Small Fiber Neuropathy
Conditions
Brief summary
This is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group, multicenter study evaluating the efficacy of VX-150 for the treatment of pain caused by small fiber neuropathy.
Interventions
DRUGVX-150
Participants received VX-150 1250 milligrams (mg) once daily (qd) orally for 6 weeks.
DRUGPlacebo
Participants received placebo matched to VX-150 for 6 weeks.
Sponsors
Vertex Pharmaceuticals Incorporated
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Body mass index (BMI) of 18.0 to 31.0 kg/m2, inclusive, and a total body weight \>50 kg * Diagnosis of small fiber neuropathy, as per European Federation Neurological Societies (EFNS)/American Academy of Neurology (AAN) guidelines, with pain for at least 3 months prior to screening * Reduction below the 5th percentile of sex and age-adjusted normal values in epidermal nerve fiber density on punch skin biopsy at the distal site of the leg performed at screening * Normal nerve conduction studies (NCS), including presence of sural response. * Average NRS score between ≥4 and ≤9 reported in the daily diary on Days -7 through -1
Exclusion criteria
* History in the past 10 years of malignancy except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 cervical carcinoma in situ * History of connective tissue disorders, sarcoidosis, Sjögren's syndrome, amyloidosis, Fabry's disease, celiac disease, lyme disease, autoimmune disorders * A known or clinically suspected infection with human immunodeficiency virus or hepatitis B or C viruses * Current clinically significant liver or kidney dysfunction * Current uncontrolled thyroid dysfunction * A diagnosis of diabetes, HbA1C ≥8% at screening * History of cardiac dysrhythmias requiring anti-arrhythmia treatment(s) * Concomitant severe pain conditions which may impair self-assessment of pain due to small fiber neuropathy Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Weekly Average of Daily Pain Intensity on the 11 Point NRS | From Baseline at Week 6 | Pain intensity was evaluated using the 11-point NRS (where 0 signified no pain and 10 signified worst imaginable pain) during the last 24 hours on the NRS each evening. Higher score indicates greater level of pain. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With >=50% Reduction in the Weekly Average of Daily Pain Intensity on the 11-Point NRS | From Baseline at Week 6 | Pain intensity was evaluated using the 11-point NRS (where 0 signified no pain and 10 signified worst imaginable pain) during the last 24 hours on the NRS each evening. Higher score indicates greater level of pain. Percentage of participants \>= 50% reduction in the weekly average of daily pain intensity on the 11-Point NRS were reported. |
| Change in the Daily Sleep Interference Scale (DSIS) | From Baseline at Week 6 | Pain-associated sleep interference was assessed using DSIS, based on an 11-point scale (where 0 signified none: pain does not interfere with sleep and 10 signified severe: pain completely interferes with sleep, unable to sleep). Higher score indicates greater pain associated sleep interference. |
| Percentage of Participants Categorized as Improved on the Patient Global Impression of Change (PGIC) Scale | At Week 6 | PGIC scale evaluated the change in activity limitations, symptoms, emotions, and overall quality of life (QoL) related to the participants painful condition on 7-point scale from 1 (improved) to 7 (worse). Participants were categorized as following: scale from 1 - 2 were categorized as improved, scale from 3 - 4 as no change and scale from 5 - 7 were categorized as worse. Percentage of participants categorized as improved on PGIC scale at week 6 were reported for this outcome measure. |
| Percentage of Participants With Greater Than or Equal to (>=) 30 Percent (%) Reduction in the Weekly Average of Daily Pain Intensity on the 11-Point NRS | From Baseline at Week 6 | Pain intensity was evaluated using the 11-point NRS (where 0 signified no pain and 10 signified worst imaginable pain) during the last 24 hours on the NRS each evening. Higher score indicates greater level of pain. Percentage of participants \>= 30% reduction in the weekly average of daily pain intensity on the 11-Point NRS were reported. |
| Pre-dose Plasma Concentration (Ctrough) of VRT-1207355 and the Metabolite VRT-1268114 | Pre-dose at Day 7 | — |
| Number of Participants With Clinically Meaningful Findings in Columbia Suicide Severity Rating Scale (C-SSRS) Responses | Day 1 up to Week 10 | The C-SSRS is an interview-based rating scale was evaluated through a series of questions about suicidal thoughts and behaviors with the possible answers yes or no. Yes represents a worse outcome. Clinically Meaningfulness of C-SSRS responses were judged by investigator based on answers received from participants. |
| Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Day 1 up to Week 10 | — |
| Change in Pain Intensity on the 11-Point NRS | From Baseline at Week 6 | Pain intensity was evaluated using the 11-point NRS (where 0 signified no pain and 10 signified worst imaginable pain) during the last 24 hours on the NRS each evening. Higher score indicates greater level of pain. Higher score indicates greater level of pain. |
Countries
Germany, Italy, Netherlands, United States
Participant flow
Pre-assignment details
A total of 89 participants were enrolled and randomized in the study.
Participants by arm
| Arm | Count |
|---|---|
| VX-150 Participants received VX-150 1250 mg qd for 6 weeks. | 46 |
| Placebo Participants received placebo matched to VX-150 for 6 weeks. | 43 |
| Total | 89 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 4 |
| Overall Study | Other | 0 | 1 |
| Overall Study | Withdrawal of consent (due to lack of efficacy) | 1 | 1 |
| Overall Study | Withdrawal of consent (for other reason) | 0 | 2 |
Baseline characteristics
| Characteristic | VX-150 | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 55.1 years STANDARD_DEVIATION 12.34 | 58.1 years STANDARD_DEVIATION 11.86 | 56.6 years STANDARD_DEVIATION 12.14 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 5 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 43 Participants | 38 Participants | 81 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Pain Intensity at Baseline on 11-point Numeric Rating Scale (NRS) | 6.433 units on a scale STANDARD_DEVIATION 1.44 | 5.990 units on a scale STANDARD_DEVIATION 1.413 | 6.219 units on a scale STANDARD_DEVIATION 1.436 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 4 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 39 Participants | 34 Participants | 73 Participants |
| Sex: Female, Male Female | 22 Participants | 21 Participants | 43 Participants |
| Sex: Female, Male Male | 24 Participants | 22 Participants | 46 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 46 | 0 / 43 |
| other Total, other adverse events | 16 / 46 | 7 / 43 |
| serious Total, serious adverse events | 0 / 46 | 3 / 43 |
Outcome results
Primary
Change in Weekly Average of Daily Pain Intensity on the 11 Point NRS
Pain intensity was evaluated using the 11-point NRS (where 0 signified no pain and 10 signified worst imaginable pain) during the last 24 hours on the NRS each evening. Higher score indicates greater level of pain.
Time frame: From Baseline at Week 6
Population: Full Analysis Set (FAS) included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| VX-150 | Change in Weekly Average of Daily Pain Intensity on the 11 Point NRS | -2.018 units on a scale | Standard Error 0.274 |
| Placebo | Change in Weekly Average of Daily Pain Intensity on the 11 Point NRS | -0.933 units on a scale | Standard Error 0.287 |
p-value: <0.000195% CI: [-1.876, -0.293]Mixed-effects Model for Repeated Measure
Secondary
Change in Pain Intensity on the 11-Point NRS
Pain intensity was evaluated using the 11-point NRS (where 0 signified no pain and 10 signified worst imaginable pain) during the last 24 hours on the NRS each evening. Higher score indicates greater level of pain. Higher score indicates greater level of pain.
Time frame: From Baseline at Week 6
Population: FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| VX-150 | Change in Pain Intensity on the 11-Point NRS | -1.7 units on a scale | Standard Error 0.3 |
| Placebo | Change in Pain Intensity on the 11-Point NRS | -1.1 units on a scale | Standard Error 0.3 |
p-value: <0.000195% CI: [-1.5, 0.3]Mixed-effects Model for Repeated Measure
Secondary
Change in the Daily Sleep Interference Scale (DSIS)
Pain-associated sleep interference was assessed using DSIS, based on an 11-point scale (where 0 signified none: pain does not interfere with sleep and 10 signified severe: pain completely interferes with sleep, unable to sleep). Higher score indicates greater pain associated sleep interference.
Time frame: From Baseline at Week 6
Population: FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| VX-150 | Change in the Daily Sleep Interference Scale (DSIS) | -1.777 units on a scale | Standard Error 0.276 |
| Placebo | Change in the Daily Sleep Interference Scale (DSIS) | -0.665 units on a scale | Standard Error 0.289 |
p-value: <0.000195% CI: [-1.911, -0.312]Mixed-effects Model for Repeated Measure
Secondary
Number of Participants With Clinically Meaningful Findings in Columbia Suicide Severity Rating Scale (C-SSRS) Responses
The C-SSRS is an interview-based rating scale was evaluated through a series of questions about suicidal thoughts and behaviors with the possible answers yes or no. Yes represents a worse outcome. Clinically Meaningfulness of C-SSRS responses were judged by investigator based on answers received from participants.
Time frame: Day 1 up to Week 10
Population: Safety Set included all participants who have received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VX-150 | Number of Participants With Clinically Meaningful Findings in Columbia Suicide Severity Rating Scale (C-SSRS) Responses | 0 participants |
| Placebo | Number of Participants With Clinically Meaningful Findings in Columbia Suicide Severity Rating Scale (C-SSRS) Responses | 0 participants |
Secondary
Percentage of Participants Categorized as Improved on the Patient Global Impression of Change (PGIC) Scale
PGIC scale evaluated the change in activity limitations, symptoms, emotions, and overall quality of life (QoL) related to the participants painful condition on 7-point scale from 1 (improved) to 7 (worse). Participants were categorized as following: scale from 1 - 2 were categorized as improved, scale from 3 - 4 as no change and scale from 5 - 7 were categorized as worse. Percentage of participants categorized as improved on PGIC scale at week 6 were reported for this outcome measure.
Time frame: At Week 6
Population: FAS. Here, 'overall number of participants analyzed' signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VX-150 | Percentage of Participants Categorized as Improved on the Patient Global Impression of Change (PGIC) Scale | 39.5 percentage of participants |
| Placebo | Percentage of Participants Categorized as Improved on the Patient Global Impression of Change (PGIC) Scale | 13.5 percentage of participants |
Secondary
Percentage of Participants With >=50% Reduction in the Weekly Average of Daily Pain Intensity on the 11-Point NRS
Pain intensity was evaluated using the 11-point NRS (where 0 signified no pain and 10 signified worst imaginable pain) during the last 24 hours on the NRS each evening. Higher score indicates greater level of pain. Percentage of participants \>= 50% reduction in the weekly average of daily pain intensity on the 11-Point NRS were reported.
Time frame: From Baseline at Week 6
Population: FAS. Here, 'overall number of participants analyzed' signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VX-150 | Percentage of Participants With >=50% Reduction in the Weekly Average of Daily Pain Intensity on the 11-Point NRS | 32.5 percentage of participants |
| Placebo | Percentage of Participants With >=50% Reduction in the Weekly Average of Daily Pain Intensity on the 11-Point NRS | 17.6 percentage of participants |
Secondary
Percentage of Participants With Greater Than or Equal to (>=) 30 Percent (%) Reduction in the Weekly Average of Daily Pain Intensity on the 11-Point NRS
Pain intensity was evaluated using the 11-point NRS (where 0 signified no pain and 10 signified worst imaginable pain) during the last 24 hours on the NRS each evening. Higher score indicates greater level of pain. Percentage of participants \>= 30% reduction in the weekly average of daily pain intensity on the 11-Point NRS were reported.
Time frame: From Baseline at Week 6
Population: FAS. Here, 'overall number of participants analyzed' signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VX-150 | Percentage of Participants With Greater Than or Equal to (>=) 30 Percent (%) Reduction in the Weekly Average of Daily Pain Intensity on the 11-Point NRS | 45.0 percentage of participants |
| Placebo | Percentage of Participants With Greater Than or Equal to (>=) 30 Percent (%) Reduction in the Weekly Average of Daily Pain Intensity on the 11-Point NRS | 26.5 percentage of participants |
Secondary
Pre-dose Plasma Concentration (Ctrough) of VRT-1207355 and the Metabolite VRT-1268114
Time frame: Pre-dose at Day 7
Population: Pharmacokinetic (PK) set included participants who received at least 1 dose of study drug and for whom the primary PK data was considered to be sufficient and interpretable.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| VX-150 | Pre-dose Plasma Concentration (Ctrough) of VRT-1207355 and the Metabolite VRT-1268114 | VRT-1207355 | 3.89 microgram per milliliter (mcg/mL) | Standard Deviation 2.73 |
| VX-150 | Pre-dose Plasma Concentration (Ctrough) of VRT-1207355 and the Metabolite VRT-1268114 | VRT-1268114 | 1.35 microgram per milliliter (mcg/mL) | Standard Deviation 0.752 |
Secondary
Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: Day 1 up to Week 10
Population: Safety set included all participants who had received at least 1 dose of the study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| VX-150 | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 29 participants |
| VX-150 | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 0 participants |
| Placebo | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 24 participants |
| Placebo | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 3 participants |