Assessing Changes in Multi-parametric MRI in MS Patients Taking Clemastine Fumarate as a Myelin Repair Therapy

Multiple Sclerosis, Relapsing-Remitting Clinical Trial

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Official title:

A Randomized, Double-Blind, Delayed Treatment, Placebo-Controlled Trial to Assess the Changes in Multi-parametric MRI in MS Patients Taking Clemastine Fumarate as a Myelin Repair Therapy

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05359653
• Other study ID #: 22-36052
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: August 1, 2023
• Est. completion date: June 1, 2025

Study information

• Verified date: September 2023
• Source: University of California, San Francisco
• Contact: Makenna Chapman, BS
• Phone: 415-745-1304
• Email: makenna.chapman[@]ucsf.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The clinical trial is intended to assess for clinical evidence of Clemastine Fumarate as a myelin repair therapy in patients with chronic inflammatory injury-causing demyelination as measured by multi-parametric MRI assessments.

No reparative therapies exist for the treatment of multiple sclerosis. Clemastine fumarate was identified along with a series of other antimuscarinic medications as a potential remyelinating agent using the micropillar screen (BIMA) developed at the University of California, San Francisco (UCSF). Following in vivo validation, an FDA IND exemption was granted to investigate clemastine for the treatment of multiple sclerosis in the context of chronic optic neuropathy. That pilot study was recently completed and is the first randomized control trial documenting efficacy for a putative remyelinating agent for the treatment of MS. The preselected primary efficacy endpoint (visual evoked potential) was met and a strong trend to benefit was seen for the principal secondary endpoint assessing function (low contrast visual acuity). That trial number was 13-11577.

This study seeks to follow up on that study and examine clemastine fumarate's protective and reparative effects in the context of chronic demyelinating brain lesions as imaged by multi-parametric MRI assessments. The investigators will be assessing the effects of clemastine fumarate as a remyelinating therapy and assessing its effect on MRI metrics of chronic lesions found in patients with a confirmed diagnosis of relapsing-remitting multiple sclerosis.

In addition to using conventional multi-parametric MRI assessments, this study will also evaluate a new MRI technique called Ultrashort Echo Time (UTE) MRI to assess the effects of clemastine fumarate as a remyelinating therapy of chronic lesions found in patients with a confirmed diagnosis of relapsing-remitting multiple sclerosis and compare it to the other assessments.

Description:

Treatments capable of remyelination are a major unmet need for multiple sclerosis and other diseases that involve myelin damage, loss, or dysfunction in the central nervous system (CNS). Chronic demyelination of axons is believed to be injurious to neurons and serves as a major contributor to irreversible cell loss that underlies permanent disability. Available MS treatments are primarily immunosuppressing, without directly addressing or fully preventing axonal degeneration and disability. Clemastine fumarate was identified along with a series of other antimuscarinic medications as a potential remyelinating agent using the micropillar screen (BIMA) developed at UCSF. The screen demonstrated that clemastine promoted the differentiation of the endogenous oligodendrocyte precursor cells (OPCs) into mature myelinating oligodendrocytes. Following in vivo validation, an FDA investigational new drug (IND) exemption was granted to investigate clemastine for the treatment of multiple sclerosis in the context of chronic optic neuropathy. That pilot study was recently completed and is the first randomized control trial documenting efficacy for a putative remyelinating agent for the treatment of MS. The preselected primary efficacy endpoint (visual evoked potential) was met and a strong trend to benefit was seen for the principal secondary endpoint assessing function (low contrast visual acuity). That trial number was 13-11577.

This clinical trial is intended to assess magnetic resonance imaging evidence of remyelination using Clemastine Fumarate in patients with chronic demyelinated lesions. Specifically speaking, the primary objective will assess various multi-parametric MRI sequences on the corpus callosum region, a region that animal models studies identified as a promising candidate for assessing remyelination. The aim was to help define the potential for MRI in measuring remyelination in MS, determine the optimal sequences and location for measuring myelin recovery, and help guide trial design for future remyelinating trials. Finally, the study is designed to assess tolerability and clinical efficacy of Clemastine using outcomes intended to assess for (a) adverse events and (b) recovery of myelin.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 74
• Est. completion date: June 1, 2025
• Est. primary completion date: June 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

• Written informed consent must be obtained prior to any assessment being performed.

• Patients diagnosed with relapsing remitting multiple sclerosis and a disease duration of < 15 years

• Male or female patients aged 18-55 years (inclusive)

• Use of appropriate contraception during period of trial (women). Before entry women must be:

• Post-menopausal for at least 1 year OR

• Surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, male partner vasectomy or otherwise incapable of pregnancy) OR

• Practicing a highly effective method of birth control if sexually active, including hormonal prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double barrier method (e.g., condoms, diaphragm or cervical cap with spermicidal foam, cream or gel), or male partner sterilization consistent with local regulations regarding use of birth control methods for patients participating in clinical trials, for the duration of their participation in the study OR

• Not heterosexually active (patients who are not heterosexually active at screening must agree to utilize a highly effective method of birth control if they become heterosexually active during their participation in the study) OR

• Practicing true abstinence (when this is in line with the preferred and usual lifestyle of the subject) Period abstinence (e.g., calendar, ovulation, symptothermal, post ovulation methods) is not an acceptable method.

Exclusion Criteria:

• Radiologic identification of marked brain atrophy relative to patients age based on recent MRI and interpretation of expert neuroradiologist or PI

• New lesion in most recent MRI (within 3 months)

• Hypersensitivity to clemastine or other arylalkylamine antihistamines, or any of the excipients.

• Treatment with corticosteroids within 30 days prior to screening.

• Expanded Disability Status Scale (EDSS) = 4.5

• History of significant cardiac conduction block.

• History of cancer.

• Suicidal ideation or behavior in 6 months prior to baseline.

• Pregnancy, breastfeeding or planning to become pregnant.

• Involved with other study protocols simultaneously without prior approval.

• Concomitant use of any other putative remyelinating therapy as determined by the investigator.

• Prior treatment with total lymphoid irradiation, T cell or T cell receptor vaccination.

• Prior treatment with alemtuzumab, mitoxantrone, or cyclophosphamide.

• Serum creatinine > 1.5 mg/dL; aspartate transaminase (AST), alanine transaminase (ALT), or alkaline phosphatase > 2 times the upper limit of normal. (Reported within 72 hours)

• History of drug or alcohol abuse within the past year.

• Untreated B12 deficiency (as determined by B12 serological assessments and metabolites including methylmalonic acid [MMA] and homocysteine) or untreated hypothyroidism.

• Clinically significant cardiac, metabolic, hematologic, hepatic, immunologic, urologic, endocrinologic, neurologic, pulmonary, psychiatric, dermatologic, allergic, renal, or other major diseases that in the PI's judgment may affect the interpretation of study results or patient safety.

• History of or presence of clinically significant medical illness or laboratory abnormality that, in the opinion of the investigator would preclude participation in the study

• Inability to participate in MRI, including extreme claustrophobia.

• Any dental braces or permanent or undetachable metals in the jaw or face.

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis (MS)
• Multiple Sclerosis Relapse
• Multiple Sclerosis, Chronic Progressive
• Multiple Sclerosis, Primary Progressive
• Multiple Sclerosis, Relapsing-Remitting
• Sclerosis

Intervention

Drug:
• Clemastine Fumarate
8 mg Clemastine tablet. Clemastine fumarate was approved by the Food and Drug Administration (FDA) for the treatment of allergic rhinitis (seasonal allergies) in 1977 and was approved for over-the-counter marketing in 1992. Clemastine is not FDA approved as a remyelinating therapy
• Placebo
Matched sugar tablet

Locations

Country	Name	City	State
United States	Sandler Neurosciences Building, Neurological Clinical Research Unit	San Francisco	California

Sponsors (2)

Lead Sponsor	Collaborator
University of California, San Francisco	United States Department of Defense

Country where clinical trial is conducted

United States, 

References & Publications (5)

Gagliardo A, Galli F, Grippo A, Amantini A, Martinelli C, Amato MP, Borsini W. Motor evoked potentials in multiple sclerosis patients without walking limitation: amplitude vs. conduction time abnormalities. J Neurol. 2007 Feb;254(2):220-7. doi: 10.1007/s00415-006-0334-5. Epub 2007 Feb 17. — View Citation

Green AJ, Gelfand JM, Cree BA, Bevan C, Boscardin WJ, Mei F, Inman J, Arnow S, Devereux M, Abounasr A, Nobuta H, Zhu A, Friessen M, Gerona R, von Budingen HC, Henry RG, Hauser SL, Chan JR. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017 Dec 2;390(10111):2481-2489. doi: 10.1016/S0140-6736(17)32346-2. Epub 2017 Oct 10. — View Citation

Marques JP, Kober T, Krueger G, van der Zwaag W, Van de Moortele PF, Gruetter R. MP2RAGE, a self bias-field corrected sequence for improved segmentation and T1-mapping at high field. Neuroimage. 2010 Jan 15;49(2):1271-81. doi: 10.1016/j.neuroimage.2009.10.002. Epub 2009 Oct 9. — View Citation

Mei F, Fancy SPJ, Shen YA, Niu J, Zhao C, Presley B, Miao E, Lee S, Mayoral SR, Redmond SA, Etxeberria A, Xiao L, Franklin RJM, Green A, Hauser SL, Chan JR. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat Med. 2014 Aug;20(8):954-960. doi: 10.1038/nm.3618. Epub 2014 Jul 6. — View Citation

Sheth V, Shao H, Chen J, Vandenberg S, Corey-Bloom J, Bydder GM, Du J. Magnetic resonance imaging of myelin using ultrashort Echo time (UTE) pulse sequences: Phantom, specimen, volunteer and multiple sclerosis patient studies. Neuroimage. 2016 Aug 1;136:37-44. doi: 10.1016/j.neuroimage.2016.05.012. Epub 2016 May 5. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Corpus Callosum Myelin Water Fraction	The efficacy of clemastine relative to placebo at increasing the myelin water fraction (MWF) (measured in %) from magnetic resonance imaging of the corpus callosum.	This will be assessed at the baseline visit.
Primary	Change from Baseline in Corpus Callosum Myelin Water Fraction at 3 Months	The efficacy of clemastine relative to placebo at increasing the myelin water fraction (MWF) (measured in %) from magnetic resonance imaging of the corpus callosum. Change = (3-month % - Baseline %)	This will be assessed at the baseline and 3-month visits.
Primary	Change from Baseline in Corpus Callosum Myelin Water Fraction at 6 Months	The efficacy of clemastine relative to placebo at increasing the myelin water fraction (MWF) (measured in %) from magnetic resonance imaging of the corpus callosum. Change = (6-month % - Baseline %)	This will be assessed at the baseline and 6-month visits.
Primary	Corpus Callosum T1 Relaxation Time	The efficacy of clemastine relative to placebo at shortening the T1 relaxation time (measured in seconds) within the corpus callosum using T1 mapping protocols in an MRI.	This will be assessed at the baseline visit.
Primary	Change from Baseline in Corpus Callosum T1 Relaxation Time at 3 Months	The efficacy of clemastine relative to placebo at shortening the T1 relaxation time (measured in seconds) within the corpus callosum using T1 mapping protocols in an MRI. Change = (3-month time - Baseline time)	This will be assessed at the baseline and 3-month visits.
Primary	Change from Baseline in Corpus Callosum T1 Relaxation Time at 6 Months	The efficacy of clemastine relative to placebo at shortening the T1 relaxation time (measured in seconds) within the corpus callosum using T1 mapping protocols in an MRI. Change = (6-month time - Baseline time)	This will be assessed at the baseline and 6-month visits.
Primary	Corpus Callosum UTE Fraction	The efficacy of clemastine relative to placebo at increasing the ultrashort echo time (UTE) fraction (measured in %) derived from magnetic resonance imaging of the corpus callosum.	This will be assessed at the baseline visit.
Primary	Change from Baseline in Corpus Callosum UTE Fraction at 3 Months	The efficacy of clemastine relative to placebo at increasing the ultrashort echo time (UTE) fraction (measured in %) derived from magnetic resonance imaging of the corpus callosum. Change = (3-month % - Baseline %)	This will be assessed at the baseline and 3-month visits.
Primary	Change from Baseline in Corpus Callosum UTE Fraction at 6 Months	The efficacy of clemastine relative to placebo at increasing the ultrashort echo time (UTE) fraction (measured in %) derived from magnetic resonance imaging of the corpus callosum. Change = (6-month % - Baseline %)	This will be assessed at the baseline and 6-month visits.
Secondary	Optic Radiation Myelin Water Fraction	The efficacy of Clemastine relative to placebo at increasing the MWF (measured in %) of the optic radiation.	This will be assessed at the baseline visit.
Secondary	Change from Baseline in Optic Radiation Myelin Water Fraction at 3 Months	The efficacy of clemastine relative to placebo at increasing the MWF (measured in %) of the optic radiation. Change = (3-month % - Baseline %)	This will be assessed at the baseline and 3-month visits.
Secondary	Change from Baseline in Optic Radiation Myelin Water Fraction at 6 Months	The efficacy of clemastine relative to placebo at increasing the MWF (measured in %) of the optic radiation. Change = (6-month % - Baseline %)	This will be assessed at the baseline and 6-month visits.
Secondary	Corticospinal Tract Myelin Water Fraction	The efficacy of clemastine relative to placebo at increasing the MWF (measured in %) of the corticospinal tract.	This will be assessed at the baseline visit.
Secondary	Change from Baseline in Corticospinal Tract Myelin Water Fraction at 3 Months	The efficacy of clemastine relative to placebo at increasing the MWF (measured in %) of the corticospinal tract. Change = (3-month % - Baseline %)	This will be assessed at the baseline and 3-month visits.
Secondary	Change from Baseline in Corticospinal Tract Myelin Water Fraction at 6 Months	The efficacy of clemastine relative to placebo at increasing the MWF (measured in %) of the corticospinal tract. Change = (6-month % - Baseline %)	This will be assessed at the baseline and 6-month visits.
Secondary	Optic Radiation T1 Relaxation time	To evaluate the efficacy of Clemastine relative to placebo at increasing the T1 relaxation time (measured in seconds) of the optic radiation.	This will be assessed at the baseline visit.
Secondary	Change from Baseline in Optic Radiation T1 Relaxation Time at 3 Months	To evaluate the efficacy of Clemastine relative to placebo at increasing the T1 relaxation time (measured in seconds) of the optic radiation. Change = (3-month time - Baseline time)	This will be assessed at the baseline and 3-month visits.
Secondary	Change from Baseline in Optic Radiation T1 Relaxation Time at 6 Months	To evaluate the efficacy of Clemastine relative to placebo at increasing the T1 relaxation time (measured in seconds) of the optic radiation. Change = (6-month % - Baseline %)	This will be assessed at the baseline and 6-month visits.
Secondary	Corticospinal Tract T1 Relaxation Time	To evaluate the efficacy of Clemastine relative to placebo at increasing the T1 relaxation time (measured in seconds) of the corticospinal tract.	This will be assessed at the baseline visit.
Secondary	Change from Baseline in Corticospinal T1 Relaxation Time at 3 Months	To evaluate the efficacy of Clemastine relative to placebo at increasing the T1 relaxation time (measured in seconds) of the corticospinal tract. Change = (3-month time - Baseline time)	This will be assessed at the baseline and 3-month visits.
Secondary	Change from Baseline in Corticospinal Tract T1 Relaxation Time at 6 Months	To evaluate the efficacy of Clemastine relative to placebo at increasing the T1 relaxation time (measured in seconds) of the corticospinal tract. Change = (6-month % - Baseline %)	This will be assessed at the baseline and 6-month visits.
Secondary	Optic radiation UTE Fraction	The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) of the optic radiation.	This will be assessed at the baseline visit.
Secondary	Change from Baseline in Optic radiation UTE Fraction at 3 Months	The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) of the optic radiation. Change = (3-month % - Baseline %)	This will be assessed at the baseline and 3-month visits.
Secondary	Change from Baseline in Optic radiation UTE Fraction at 6 Months	The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) of the optic radiation. Change = (6-month % - Baseline %)	This will be assessed at the baseline and 6-month visits.
Secondary	Corticospinal Tract UTE Fraction	The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) of the corticospinal tract.	This will be assessed at the baseline visit.
Secondary	Change from Baseline in Corticospinal Tract UTE Fraction at 3 Months	The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) of the corticospinal tract. Change = (3-month % - Baseline %)	This will be assessed at the baseline and 3-month visits.
Secondary	Change from Baseline in Corticospinal Tract UTE Fraction at 6 Months	The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) of the corticospinal tract. Change = (6-month % - Baseline %)	This will be assessed at the baseline and 6-month visits.
Secondary	Lesion of interest (LOI) MWF	The efficacy of clemastine relative to placebo at increasing MWF (measured in %) of the lesion(s) of interest, stratified based on enhancement status on prior MRIs.	This will be assessed at the baseline visit.
Secondary	Change from Baseline in LOI MWF at 3 Months	The efficacy of clemastine relative to placebo at increasing MWF (measured in %) of the lesion(s) of interest, stratified based on enhancement status on prior MRIs. Change = (3-month % - Baseline %)	This will be assessed at the baseline and 3-month visits.
Secondary	Change from Baseline in LOI MWF at 6 Months	The efficacy of clemastine relative to placebo at increasing MWF (measured in %) of the lesion(s) of interest, stratified based on enhancement status on prior MRIs. Change = (6-month % - Baseline %)	This will be assessed at the baseline and 6-month visits.
Secondary	LOI T1 Relaxation Time	The efficacy of clemastine relative to placebo at increasing T1 relaxation time (measured in seconds) of the lesion(s) of interest, stratified based on enhancement status on prior MRIs.	This will be assessed at the baseline visit.
Secondary	Change from Baseline in LOI T1 Relaxation Time at 3 Months	The efficacy of clemastine relative to placebo at increasing T1 relaxation time (measured in seconds) of the lesion(s) of interest, stratified based on enhancement status on prior MRIs. Change = (3-month time - Baseline time)	This will be assessed at the baseline and 3-month visits.
Secondary	Change from Baseline in LOI T1 Relaxation Time at 6 Months	The efficacy of clemastine relative to placebo at increasing T1 relaxation time (measured in seconds) of the lesion(s) of interest, stratified based on enhancement status on prior MRIs. Change = (6-month time - Baseline time)	This will be assessed at the baseline and 6-month visits.
Secondary	LOI UTE Fraction	The efficacy of clemastine relative to placebo at increasing UTE fraction (measured in %) of the lesion(s) of interest, stratified based on enhancement status on prior MRIs.	This will be assessed at the baseline visit.
Secondary	Change from Baseline in LOI UTE Fraction at 3 Months	The efficacy of clemastine relative to placebo at increasing UTE fraction (measured in %) of the lesion(s) of interest, stratified based on enhancement status on prior MRIs. Change = (3-month % - Baseline %)	This will be assessed at the baseline and 3-month visits.
Secondary	Change from Baseline in LOI UTE Fraction at 6 Months	The efficacy of clemastine relative to placebo at increasing UTE fraction (measured in %) of the lesion(s) of interest, stratified based on enhancement status on prior MRIs. Change = (6-month % - Baseline %)	This will be assessed at the baseline and 6-month visits.
Secondary	Whole Brain MWF	The efficacy of clemastine relative to placebo at increasing MWF (measured in %) across the whole-brain divided into regions of normal-appearing white matter (NAWM), cortical gray matter, and deep gray matter.	This will be assessed at the baseline visit.
Secondary	Change from Baseline in Whole Brain MWF at 3 Months	The efficacy of clemastine relative to placebo at increasing MWF (measured in %) across the whole-brain divided into regions of normal-appearing white matter (NAWM), cortical gray matter, and deep gray matter. Change = (3-month % - Baseline %)	This will be assessed at the baseline and 3-month visits.
Secondary	Change from Baseline in Whole Brain MWF at 6 Months	The efficacy of clemastine relative to placebo at increasing MWF (measured in %) values across the whole-brain divided into regions of normal-appearing white matter (NAWM), cortical gray matter, and deep gray matter. Change = (6-month % - Baseline %)	This will be assessed at the baseline and 6-month visits.
Secondary	Whole Brain T1 Relaxation Time	The efficacy of clemastine relative to placebo at increasing T1 relaxation time (measured in seconds) across the whole-brain divided into regions of normal-appearing white matter (NAWM), cortical gray matter, and deep gray matter.	This will be assessed at the baseline visit.
Secondary	Change from Baseline in Whole Brain T1 Relaxation Time at 3 Months	The efficacy of clemastine relative to placebo at increasing T1 relaxation time (measured in seconds) across the whole-brain divided into regions of normal-appearing white matter (NAWM), cortical gray matter, and deep gray matter. Change = (3-month time - Baseline time)	This will be assessed at the baseline and 3-month visits.
Secondary	Change from Baseline in Whole Brain T1 Relaxation Time at 6 Months	The efficacy of clemastine relative to placebo at increasing T1 relaxation time (measured in seconds) across the whole-brain divided into regions of normal-appearing white matter (NAWM), cortical gray matter, and deep gray matter. Change = (6-month time - Baseline time)	This will be assessed at the baseline and 6-month visits.
Secondary	Whole Brain UTE Fraction	The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) across the whole-brain divided into regions of normal-appearing white matter (NAWM), cortical gray matter, and deep gray matter.	This will be assessed at the baseline visit.
Secondary	Change from Baseline in Whole Brain UTE Values at 3 Months	The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) across the whole-brain divided into regions of normal-appearing white matter (NAWM), cortical gray matter, and deep gray matter. Change = (3-month % - Baseline %)	This will be assessed at the baseline and 3-month visits.
Secondary	Change from Baseline in Whole Brain UTE Values at 6 Months	The efficacy of clemastine relative to placebo at increasing the UTE fraction (measured in %) across the whole-brain divided into regions of normal-appearing white matter (NAWM), cortical gray matter, and deep gray matter. Change = (6-month % - Baseline %)	This will be assessed at the baseline and 6-month visits.
Secondary	Clemastine Tolerability	The tolerability of Clemastine in this population. This will include a special focus with regards to fatigue as this is a major symptom for patients suffering from multiple sclerosis.	This will be assessed at the baseline visit.
Secondary	Change from Baseline in Clemastine Tolerability at 3 Months	The tolerability of Clemastine in this population. This will include a special focus with regards to fatigue as this is a major symptom for patients suffering from multiple sclerosis. Change = (3-month tolerability - Baseline tolerability)	This will be assessed at the baseline and 3-month visits.
Secondary	Change from Baseline in Clemastine Tolerability at 6 Months	The tolerability of Clemastine in this population. This will include a special focus with regards to fatigue as this is a major symptom for patients suffering from multiple sclerosis. Change = (6-month tolerability - Baseline tolerability)	This will be assessed at the baseline and 6-month visits.
Secondary	Informative Outcomes	Which secondary or tertiary outcomes are likely to be informative for future remyelinating trials in optic neuritis (and other related indications).	This will be assessed at the baseline visit.
Secondary	Informative Outcomes at 3 Months	Which secondary or tertiary outcomes are likely to be informative for future remyelinating trials in optic neuritis (and other related indications).	This will be assessed at the 3-month visit.
Secondary	Informative Outcomes at 6 Months	Which secondary or tertiary outcomes are likely to be informative for future remyelinating trials in optic neuritis (and other related indications).	This will be assessed at the 6-month visit.