Wednesday, 17 June 2015

ClinicSpeak: Chelmsford MS Roadshow

Thank you to the MS Team in Chelmsford and the MSers who attended last night. #ClinicSpeak #MSBlog #MSResearch

"Mouse Doctor and I did our second MS Roadshow of the season in Chelmsford last night. Many thanks to local MS team for setting-up and hosting the meeting.  You are simply great. The focus of the roadshow was on progressive MS and the current trial activity in the field including symptomatic treatments. The aim of these meetings to bring our research to the community and to encourage people with MS to put themselves forward for clinical trials. I started the meeting with an overview of the progressive MS and some of the recent insights into the disease and the rationale for combining therapies to tackle the progressive phase of the disease. I summarised the current commercial trials in progress, including those that are fully recruited and others that are still open for recruitment. Mouse Doctor then presented his wonderful story from mouse-to-man in relation to VSN16 and Canbex. I concluded with a talk about the PROXIMUS and MS-SMART trials. We then had a Q&A session during which I was taken to task about the age restriction applied to participants in  certain trials. In relation to the PROXIMUS trial, I justified it by quoting the literature that spinal fluid neurofilament levels go up with age and we didn't want the effect of ageing confounding the results. I had no answer for  the 70 cut-off for the Canbex spasticity study. The following are the presentations from last night. Unfortunately, the whole research team couldn't make the event but I have appended their presentations as well."


In summary the following are the clinical trials that we are currently recruiting for:

STUDY 1

Protective Role of Oxcarbazepine in Multiple Sclerosis (PROXIMUS)

Eligibility:

  1. Ages Eligible for Study: 18 Years to 60 Years
  2. Genders Eligible for Study: Both
  3. Accepts Healthy Volunteers: No
Inclusion Criteria:
  1. A diagnosis of definite multiple sclerosis
  2. Treatment with DMDs for at least 6 months
  3. EDSS score between 3.5 and 6.0
  4. No history of relapses in the preceding 6 months
  5. A history of slow progression of disability, objective or subjective, over a period of at least 6 months
  6. Age 18-60 years
Exclusion Criteria:
  1. Pregnant or breastfeeding or unwilling to use adequate contraception.
  2. Participants who do not take a DMDs for MS.
  3. A clinical relapse or pulsed intravenous or oral steroids in the 6 months preceding the baseline assessment.
  4. Participants presenting with medical disorder deemed severe or unstable by the CI such as poorly controlled diabetes or arterial hypertension, severe cardiac insufficiency, unstable ischemic heart disease, abnormal liver function tests (>2.5 times ULN) and abnormal complete blood count (in particular leukopenia, as defined by a lymphocyte count <500, neutrophil count <1.5 or platelet count <100, or thrombocytopenia <1.5 LLN), or any medical condition which, in the opinion of the chief investigator, would pose additional risk to the participant.
  5. Infection with hepatitis B or hepatitis C or human immunodeficiency virus.
  6. Participants receiving other sodium or calcium channel blockers in the previous 12 weeks
  7. Exposure to any other investigational drug within 30 days of enrolment in the study.
  8. Judged clinically to have a suicidal risk in the opinion of the investigator based upon a clinical interview and the Columbia Suicide-Severity Rating Scale (CSSRS).
  9. Prior history of malignancy unless an exception is granted by the Chief Investigator.
  10. History of uncontrolled drug or alcohol abuse within 6 months prior to enrolment into the study.
  11. Past untoward reactions to OxCbz or Cbz
STUDY 2

MS-SMART: Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial

Eligibility:

  1. Ages Eligible for Study: 25 Years to 65 Years
  2. Genders Eligible for Study: Both
  3. Accepts Healthy Volunteers: No
Inclusion Criteria:
  1. Confirmed diagnosis of SPMS. Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years. Evidence of progression, either an increase of at least one point in EDSS or clinical documentation of increasing disability in patient notes
  2. Expanded Disability Status Scale (EDSS) 4.0-6.5
  3. Aged 25 to 65 inclusive
  4. Women and men with partners of childbearing potential must be using an appropriate method of contraception to avoid any unlikely teratogenic effects of the 3 drugs from time of consent, to 6 weeks after treatment inclusive
  5. Women must have a negative pregnancy test within 7 days prior to the baseline visit unless not of child bearing potential (e.g. have undergone a hysterectomy, bilateral tubal ligation or bilateral oophorectomy or they are postmenopausal)
  6. Willing and able to comply with the trial protocol (e.g. can tolerate MRI and fulfils the requirements for MRI, e.g. not fitted with pacemakers or permanent hearing aids), ability to understand and complete questionnaires
  7. Written informed consent provided
Exclusion Criteria:
  1. Pregnancy or breast feeding patients
  2. Baseline MRI scan not of adequate quality for analysis (e.g. too much movement artefact)
  3. Significant organ co-morbidity (e.g. malignancy or renal or hepatic failure)
  4. Relapse within 3 months of baseline visit
  5. Patients who have been treated with iv or oral steroids within 3 months of baseline visit (these patients can undergo future screening visits once the 3 month window has expired)
  6. Commencement of fampridine within 6 months of baseline visit
  7. Use of immunosuppressants (e.g. azathioprine, methotrexate, cyclosporine) or disease modifying treatments (β-interferons, glatiramer) within 6 months of baseline visit
  8. Use of fingolimod/fumarate/teriflunomide/laquinomod/or other experimental disease modifying treatment (including research of an investigational medicinal product) within 12 months of baseline visit
  9. Use of mitoxantrone/ natalizumab/ alemtuzumab/ daclizumab if treated within 12 months of baseline visit
  10. Primary progressive MS
  11. Relapsing-remitting MS
  12. Known hypersensitivity to the active substances and their excipients to any of the active drugs for this trial
  13. Use of: lithium, chlorpropamide, triamterene and spironolactone within 6 months of the baseline visit
  14. Current use of potassium supplements
  15. Current use of tamoxifen
  16. Current use of herbal treatments containing St. John's Wort
  17. Significant signs of depression
  18. Use of an SSRI within 6 months of the baseline visit
  19. Use of monoamine oxidase inhibitors, phenytoin, L-tryptophan) and/or neuroleptic drugs within 6 months of the baseline visit
  20. A Beck Depression Index score of 19 or higher
  21. Bipolar disorder
  22. Receiving or previously received Electro-Convulsive Therapy
  23. Epilepsy/seizures
  24. Glaucoma
  25. Patients with a history of bleeding disorders or currently on anticoagulants
  26. Routine screening blood values (LFT) >/ 3 x upper limit of normal (ULN) of site reference ranges (ALT/AST, bilirubin, ˠGT)
  27. Potassium <2.8mmol/l or >5.5mmol/l
  28. Sodium <125mmol/l
  29. Creatinine >130µmol/l
  30. WBCs <3 x 109/l
  31. Lymphocytes <0.8 x 109/l
  32. Neutrophil count <1.0 x 109 /l
  33. Platelet count <90 x 109 /l
  34. Haemoglobin <80g/l
STUDY 3

Arpeggio Study: A Phase 2 Clinical Study in Subjects With Primary Progressive Multiple Sclerosis to Assess the Efficacy, Safety and Tolerability of Two Oral Doses of Laquinimod Either of 0.6 mg/Day or 1.5mg/Day (Experimental Drug) as Compared to Placebo.

Eligibility: 

  1. Ages Eligible for Study: 25 Years to 55 Years
  2. Genders Eligible for Study: Both
  3. Accepts Healthy Volunteers: No
Inclusion Criteria:
  1. Patients must have a confirmed and documented PPMS diagnosis as defined by the 2010 Revised McDonald criteria
  2. Baseline magnetic resonance imaging (MRI) showing lesions consistent with PPMS in either or both brain and spinal cord
  3. Patients must have an Expanded Disability Status Scale (EDSS) score of 3 to 6.5, inclusive, at both screening and baseline visits
  4. Documented evidence of clinical disability progression in the 2 years prior to screening.
  5. Functional System Score (FSS) of > or equal 2 for the pyramidal system or gait impairment due to lower extremity dysfunction
  6. Patients must be between 25 to 55 years of age, inclusive
  7. Women of child-bearing potential must practice an acceptable method of birth control for 30 days before taking the study drug, and 2 acceptable methods of birth control during all study duration and until 30 days after the last dose of treatment is administered.
  8. Patients must sign and date a written informed consent prior to entering the study.
  9. Patients must be willing and able to comply with the protocol requirements for the duration of the study.
Exclusion Criteria:
  1. Patients with history of any multiple sclerosis (MS) exacerbations or relapses, including any episodes of optic neuritis.
  2. Progressive neurological disorder other than PPMS.
  3. Any MRI record showing presence of cervical cord compression.
  4. Baseline MRI showing other findings (including lesions that are atypical for PPMS) that may explain the clinical signs and symptoms.
  5. Relevant history of vitamin B12 deficiency.
  6. Positive human T-lymphotropic virus Type I and II (HTLV-I/II) serology.
  7. Use of experimental or investigational drugs in a clinical study within 24 weeks prior to baseline. Use of a currently marketed drug in a clinical study within 24 weeks prior to baseline would not be exclusionary, provided no other exclusion criteria are met.
  8. Use of immunosuppressive agents, or cytotoxic agents, including cyclophosphamide and azathioprine within 48 weeks prior to baseline.
  9. Previous treatment with fingolimod (GILENYA®, Novartis), dimethyl fumarate (TECFIDERA®, Biogen Idec Inc), glatiramer acetate (COPAXONE®, Teva), interferon-β (either 1a or 1b), intravenous immunoglobulin, or plasmapheresis within 8 weeks prior to baseline.
  10. Use of teriflunomide (AUBAGIO®, Sanofi) within 2 years prior to baseline, except if active washout (with either cholestyramine or activated charcoal) was done 2 months or more prior to baseline.
  11. Prior use of monoclonal antibodies ever, except for:
  12. natalizumab (TYSABRI®, Biogen Idec Inc), if given more than 24 weeks prior to baseline AND the patient is John Cunningham (JC) virus antibody test negative (as per medical history)
  13. rituximab, ocrelizumab, or ofatumumab, if B cell count (CD19, as per medical history) is higher than 80 cells/μL
  14. Use of mitoxantrone (NOVANTRONE®, Immunex) within 5 years prior to screening. Use of mitoxantrone >5 years before screening is allowed in patients with normal ejection fraction and who did not exceed the total lifetime maximal dose.
  15. Previous use of laquinimod.
  16. Chronic (eg, more than 30 consecutive days or monthly dosing, with the intent of MS disease modification) systemic (intravenous, intramuscular or oral) corticosteroid treatment within 8 weeks prior to baseline.
  17. Previous use of cladribine or alemtuzumab (LEMTRADA®, Sanofi).
  18. Previous total body irradiation or total lymphoid irradiation.
  19. Previous stem cell treatment, cell-based treatment, or bone marrow transplantation of any kind.
  20. Patients who underwent endovascular treatment for chronic cerebrospinal venous insufficiency (CCSVI) within 12 weeks prior to baseline.
  21. Use of moderate/strong inhibitors of cytochrome P450 (CYP) 3A4 within 2 weeks prior to baseline.
  22. Use of inducers of CYP3A4 within 2 weeks prior to baseline.
  23. Pregnancy or breastfeeding.
  24. Serum levels ≥3× upper limit of the normal range (ULN) of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) at screening.
  25. Serum direct bilirubin which is ≥2×ULN at screening.
  26. Patients with a clinically significant or unstable medical or surgical condition that (in the opinion of the Investigator) would preclude safe and complete study participation, as determined by medical history, physical examinations, electrocardiogram (ECG), laboratory tests or chest X-ray.
  27. A known history of hypersensitivity to gadolinium (Gd).
  28. Glomerular filtration rate (GFR) < or equal 60 mL/min at screening visit.
  29. Inability to successfully undergo MRI scanning, including claustrophobia.
  30. Known drug hypersensitivity that would preclude administration of laquinimod, such as hypersensitivity to mannitol, meglumine or sodium stearyl fumarate.

STUDY 4

BG00012 and Disability Progression in Secondary Progressive Multiple Sclerosis (SPMS) (INSPIRE)

Eligibility: 

  1. Ages Eligible for Study: 18 Years to 58 Years
  2. Genders Eligible for Study: Both
  3. Accepts Healthy Volunteers: No
Key Inclusion Criteria:
  1. Onset of SPMS at least 1 to 2 years prior to randomization. SPMS is defined as relapsing-remitting disease followed by progression of disability independent of or not explained by relapses.
  2. Have documented confirmed evidence of disease progression independent of clinical relapses over the 1 year prior to randomization.
  3. Have EDSS score of 3.0 to 6.5, inclusive.
  4. Have an multiple sclerosis (MS) Severity Score of 4 or higher.
Key Exclusion Criteria:
  1. Have a diagnosis of relapsing remitting multiple sclerosis (RRMS) or primary progressive MS as defined by the revised McDonald criteria.
  2. Had a recent clinical relapse (within 3 months) prior to randomization.
  3. Uncontrolled intercurrent illness including, but not limited to- ongoing or active infection; symptomatic congestive heart failure; unstable angina pectoris; cardiac arrhythmia; serious or acute liver, kidney, or bone marrow dysfunction; uncontrolled diabetes; serious or acute psychiatric illness that would limit compliance with study requirements.
Note: Other protocol-defined Inclusion/Exclusion criteria may apply


STUDY 5


Canbex - Phase II proof of concept trial VSN16R
Investigators: R Farrell (CI) UCLH, Dr Clarence Liu (Barts Health), Professor Jeremy Hobart (Plymouth)

4 phases: 
  1. Screening and wash out 
  2. Daily single escalating dose – 5 days 
  3. Three weeks twice daily stable dosing 
  4. Washout and end of study review
Eligibility: 
  1. Be between 18 and 70 years of age 
  2. Have MS 
  3. Able to walk 20 metres ( with aid as needed) 
  4. Have spasticity 
  5. Not on medication or willing to withdraw current medication
CoI: multiple; please note you cannot self-refer for clinical trials you have to be referred via your neurologist, clinical nurse specialist or general practitioner. 

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