−11.0;5.4) | 0.74 | 5.5 (−3.4;15.2) | 0.16 | 0.54 | 0.30 |
ONLS
| −5.3 (19.3) | −6.5 (18.5) | 4.8 (24.2) |
12.3 (28.4)
| −3.9 (−14.2;7.6) | 0.72 | 6.9 (−3.8;18.8) | 0.15 | 14.4 (0.55;30.2) | 0.043* | 0.28 | 0.006* |
6MWT (m)
| 9.0 (8.3) | 6.2 (8.3) | 6.4 (9.4) |
9.9 (6.9)
| −2.4 (−6.2;1.5) | 0.85 | −2.4 (−6.6;2.0) | 0.82 | 0.7 (−3.2;4.7) | 0.38 | 0.11 | 0.16 |
9HPT (s)
| 4.9 (11.4) | −1.2 (11.7) | 5.6 (9.9) |
7.8 (12.1)
| −4.6 (−10.3;1.5) | 0.89 | −0.2 (−5.3;5.2) | 0.52 | 0.3 (−5.7;6.6) | 0.47 | 0.15 | 0.092 |
Ankle Dorsiflexion (Nm)
| 20.2 (88.4) | −3.6 (43.0) |
81.5 (369.6)
| 20.4 (64.1) | −4.0 (−21.7;17.8) | 0.63 | 11.4 (−15.4;46.8) | 0.26 | 8.2 (−13.8;35.9) | 0.28 | 0.11 | 0.16 |
Grip (kg)
| 9.9 (24.2) | 1.3 (15.6) | 4.7 (12.5) |
11.7 (18.1)
| −7.1 (−15.6;2.1) | 0.90 | −3.6 (−11.8;5.4) | 0.75 | 1.6 (−7.7;11.9) | 0.39 | 0.12 | 0.15 |
CMAP (milliV)
| 34.4 (62.0) | 1.4 (38.7) | 22.9 (62.6) |
64.2 (208.5)
| −25.1 (−44.8;1.5) | 0.94 | −9.2 (−27.3;13.5) | 0.77 | −5.1 (−27.1;23.6) | 0.63 | −0.001 | 0.50 |
MCV (m/s)
| 3.7 (8.5) | 3.0 (11.5) | 5.7 (12.3) |
9.0 (17.6)
| −1.0 (−6.5;4.9) | 0.61 | 0.5 (−4.8;6.2) | 0.44 | 2.8 (−3.4;9.4) | 0.23 | 0.11 | 0.18 |
DML (ms)
| 0.4 (8.8) | 3.6 (21.7) |
15.3 (35.8)
| 8.4 (21.7) | 3.4 (−4.3;11.7) | 0.24 | 13.8 (4.2;24.3) | 0.009* | 8.0 (0.59;16.0) | 0.038* | 0.21 | 0.035* |
SNAP (microV)
| 12.4 (121.7) | 11.5 (88.2) |
23.3 (128.4)
| 5.2 (69.0) | −1.2 (−42.9;71.0) | 0.52 | 8.7 (−31.2;71.6) | 0.38 | 13.9 (−24.1;71.0) | 0.29 | 0.09 | 0.30 |
SCV (m/s)
| 3.4 (11.0) | 5.3 (11.2) | 29.5 (63.4) |
30.5 (10.0)
| 1.5 (−5.8;9.4) | 0.36 | 17.5 (−5.5;46.2) | 0.11† | 26.6 (15.5;38.8) | 0.00037* | 0.42 | 0.01* |
Mean % of improvement
|
PXT3003 HD
versus
PLI
| |||
---|---|---|---|---|
PLI
(
n
= 61)
|
PXT3003 HD
(
n
= 19)
|
Estimate
|
P
-value
| |
CMTNS
| −0.1 (19.0) |
7.7 (18.4)
| 8.0 (0.4;16.2) | 0.042* |
ONLS
| −2.2 (21.2) |
12.3 (28.4)
| 12.1 (2.0;23.2) | 0.024* |
6MWT (m)
| 7.1 (8.6) |
9.9 (6.9)
| 2.6 (−0.73;6.1) | 0.099 |
9HPT (s)
| 3.1 (11.3) |
7.8 (12.1)
| 1.2 (−3.4;6.0) | 0.33 |
Ankle Dorsiflexion (Nm)
|
33.1 (223.2)
| 20.4 (64.1) | 5.5 (−12.8;27.7) | 0.32 |
Grip (kg)
| 5.1 (17.9) |
11.7 (18.1)
| 6.0 (−1.2;13.7) | 0.088 |
CMAP (milliV)
| 19.6 (56.5) |
64.2 (208.5)
| 6.6 (−15.8;35.1) | 0.33 |
MCV (m/s)
| 4.2 (10.9) |
9.0 (17.6)
| 2.5 (−2.4;7.7) | 0.21 |
DML (ms)
| 6.7 (25.6) |
8.4 (21.7)
| 2.2 (−5.1;10.0) | 0.31 |
SNAP (microV)
|
15.9 (110.2)
| 5.2 (69.0) | 12.0 (−23.9;64.9) | 0.31 |
SCV (m/s)
| 12.7 (38.0) |
30.5 (10.0)
| 20.1 (2.4;40.8) | 0.030* |
Patients non-deteriorating after one year under HD appear less affected at baseline
Placebo
(
n
= 19)
|
PXT3003 LD
(
n
= 21)
|
PXT3003 ID
(
n
= 21)
|
PXT3003 HD
(
n
= 19)
|
HD
versus
Placebo
|
HD
versus
PLI
| |||
---|---|---|---|---|---|---|---|---|
Non-deteriorated
| 10 (52%) | 10 (48%) | 9 (43%) | 15 (79%) | Relative Risk |
P-value | Relative Risk |
P-value |
1.5 (1.03;1.77) | 0.047* | 1.66 (1.24;1.93) | 0.010* |