Clinical trial NCT03536559: Nanocrystalline Gold to Treat Remyelination Failure in Chronic Optic Neuropathy In Multiple Sclerosis
Official title: A Phase 2, Randomized, DB-PC, Parallel Group Study for the Treatment of Visual Pathway Deficits In Chronic Optic Neuropathy to Assess the Efficacy, Safety, Tolerability and Pharmacokinetics of CNM-Au8 For Remyelination In Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Relapsing Remitting Multiple Sclerosis
Optic Neuropathy
Optic; Neuritis, With Demyelination
Keywords: gold
nanocrystal
multifocal visual evoked potential
full field visual evoked potential
low contrast vision
low contrast letter acuity
remyelination
demyelination
Lead sponsor: Clene Nanomedicine
Sponsor class: INDUSTRY
Collaborators: name: Clene Australia Pty Ltd.
First posted: 2018-05-24
Enrollment: 73
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: randomized, double-blind, parallel group, placebo controlled study
Primary purpose: TREATMENT

Brief summary: The objective of this trial is to assess the efficacy and safety of CNM-Au8 as a remyelinating treatment for vision-impairing MS lesions in participants who have chronic vision impairment as a result of Relapsing-Remitting Multiple Sclerosis. The primary endpoint is to assess the efficacy and safety of CNM-Au8 as a remyelinating therapy in patients with stable RMS. The secondary endpoint is Change in Functional Composite Responder Analysis Score from Baseline to Week 24.

Detailed description: This is a randomized, double-blind, parallel-group, placebo-controlled study of the efficacy, safety, and pharmacokinetics of CNM-Au8 in stable RRMS patients who have Chronic Optic Neuropathy evidence by low contrast letter acuity deficits at Screening.

Patients will be screened over a 6-week period. Patients who meet the inclusion criteria and none of the exclusionary criteria will be enrolled into the clinical study.

All enrolled patients will have their visual baseline established in both eyes by functional, electrophysiological (at participating research sites), and morphological tests.

For each patient, the eye with the worst Baseline LCLA score will be considered as the affected eye. The other eye will be considered as the fellow eye. If both eyes have the same LCLA score at Baseline, then one eye will be randomly selected by the statistician to assess as the designated affected eye. Efficacy endpoints will be assessed in both the affected and the fellow eyes. Patients will be randomized to one of three groups: placebo, or one of two doses of CNM-Au8. All patients will receive their randomized investigational product (IP) dose daily over at least 24 consecutive weeks during the Fixed Duration Treatment Period. The study will also have a blinded Variable Duration Treatment Period for up to an additional 24-weeks (up to a 48-week maximum blinded duration) until the last-patient enrolled completes his/her Week 24 study visit per the study scheme in Figure 2. When the last enrolled patient completes his or her Week 24 visit, patients enrolled in the Variable Duration Treatment Period will complete the End-of-Study (EOS) visit at their next scheduled study visit.

The primary efficacy outcome measure will be assessed Efficacy will be assessed as an improvement in best-corrected low contrast letter acuity (BC-LCLA). Safety will be assessed up through the frequency of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and discontinuations due to adverse events (AEs), and changes in safety assessments (e.g., vitals, ECG, C-SSRS).

The study will remain blinded until the study database is locked.

All patients who are discontinued from treatment will complete the End-of-Study (EOS) assessment.

At the end of the Variable Duration Treatment Period, patients will complete an EOS assessment and then may choose either to exit the study, or receive open-label CNM-Au8 in a separate Open-Label Safety Extension Study.

An independent DSMB will be responsible for monitoring the safety of the study on a quarterly basis and ad hoc at the request of the DSMB or the Sponsor (e.g., in the event of unexpected SAEs) to review data throughout the Fixed Duration Treatment Period and the Variable Duration Treatment Period. The DSMB may make recommendations on the conduct of the study, including study termination. Appropriate procedures will be detailed in a DSMB Charter that will define disclosure of any findings along with patient- and study-stopping criteria.

There will be four study periods:

1. A six-week screening period (Screening Period);
2. A fixed 24-week double-blind, randomized treatment period (Fixed Duration Treatment Period);
3. A variable-duration, double-blind treatment period (Variable Duration Treatment Period) where patients continue the previously randomized treatment for up to an additional 24 weeks (total blinded duration of 48- weeks). This period will end for all patients when the last-enrolled patient reaches his or her 24-week visit (LP-24Wk) at which time patients in the Variable Duration Treatment Period will complete the EOS Visit at their next scheduled study visit;
4. A four-week follow-up period (Safety Follow-Up Period) for patients not continuing in the separate Open-Label Long-Term Safety Extension Study.

Following the end of the blinded treatment period, all patients who complete the 24-week Fixed Duration Treatment Period may be eligible to receive open-label CNM-Au8 in a separate Open-Label Long-Term Safety Extension Study.

Eligibility criteria: Inclusion Criteria:

1. At least 18 years of age and up to 55 years of age (inclusive) at Screening.
2. Clinical diagnosis of Relapsing Multiple Sclerosis (meeting McDonald criteria, 2010) who have had RMS no longer than 15 years from diagnosis.
3. Maximum Best Corrected High Contrast Visual Acuity (BC-HCVA) deficit on the Early Treatment Diabetic Retinopathy Study (ETDRS) Chart of 20/200 (6/60 metric) in both eyes.

   a. BC-HCVA is defined as the last line on the Early Treatment Diabetic Retinopathy Study (ETDRS) Chart that a patient is able to read three (3) or more letters correctly.
4. Best Corrected Low Contrast Letter Acuity (BC-LCLA) (by 2.5% Sloan Chart) must be 20/40 (6/12 metric) (inclusive) or worse in the affected eye and 20/32 (6/9.5 metric) or worse in the fellow eye; and the BC-LCLA must be worse than BC-HCVA for the respective value in both eyes.

   a. BC-LCLA is defined as the last line on the 2.5% Sloan Chart that a patient is able to read three (3) or more letters correctly.
5. Retinal Nerve Fiber Layer (RNFL) thickness ≥ 70 μm.
6. Stable disease activity based on the investigator's judgment over the previous 6 months.
7. All hematological parameters and biochemical parameters that fall outside the Within Normal Limits range must be assessed as Not Clinically Significant (NCS) and deemed stable or transient in nature.
8. Able to understand and give written informed consent.

Exclusion Criteria:

1. History of AQP4, MOG Ab(+) status, or ≥ 3 segments lesion in the spinal cord.
2. Any diagnosis other than RMS that could explain the patient's signs and symptoms.
3. An acute optic neuritis episode within the prior 6 months.
4. Clinical relapse requiring systemic steroid treatment within the prior 3 months (pre- treatment with systemic steroids during the administration of disease-modifying therapies \[DMT\] may be allowed after discussion with the Sponsor's Medical Monitor but must not be administered within 30 days of a planned VEP or MRI assessment).
5. Unstable treatment with a disease-modifying therapy (DMT) defined as a treatment change within prior 3-months unless due to intolerability.
6. Current treatment with immunosuppressive or immunomodulatory therapy other than those approved for the treatment of MS.
7. Any treatment with drugs known or suspected of producing retinal or optic nerve toxicity including hydroxychloroquine, chloroquine, clofazimine, vigabatrin, or ethambutol.
8. Any history of ophthalmological cause for retinal damage other than MS (e.g. cataracts, uveitis, macular degeneration, macular exudate, macular edema, glaucoma, severe astigmatism, ocular trauma, neuromyelitis optica, ischemic optic neuropathy, congenital nystagmus, retinal detachment, amblyopia, optic disk drusen).
9. Severe refractive defects: refractive errors (-6 dioptres to +6 dioptres or more in either eye, or axial eye length \>26 mm), hypermetropia (\> 6 dioptres; cylinder \> 3 dioptres); or based on the investigators judgment any other ophthalmic diseases that would confound the study results or assessment of Visual Evoked Potential (VEPs), Best Corrected Visual Acuity (BCVA), Low Contrast Letter Acuity (LCLA), or Optical Coherence Tomography (OCT).
10. History diabetic retinopathy or a previous diagnosis of Diabetes Mellitus or history of prior impaired fasting glucose ≥126 mg/dL (or ≥ 200 mg/dL after oral glucose tolerance test).
11. History of human immunodeficiency virus (HIV), hepatitis C (HepC) virus antibody, or hepatitis B (HepB) virus antibody.
12. History of gold allergy.
13. Patients taking stimulant medications (including: amphetamine, dextroamphetamine, lisdexamfetamine, methylphenidate, or modafinil) who have not been on a stable dose greater than or equal to 30 days. Changes to dose will not be allowed during the course of the trial).
14. Patients taking clemastine fumarate, 4-aminopyridine (fampridine), or high dose Biotin (\>300 mg/day).
15. Females who have a positive serum pregnancy test result at Screening or Baseline, or who are pregnant, breastfeeding, or planning to conceive during the study or within 180 days after study completion.
16. History or evidence of substance abuse or alcohol abuse within 5 years prior to Screening, including alcoholism; or severe tobacco use (\>1 pack/day).
17. Clinical history of toxic neuropathy (e.g., secondary to treatment with ethambutol, isoniazid, linezolid, gentamycin, chloramphenicol, vincristine, or penicillamine).
18. Current enrollment in any other drug or device treatment study within 3 months prior to Baseline. Participation in an observational non-interventional study (i.e., no drug or device therapy) is not an exclusion criterion.
19. Inability to undergo any planned study procedures such as LCLA, VEP, MRI, or OCT; history of severe hypersensitivity to gadolinium-DTPA or reduced renal clearance (GFR must be ≥ 45 mL/min at Screening), claustrophobia; or inability to comply with study requirements based on Investigator judgment.
20. Patients with clinically significant hepatic or renal dysfunction or clinical laboratory findings that would limit the interpretability of change in liver or kidney function, or those with low platelet counts (\< 150 x 10\^9 per liter) or eosinophilia (absolute eosinophil count of ≥ 500 eosinophils per microliter) at Screening.
21. Based on the investigator's judgment, concurrent chronic or acute illness or unstable medical condition that may deteriorate that could confound the results of safety assessments, increase risk to the patient, or lead to difficulty complying with the protocol; including severe disc edema or hemorrhage, any clinically significant cardiac, endocrinological, hematological, hepatic, immunological, metabolic, urological, pulmonary, neurological (any progressive neurological disorder other than RRMS), dermatological, psychiatric (any untreated or unstable psychiatric disease including depression, bipolar and psychosis), renal, severe allergic or anaphylactic reactions, autoimmune, or other major confounding diseases.
22. Any history of previous malignancy, with the exception of basal cell carcinoma of the skin or in situ carcinoma of the cervix, post documented full resections, with clean margins.
23. Patient is considered a suicide risk in the opinion of the Investigator, has previously made a suicide attempt, or is currently demonstrating active suicidal ideation.

Primary outcomes:
measure: Measures of Visual Function
timeFrame: Baseline to 48 weeks
Secondary outcomes:
measure: Other Measures of Neurological Function
timeFrame: Baseline up to 48 weeks
Other outcomes:
measure: Multifocal Visual Evoked Potential (mfVEP) Latency
timeFrame: Every 12 weeks following the 6-month primary endpoint, up to 48-weeks
measure: Multifocal Visual Evoked Potential (mfVEP) Amplitude
timeFrame: Every 12 weeks following the 6-month primary endpoint, up to 48-weeks
measure: Full field Visual Evoked Potentials (ff-VEP) latency
timeFrame: At three month intervals beginning at 12-weeks, up to 48-weeks
measure: Full field Visual Evoked Potentials (ff-VEP) amplitude
timeFrame: At three month intervals beginning at 12-weeks, up to 48-weeks
measure: Optical Coherence Tomography (OCT)
timeFrame: At three month intervals beginning at 24-weeks, up to 48-weeks
measure: Magnetic Resonance Imaging (MRI)
timeFrame: At three month intervals beginning at 24-weeks, up to 48-weeks
measure: Change in Best High Contrast Visual Acuity Testing (HCVA)
timeFrame: Every 6-weeks, up to 48-weeks
measure: Expanded Disability Status Scale (EDSS)
timeFrame: At three month intervals beginning at 12-weeks, up to 48-weeks
measure: 9-Hole Peg Test
timeFrame: Every 12-weeks, up to 48-weeks
measure: Symbol Digit Modality Test (SDMT)
timeFrame: At three month intervals beginning at 12-weeks, up to 48-weeks
measure: National Eye Institute Visual Function Questionnaire (NEI-VFQ-25)
timeFrame: At three month intervals beginning at 12-weeks, up to 48-weeks
measure: Ten-item Neuro-Ophthalmic Supplement (10-item NOS)
timeFrame: At three month intervals beginning at 12-weeks, up to 48-weeks
measure: Six-Minute Walk Test (6MWT)
timeFrame: At three month intervals beginning at 12-weeks, up to 48-weeks
measure: Timed 25-Foot Walk Test
timeFrame: Every 12-weeks, up to 48-weeks
measure: Individual OR Lesion MRI Analysis
timeFrame: Week 24 and week 48.
measure: Myelin Water Fraction MRI Analysis
timeFrame: Week 24 and Week 48
measure: Whole Brian Diffusion Tensor Imaging (DTI) divided by Magnetization Transfer Ratio (MTR)
timeFrame: Week 24 and week 48
measure: Whole Brian White Matter Diffusion Tensor Imaging (DTI) divided by Magnetization Transfer Ratio (MTR)
timeFrame: Week 24 and week 48
measure: Whole Brian Lesion Diffusion Tensor Imaging (DTI) divided by Magnetization Transfer Ratio (MTR)
timeFrame: Week 24 and week 48
measure: Optic Radiation Diffusion Tensor Imaging (DTI) divided by Magnetization Transfer Ratio (MTR)
timeFrame: Week 24 and week 48
measure: Optic Radiation Lesion Diffusion Tensor Imaging (DTI) divided by Magnetization Transfer Ratio (MTR)
timeFrame: Week 24 and week 48
measure: Change in Best Corrected Low-Contrast Letter Acuity (BC-LCLA)
timeFrame: Baseline up to 48 weeks
Locations:
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: New Lambton Heights
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Sydney Brain Mind Centre
state: New South Wales
city: Woolloongabba
country: Australia
facility: Princess Alexandria Hospital
state: Queensland
city: Hobart
country: Australia
facility: Menzies Institute for Medical Research
state: Tasmania
city: Melbourne
country: Australia
facility: Alfred Health
state: Victoria
city: Vancouver
country: Canada
facility: University of British Columbia
state: British Columbia
Study officials:
affiliation: University of Sydney
name: Heidi Beadnall, MD
role: PRINCIPAL_INVESTIGATOR
References: