Wednesday, 16 January 2013

The INSPIRE Trial: the Charcot Project launches its first trial

#MSBlog: At last its official our first anti-viral trial in MS! Although I have been arguing that the anti-CD20 therapies are working as anti-EBV agents. 

A Phase II Baseline Versus Treatment Study to Determine the Efficacy of Raltegravir (Isentress) in Preventing Progression of Relapsing Remitting Multiple Sclerosis as Determined by Gadolinium-enhanced MRI

There is accumulating research evidence that Human Endogenous Retrovirus (HERV) and herpes viruses (in particular Epstein-Barr Virus) are involved in the pathogenesis of multiple sclerosis. People with active MS have higher levels of HERVs than people either without MS or who have other neurological conditions. It has been shown that HERVs may produce neurotoxic proteins/antigens associated with MS activity and disease progression. This is the first clinical trial investigating the hypothesis that the antiretroviral drug raltegravir may suppress HERV activity and ameliorate progression of relapsing remitting MS. Raltegravir is an integrase inhibitor which blocks retroviral replication. A recent experimental study suggests that raltegravir may also be active against herpes viruses.


Eligible participants (see Inclusion/Exclusion Criteria) will be observed for 3 months having monthly brain Gadolinium enhanced MRIs and blood/urine/saliva sampling (baseline). Then they will be treated with raltegravir (one 400mg pill taken twice a day) for 3 months. During treatment period participants will continue to have monthly MRIs and blood/saliva/urine sampling. Participants will have monthly clinical and neurological examinations and they will complete questionnaires assessing response to treatment. Participants will have screening and study visits at The Royal London Hospital, Whitechapel. Monthly MRIs will be performed at the Institute of Neurology, UCL, Queen Square, London.


Eligibility
Inclusion Criteria:
  1. Patients between 18-55 years of age.
  2. Diagnosis of MS, according to the revised McDonald Criteria 2010.
  3. EDSS score of 0-6.0 inclusive.
  4. Documented at least one relapse within the past 12 months or at least one Gd-enhanced lesion on the brain MRI detected within 3 months prior to screening date
  5. Gd-enhanced lesion on screening MRI (if MRI not used to meet screening criteria above).
  6. Female patients of childbearing potential will be expected to be on appropriate contraception (hormonal or barrier method of birth control; abstinence) from time of consent until 6 weeks after treatment discontinuation. (the repeated administration of gadolinium and MRI are not recommended during pregnancy). NOTE: Subjects are considered not of child bearing potential if they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal.
  7. Females of childbearing potential must have a negative urine pregnancy test prior to every MRI scan/ within 7 days prior to being registered for protocol therapy.
  8. Must give written informed consent and authorize the release and use of protected health information, as required by local law.
  9. Able and willing to undergo blood, saliva and urine sampling at regular intervals as defined by the protocol.
  10. Able and willing to receive Gadolinium enhanced MRI's at regular intervals as defined by the protocol.
  11. Able to comply with study requirements.
Exclusion Criteria:
  1. Pregnant or breastfeeding or unwilling to use contraception.
  2. Treatment with immunosuppressive, immunomodulatory or experimental treatments within the last 6 months of enrolment in the study, but excluding pulsed intravenous or oral steroids for treatment of MS relapse.
  3. No pulsed intravenous or oral steroids in the 30 days preceding the baseline assessment.
  4. Patients 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 <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 patient.
  5. Presence of human immunodeficiency virus antibodies.
  6. Patients receiving proton pump inhibitors (e.g. omeprazole/esomeprazole)
  7. Patients with active hepatitis B or/and C with liver function tests >2.5 times ULN
  8. Exposure to any other investigational drug within 30 days of enrolment in the study.
  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. Patients treated with Rifampicin in past four weeks.
ClinicalTrials.gov Identifier: NCT01767701


"Who would of thought that when we launched The Charcot Project a year ago that we would have a trial off the ground in just over 12 months. Without Prof. Julian Gold's dedication  energy, persistent and organisational abilities this would not have been possible. We would also like to thank our initial sponsors Mr and Mrs Anon. and AIMS2CURE for supporting the launch of The Charcot Project despite the widespread scepticism of the viral hypothesis in the field of MS. Thanks to Merck for taking a risk on us delivering this study. Hopefully, in 2 years time this trial will cause the paradigm shift I have been predicting will occur for some time! We have had over 15 grants turned down around the viral hypothesis of MS, so getting this one off the ground is very special indeed. We would also like to acknowledge all the scientists in the field who have been working so diligently on HERVs and MS, in particular Dr. HervĂ© Perron, without their persistence we would not have been able to make the scientific case for this study."


Additional reading: raltegravir


CoI: multiple, this trial is being funded by Merck

41 comments:

  1. Please note this is Merck USA not Merck Serono (Germany)

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  2. This is great news, and I think you're a rock star for getting it off the ground so quickly. One question, if it works, does that mean we'll be taking 2 pills a day forever, like BG-12? Or is there a chance this could take us closer to a cure?

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  3. Makes a refreshing change to see someone get off their bum and do something unlike the many armchair scientists.

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  4. I hope for all of you and all of us that the trial deliver solid & satisfactory results! Congrats.

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  5. Like the others, wishing you well and congrats - hopefully your results will contribute to understanding MS, and ultimately to therapy/prevention/cure... Great news

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  6. Are you excluding PPMS/SPMS patients because its harder to measure progress or you think this drug won't be effective in those cases?

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    1. At this time we need to use MRI as an outcome; PP & SPMS have less MRI activity than RRMSers. If this study is positive we will need to reconsider our position regarding progressive MSers.

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  7. Bravo! All the luck on this project. A dogma change would be the best thing that could happen to us MSers. We would be nearer to the root cause and hence to the cure. Maybe the outcome to be measured (MRI activity after 3 months time) will be too risky, as it won't measure disease activity when BBB is closed, but at last there is a clinical trial that does not last 5 years!

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  8. Excellent news and plaudits are due to the Prof Gs for getting this up and running in the face of opposition from the inertia generating dogmatists.

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  9. Nice. From chemotherapy drugs to anti-HIV drugs. Progress or embarrassment? Is there anything left that hasn't been tested in MS yet?

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    1. Pls watch this talk on trial-and-error VV. It's most interesting

      www.ted.com/talks/tim_harford.html

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    2. Antiviral drugs were used in MS more than 100 years ago (trial). They were abandoned (error). Here they come again, celebrate.

      What is the semantics of using both alemtuzumab and raltegravir for the same disease? Probable ignorance of the fundamentals of it.

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    3. All antivirals aren't the same

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    4. "Antiviral drugs were used in MS more than 100 years ago (trial)."

      I'm curious about this - can you give us some more information?

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    5. Antiviral drugs didn't exist 100 years ago

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    6. "Antiviral drugs didn't exist 100 years ago"

      Precisely. Penicllin, the first antibiotic, wasn't developed until after WWI. So, I was curious what antivirals doctors were using for MS before that, and how they even knew they were using antivirals.

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    7. Furthermore penicillin is an anti-biotic i.e. it is anti-bacterial and not anti-viral.

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  10. Congrats!
    2 additional things:

    EBV
    R-R-P-F-F

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  11. Vasilis u realy sometimes have a good arguments and questions plz tell me what is your theory of ms , i think that imune response is secondary and if u kill imune response u have big risk 4 infections lime pml and cancer but u still do not slowing progresion coz progresion is primary and lesion s on the brain r secondary ( plz note this that i am amateur on this field but from my corner of perspective this is logic ) if u reduce lesions with inf b 30 % percent u have 30 % percent chance of infections or cancer if u have 80 % percent reducing lesions u have much bigger risk for inf or can still Still distability rate is same . :( i am hoping that i am wrong about this

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  12. Maybe join the VV fan club on his/her own BLOG, which he/she said they had, where he/she can enlighten us......Oh I forgot he/she doesn't want to us to know it, maybe afraid we may visit.

    Sometimes the arguments are well.....we won't go there

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  13. Sasha, what i think about MS is not my theory. For the most part it is Dr. Franz Schelling's theory. You might want to google him.

    It's nice to hear that a malfunctioning immune system is not appealing as an explanation to you. I agree that lesions are merely the signs of the damage, an indicator much like the temperature indicator in cars: by turning it off you do not lower the temperature, but increase the risk of burning the engine.

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    1. That's your theory VV. Other theories are available ;-)

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  14. I was diagnosed 20 years ago. I went to the 4th MS Research Day yesterday and heard the presentation by Julian Gold. I haven't been so excited about the possibility of real progress towards a cure for MS since I was diagnosed. Using very powerful drugs such as Tysabri that modify the immune response (at potentially very high risk) is one thing, understanding the causal agent, the mechanism of its action and directly targeting it is so much more powerful. I'm crossing (with difficulty) all my fingers that the trial results will be positive.

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  15. How does EBV, or any other virus, account for the fact that cerebral MS lesions spread along a select system of cerebral veins in a countercurrent direction to the normal venous and interstitial fluid flows? Typical cerebral MS lesions expand on one side of a plaque vein requiring well directed mechanical impacts that no microscopic agent can conceivably provide. Precisely how is it suggested viruses cause mechanical impacts and lesion patterns involving primary alterations to strong walled periventricular collecting veins (as observed by Putnam and Adler)?

    Sir Robert Carswell - Pathological Anatomy - wrote "in inflammation the local congestion commences in the capillaries, afterwards extends to the small veins, but never to large branches; in mechanical congestion (by venous flow inversion) the blood accumulates first in the venous trunks, which are always conspicuous, and afterwards in the branches and capillaries".

    As Dr Franz Schelling notes in his book (http://www.ms-info.net/ms_040504.pdf) Carswell offers the master key to understanding MS.. Cerebral lesion formations advance in the direction from wide vein stems UPWARDS towards narrow venous roots.

    For informed consent to be given will patients taking part in anti-viral clinical trials be given full details of the venous pathology underlying the formation of their lesions together with possible explanations for this?

    Alison Fisher

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    1. Dear Alison
      You quote from the bible of the CCSVI:-),

      I wonder if I can get a pathologist to do a guest post and critique it. Yes inflammation starts around capaillaries, actually I think it is post capillary venules (small veins after the capillary) because this is where the blood flow has a low pressure that facilitates cells sticking to the blood vessel wall.

      I have asked a few about doing a post, but none have shown any interest in doing it.

      For informed consent will patients be given details of venous pathology
      underlying the formation of their lesions. Why would we do this? On the basis of a web report, which we don't know if it was peer-reviewed and so could be full of inaccuracies, on one the basis of what triggers MS lies within the CNS, from which the rest follows, I am sure it will be explained why the study is being done. Most people will no doubt come here and your comment of concern will be plain to see.

      The Charcot project is testing a hypothesis about a viral cause of MS
      it is being conducted in a controlled trial with informed consent. The vascular hypothesis is likewise being tested in trials with informed consent, will they be told about the viral hypothesis I doubt it very much.
      problem,

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    2. "How does EBV, or any other virus, account for the fact that cerebral MS lesions spread along a select system of cerebral veins in a countercurrent direction to the normal venous and interstitial fluid flows?"

      They may spread along the veins in the Virchow-Robin spaces! Another reason is simply this is the biological mechanism used by the immune system to traverse the blood vessel; all lymphocytes leave via veins.

      "Typical cerebral MS lesions expand on one side of a plaque vein requiring well directed mechanical impacts that no microscopic agent can conceivably provide."

      Not sure you can claim this without data! To the best of my knowledge MS lesions generally expand circumferentially.

      "Precisely how is it suggested viruses cause mechanical impacts and lesion patterns involving primary alterations to strong walled periventricular collecting veins (as observed by Putnam and Adler)?"

      Would need an animal model for this! I think we have one in the Japanese Macques that develop an MS-like disease after being infected with a gamma herpes virus. Let's wait for the detailed pathology on this animal model before further comment. You will also need to speak to neuropathologists to get a detailed answer on this.

      "Sir Robert Carswell - Pathological Anatomy - wrote "in inflammation the local congestion commences in the capillaries, afterwards extends to the small veins, but never to large branches; in mechanical congestion (by venous flow inversion) the blood accumulates first in the venous trunks, which are always conspicuous, and afterwards in the branches and capillaries". "

      Unfortunately, Carswell was wrong. It is not capillaries but venules!

      "As Dr Franz Schelling notes in his book (http://www.ms-info.net/ms_040504.pdf) Carswell offers the master key to understanding MS.. Cerebral lesion formations advance in the direction from wide vein stems UPWARDS towards narrow venous roots."

      I wouldn't quote Carswell in 2013, pathological techniques and stains have developed so much in the last 50 years. You are better off reading the current pathological literature. I suggest starting off with Bruce Trapp (Cleveland), John Prineas (Sydney), Margaret Esiri (Oxford) and Paul van den Valk (Amsterdam).

      "For informed consent to be given will patients taking part in anti-viral clinical trials be given full details of the venous pathology underlying the formation of their lesions together with possible explanations for this?"

      Yep, why not! We know MS has perivenous infiltrates. So do most, if not all, viral encephalitides. The veins are what the immune system uses as their doorway in and out of the blood system.

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  16. Realising I am too old anyway , at 56 1/2 . oh well.

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  17. Any update on this trial?

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  18. I'm 56 and SPMS. Had massive herpes outbreak at 25, 5 years before post optic neuritis MS diagnosis. Gut feeling two were connected...very well done indeed for getting this moving. Move on to us SPMSers as soon as you can X

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  19. Belatedly, I would like to add congratulations for daring to thnk outside the box and not being led by paternalistic lucrative fashions! Hope the trial results are encouraging for us all. (My diagnosis is now SPMS).
    Jill

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  20. there is also a monoclonal antibody trial against HERV in lupus, if i am not mistaken. great to see this idea gaining ground, much overdue.

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  21. I listened to your fascinating and heartening talk at the Chilterns MS Therapy Centre 28 Sept 2013. Thank you. Would you please clarify whether there are few/many/no people with HIV who also have MS? I came away not being sure abo9ut what you said on this aspect.
    Thanks very much (understatement!)

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    1. Being HIV positive protects people from developing MS. Why? It may be related to the drugs that are used to treat HIV. This is why we are testing an anti-HIV drug in MS in the INSPIRE trial.

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  22. Linda Jean said

    I wish someone would contact me. I want to follow this study closely. I am a 67 yo female diagnosed with ms only 7 yrs ago. But i believe I ve had it since I was 16 when I had a severe case if mono. While I have gad RRMS I t has become aoapMS. I have no mobility problems. Makesxsensecas my over 9 lesiobsxare in my brain not ny spinal cord. Ny worae symptonsxare terrible peripheral nrrve pain. And in right cheek and right area of my mouth. My belief is this is viral. I would to try an anti viral. My daughter is nurse practitioner. She wants me to take acyclovir and more lyrica. I want a strong antiviral!

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    1. We need to wait and see how the INSPIRE does and do not recommended people try these until there is evidence to support this.

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  23. I agree, its viral related. I encountered viral attack last year within 5 day after exposure via kiss and hug with person. Since then my vision and body declining. Two docs asked if ive been tested for MS. But PCP does not approve referral to neurologist. Issues feels like HSV and bumps in throat look similar to HPV. Request for antiviral denied.

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  24. Hi,

    Has this trial come to a conclusion yet? Are there any follow up trials that I can volunteer for? I have only recently been diagnosed and yet to start BG-12, so very keen to find anything else that might help.

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  25. No not yet,it will be next year. As to follow up trials... once financing gets put in place new trials will go ahead

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