The primary objective of this study is to evaluate the efficacy of BIIB074 in treating pain experienced by subjects with confirmed SFN that is idiopathic or associated with diabetes mellitus.Sub study objective:Corneal Confocal Microscopy (CCM) as a…
ID
Source
Brief title
Condition
- Other condition
- Diabetic complications
Synonym
Health condition
Small Fibre Neurophaty that is Idiopathic or associated with Diabetes Mellitus
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of this study is to evaluate the efficacy of BIIB074 in
treating pain experienced by subjects with confirmed SFN that is idiopathic or
associated with diabetes mellitus.
The primary endpoint that relates to this objective is the change from Baseline
to Week 12 of the double-blind period in the mean average daily pain (ADP)
score on an 11-point Numerical Rating Scale (NRS), where 0 = no pain and 10 =
worst pain imaginable.
A secondary endpoint that relates to the primary objective is the change from
Randomization to Week 12 of the double-blind period in mean ADP score on the
11-point NRS.
Secondary outcome
1. To evaluate the effect on worst pain, neuropathic pain quality, sleep
interference due to pain, patient global impression, use of rescue medication,
and SFN symptoms
in subjects treated with BIIB074.
The endpoints that relate to this objective are as follows:
• Change from Baseline to Week 12 of the double-blind period in mean worst
daily pain (WDP) score on the 11-point NRS.
• Change from Baseline to Week 12 of the double-blind period in mean sleep
interference score on the 11-point NRS.
• Change from Baseline to Week 12 of the double-blind period in Neuropathic
Pain Symptom Inventory (NPSI) total score and sum score of symptoms of
neuropathic pain (burning and pressing).
• Proportion of subjects with at least a 2-point reduction from Baseline to
Week 12 of the double-blind period in mean ADP.
• Proportion of subjects with at least a 30% reduction from Baseline to Week 12
of the double-blind period in mean ADP.
• Amount of rescue medication (paracetamol/acetaminophen) used for SFN pain
during the double-blind period.
• Patient Global Impression of Change (PGIC) measured at Week 12 of the
double-blind period (7-point scale).
• Change from Baseline to Week 12 of the double-blind period in the Brief Pain
Inventory-Short Form (BPI-SF) interference score.
2. To investigate the safety and tolerability of BIIB074 in subjects with SFN.
The endpoint that relates to this objective is the incidence of adverse events
and serious adverse events during the double blind period.
3. To characterize the pharmacokinetics (PK) of BIIB074 insubjects with SFN.
The endpoints that relate to this objective include population-derived PK
parameters and estimates of exposure (maximum observed concentration and area
under the
concentration-time curve) at steady state.
Background summary
BIIB074 is a state- and use-dependent Nav1.7 channel blocker. Nav1.7 has been
validated as a key pain target by human genetic linkage. Sodium channels are
important for nerve impulse conduction, including within pain sensitive
nociceptive fibres and within the pain pathway in the spinal cord and brain.
Based on nonclinical and clinical data, BIIB074 is being tested in a number of
neuropathic pain conditions.
Small fibre neuropathy (SFN) is a neuropathic pain condition caused by damage
to small unmyelinated (C fibres) and thinly myelinated (A delta) peripheral
nerve fibres and is characterized by severe pain that typically begins in the
feet or hands [Hovaguimian and Gibbons 2011]. Diabetes and impaired glucose
tolerance are the most common causes of SFN, although for a significant portion
of patients, SFN is idiopathic as no cause can be identified. With no
treatments indicated specifically for this type of neuropathic pain and with
other pain medications, including opioids, being used with limited efficacy and
poor tolerability, there is a high unmet medical need for new effective
therapies.
Study objective
The primary objective of this study is to evaluate the efficacy of BIIB074 in
treating pain experienced by subjects with confirmed SFN that is idiopathic or
associated with diabetes mellitus.
Sub study objective:
Corneal Confocal Microscopy (CCM) as a Screening, Predictive, and Surrogate
Endpoint Biomarker for study 802NP206: A Phase 2 Placebo-
Controlled, Double-Blind, Enriched Enrollment Randomized Withdrawal Study to
Evaluate the Efficacy and Safety of BIIB074 in Treating Pain
Experienced by Subjects With Confirmed Small Fibre Neuropathy That is
Idiopathic or Associated With Diabetes Mellitus.
Exploratory Objectives:
To evaluate the relationship of quantitative corneal nerve morphology via CCM
with SFN diagnosis.
To evaluate the relationship of quantitative corneal nerve morphology via CCM
with initial response to BIIB074.
To evaluate the relationship of quantitative corneal nerve morphology via CCM
with response to continued BIIB074 treatment or placebo for 12
weeks.
Study design
This is a multicenter, double-blind, enriched enrollment randomized withdrawal
study designed to evaluate the efficacy and safety of 200 mg and 350 mg twice
daily (BID) of BIIB074 compared with placebo in treating pain experienced by
subjects with confirmed SFN that is idiopathic or associated with diabetes
mellitus (glycosylated hemoglobin A1c [HbA1c] <=11%).
The duration of study participation will be approximately 26 weeks, including a
screening assessment period of up to 21 days, a taper period (if applicable) of
up to 14 days, a 5-day washout period, a 4-week open-label run-in period, a
12-week double-blind period, and a 4-week follow-up period.
Subjects who meet all eligibility criteria including a confirmed abnormality in
a single skin biopsy during the screening assessment period, will enter the
taper period (if applicable). During the taper period, subjects will be
required to titrate down, if needed. Subjects can enter the washout period as
soon as they discontinue the medications used for pain.
Subjects who meet all screening assessments and are not taking any medications
used for pain can enter the 5-day washout period directly from the screening
assessment period. No medications used for pain will be allowed during the
washout period (see Section 7).
During the open-label run-in period all subjects will receive BIIB074 at 350 mg
BID. Subjects who respond to BIIB074 (350 mg BID) in the open-label run-in
period and meet all other randomization criteria (see Section 8.6) will be
randomly assigned to receive either BIIB074 at 200 mg or 350 mg BID or placebo
BID during the 12-week
double-blind period.
Rescue medication (paracetamol/acetaminophen) may be used within dosing
limitations, if needed, to treat SFN pain during the open-label run-in and
double-blind periods of the study.
Intervention
The duration of study participation will be approximately 26 weeks, including a
screening assessment period of up to 21 days, a taper period (if applicable) of
up to 14 days, a 5-day washout period, a 4-week open-label run-in period, a
12-week double-blind period, and a 4-week follow-up period.
Subjects who meet all eligibility criteria including a confirmed abnormality in
a single skin biopsy during the screening assessment period, will enter the
taper period (if applicable).
During the taper period, subjects will be required to titrate down, if needed.
Subjects can enter the washout period as soon as they discontinue the
medications used for pain.
Subjects who meet all screening assessments and are not taking any medications
used for pain can enter the 5-day washout period directly from the screening
assessment period. No medications used for pain will be allowed during the
washout period.
During the open-label run-in period all subjects will receive BIIB074 in 2
tablets at total concentration of 350 mg BID for 2 times a day. Subjects who
respond to BIIB074 (350 mg BID) in the open-label run-in period and meet all
other randomization criteria (will be randomly assigned to receive either
BIIB074 at 200 mg or 350 mg BID or placebo BID 2 times a day during the 12-week
double-blind period.
Rescue medication (paracetamol/acetaminophen) may be used within dosing
limitations, if needed, to treat SFN pain during the open-label run-in and
double-blind periods of the study
Study burden and risks
There are no therapies specifically indicated for the treatment of pain
associated with SFN. Management of SFN is focused on addressing the underlying
disease and/or pain management. Pain medications, including opioids, have been
used with limited efficacy and poor tolerability.
Based on limitations associated with currently available treatment, including
limited efficacy, and/or serious side effects, there is a need for the
development of alternative treatments for neuropathic pain associated with SFN
that are both effective and generally well tolerated.
A recent study in patients with idiopathic SFN showed that a portion of
patients had a mutation in the SCN9A or SCN10A gene encoding the sodium channel
Nav1.7 or Nav1.8, respectively, and a mutation in Nav1.7 has also been found in
patients with inherited pain-disorders such as inherited EM or paroxysmal
extreme pain disorder [Waxman 2013].
BIIB074 is a state- and use-dependent Nav1.7 channel blocker. Based on its
mechanism of action, nonclinical safety profile, and experience in clinical
studies to date, BIIB074 may provide an effective treatment for pain associated
with SFN.
Biogen Iden Research Limited Innovation House, 70Norden Road
Maidenhead, Berkshire SL6 4AY
GB
Biogen Iden Research Limited Innovation House, 70Norden Road
Maidenhead, Berkshire SL6 4AY
GB
Listed location countries
Age
Inclusion criteria
Key Inclusion Criteria:
1. This study will be conducted in subjects who have had a diagnosis of
at least probable SFN length-dependent distribution for >=6 months and
<=10 years , based on clinical diagnosis and confirmed by intraepidermal
nerve fibre density (IENFD) values, and
weekly mean average daily pain (ADP) score of >=5 and <=9 on an 11-
point Pain Intensity Numeric Rating Scale (PI-NRS) over the last 7 days
of Screening.
2. In addition to these criteria, subjects with diabetes will be required to
have HbA1c <=11%, treated with oral hypoglycemics and/or
subcutaneous insulin or diet, no evidence of ulcers, advanced
retinopathy (defined as greater than State 3 [moderate non-proliferative
diabetic retinopathy]) (DCCT/EDIC Research Group 2017), severe
nephropathy, or clinically significant obstructive atherosclerotic disease
(e.g. current unstable angina or myocardial infacrtion within 6 months of
Screening), or current class IV heart failure to be eligible for the study.
NOTE: Other protocol defined Inclusion criteria may apply
Exclusion criteria
Key Exclusion Criteria:
1. Previous exposure to BIIB074 (formerly known as CNV1014802 or
GSK1014802).
2. Use of capsaicin patch within 3 months prior to Screening.
3. Unable or unwilling to discontinue concomitant medications for
neuropathic pain during the 2 week
taper period, which overlaps the first week of the openlabel run-in
period.
4. Unable or unwilling to comply with the prohibited concomitant
medication restrictions, including but not limited to
UDPglucuronosyltransferase
(UGT) inducers and inhibitors, monoamine
oxidase inhibitors (MAOIs), and Nav blockers.
5. Use of over-the-counter medications, vitamin and mineral
supplements, herbal remedies (including St. John's wort), dietary
supplements, or foods (including
grapefruit juice) that affect UGTs.
6. Unable or unwilling to discontinue medications that are P-glycoprotein
substrates with a narrow therapeutic
index, including but not limited to digoxin.
7. History of hemophilia or Von Willebrand's disease, or use of
anticoagulants that may result in bleeding risk during the skin biopsy.
8. Any contraindication, as determined by the Investigator, to
performing a skin biopsy for intraepidermal nerve fibre analysis.
9. Current hepatitis C infection (defined as positive hepatitis C virus
[HCV] antibody and detectable HCV ribonucleic acid [RNA}. Participants
with positive HCV antibody and undetectable HCV RNA are eligible to
participate in the study (United States Centers for Disease Control and
Prevention).
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-000991-27-NL |
| CCMO | NL62483.018.17 |