the HYPE study

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It is clear that many MSers on continuous anti-CD20 therapy are concerned about the risk of developing hypogammaglobulinaemia and subsequent infections. Yesterday, I spoke to several neurologists at the O’HAND investigators meeting in Barcelona who informed me that they are considering giving their ocrelizumab-treated patients hyperimmune globulin replacement therapy (HYPE-Ig-RT) when they develop hypogammaglobulinaemia to prevent serious and potentially fatal infections. 

The problem I have with this is that HYPER-Ig-RT is expensive and for it to be covered by the NHS we will need to show that it is cost-effective. In response to these discussions Owen Pearson, an MSologist from Swansea, and I came up with the design of the HYPE study below.

The HYPE study

This is a randomised placebo-controlled trial to assess whether or not  HYPE-Ig-RT will work, i.e. reduce the risk of serious infection, infections and mortality in MSers on continuous anti-CD20 therapy. Please note we don’t think this study should be limited to ocrelizumab-treated MSers but should be open to any patient on anti-CD20 therapy, including those on rituximab and ofatumumab. 

What do you think of the HYPE study? Do we have clinical equipoise? 

Please remember for the payers, i.e. NHS England and insurance companies, to pay for HYPER-Ig-RT we need class 1 evidence to make the financial case to them. This study will test the hypothesis that HYPE-Ig-RT will derisk continuous anti-CD20 therapies and prevent some of the infectious complications related to hypogammaglobulinaemia. 

What is the risk of serious infections on anti-CD20 therapies? 

The following figures put the serious infection risk, i.e. infections requiring hospitalisation, on ocrelizumab in context. The overall figure is 2.24 serious infections per 100 patient-years. In other words for every 45 patients on ocrelizumab for 12 months one patient will be admitted to hospital with a serious infection. However, if you develop low IgG levels (hypogammaglobulinaemia) the risk rises to 5.48 serious infections per 100 patient-years or for every 18 patients on ocrelizumab for 12 months one patient will be admitted with a serious infection. This is why we are now monitoring peripheral blood immunoglobulin levels on an annual basis in all our patients on anti-CD20 therapy.

Derfuss et al. Serum Immunoglobulin Levels and Risk of Serious Infections in the Pivotal Phase III Trials of Ocrelizumab in Multiple Sclerosis and Their Open-Label Extensions. ECTRIMS 2019, 

CoI: multiple

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

20 comments

  • For example, the dose of immunoglobulin replacement therapy indicated for:

    1. Primary immunodeficiency syndromes with impaired antibody production
    2. Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia (CLL), in whom prophylactic antibiotics have failed or are contra-indicated.
    3. Hypogammaglobulinaemia and recurrent bacterial infections in multiple myeloma (MM) patients.
    4. Hypogammaglobulinaemia in patients pre- and post-allogeneic haematopoietic stem cell transplantation (HSCT).

    In replacement therapy the dose may need to be individualised for each patient dependent on the pharmacokinetic and clinical response. The following dose regimens are given as a guideline.

    The dose regimen should achieve a trough level of IgG (measured before the next infusion) of at least 5 to 6 g/l and aim to be within the reference interval of serum IgG for age. A loading dose of at least 0.2 to 0.5 g/kg (1 to 2.5 ml/kg) body weight may be required. This may need to be divided over several days, with a maximal daily dose of 0.1 to 0.15 g/kg. After steady state IgG levels have been attained, maintenance doses are administered at repeated intervals to reach a cumulative monthly dose of the order of 0.3 to 1.0 g/kg (see section 5.2 for details). Each single dose may need to be injected at different anatomic sites.

    Trough levels should be measured and assessed in conjunction with the incidence of infection. To reduce the rate of infection, it may be necessary to increase the dose and aim for higher trough levels.

    Source: https://www.medicines.org.uk/emc/product/9191/smpc

    • Hypogammaglobulinaemia is defined as immunoglobulin levels below the lower limit of normal. The latter is usually based on population norms; I suspect levels below 2 standard deviations from the norm; i.e. normal ranges for adults are:

      IgG 6.0 – 16.0g/L
      IgA 0.8 – 3.0g/L
      IgM 0.4 – 2.5g/L

      The above does not capture qualitative defects; i.e. how good are your antibodies in fighting and preventing infection? This is why immunologists only tend to take low levels seriously if you are having recurrent infections.

  • I know you are all very clever, amazing people here;but seriously we are all humans, not lab rodents to experimented upon?! Or cash cows for the parasitical pharma to feed off.

    Hypogammaglobulinaemia
    Sounds hideous and horrible and time consuming and very expensive….
    So Remind me again of how Ocrevus benifts out weigh the risks and improve quality of life. I’m not on it, but nearly was. (I’m 26 years in and still live independently FYI)
    It’s like a unicorn being blown up by a fairy, realising that it causes way more problems than it solves

    I’m disappointed for people searching for a miracle and frankly gutted for those already on it.

    Also Very perturbed that money is being thrown at research that is pointless (even I know that it’s lack of vit d in the womb is the problem
    – havnt u noticed how many people with MS are Arians…duh)

    The pharmas’ have plenty of other maladies they can make millions off, by treating; not curing; but boy just think how much money could be made finding a cure…..so for heaven’s sake, can everyone not stop lining their pockets; research a cure and stop using MS’ers us as research fodder to fulfil big budgets

    (Please convey to Barcelona Bods )

    • Re: “Hypogammaglobulinaemia: Sounds hideous and horrible and time-consuming and very expensive”

      Yes and no. Hypogammaglobulinaemia is a potential side effect of continuous immunosuppression and needs to be acknowledged as such. Al we are saying is that is should be screened for and if associated with infections treated. Derisking immunosuppression to make it safer is what we are suggesting. Why wouldn’t you try and make an MS treatment safer?

  • I know you are all very clever, amazing people here;but seriously we are all humans, not lab rodents to experimented upon?! Or cash cows for the parasitical pharma to feed off.

    Hypogammaglobulinaemia
    Sounds hideous and horrible and time consuming and very expensive….
    So Remind me again of how Ocrevus benifts out weigh the risks and improve quality of life. I’m not on it, but nearly was. (I’m 26 years in and still live independently FYI)
    It’s like a unicorn being blown up by a fairy, realising that it causes way more problems than it solves

    I’m disappointed for people searching for a miracle and frankly gutted for those already on it.

    Also Very perturbed that money is being thrown at research that is pointless (even I know that it’s lack of vit d in the womb is the problem
    – havnt u noticed how many people with MS are Arians…duh)

    The pharmas’ have plenty of other maladies they can make millions off, by treating; not curing; but boy just think how much money could be made finding a cure…..so for heaven’s sake, can everyone not stop lining their pockets; research a cure and stop using MS’ers us as research fodder to fulfil big budgets
    (Please convey to Electrims Barcelona…)

    • One of my closest friends with MS having chronic infection problems decided to forgo all FDA approved DMTs and try the Wheldon protocol instead. Three years and counting she views that choice as one the best decisions she ever made. I understand why when I compare her health and quality of life before and now.

      It is possible MSers with persistent recurring infections may require HYPE-Ig-RT if they choose an anti-CD20 therapy. For that group of patients it could be extremely important.

      • I am sure equally there are people who tried the Sheldon protocol and did not fare so well. The internet is awash with claims and if they were so great the MS Society in UK would not be having a new campaign to stop MS.

        • “I am sure equally there are people who tried the Sheldon (Wheldon) protocol and did not fare so well.”

          Unless you personally can vouch for someone who ‘did not fare so well’ on Wheldon’s protocol as I can vouch for someone having success on it, you are 100% less sure, not equally sure. Perhaps, you can. But if not, I would urge less certainty about things not known.

          There have been umpteen campaigns to stop MS. Perhaps, one reason for the slow progress is discrediting what doesn’t reinforce our current bias.

          We have no scientific studies suggesting what effect Wheldon protocol has in MS so let’s dismiss whatever doesn’t fit present thought. Let’s ignore people like this lady who ceased taking copaxone and Aubagio, which made her ill, and found success with something else which has worked for at least two people… Dr. Wheldon’s wife and the lady I referenced.

          A PwMS experiencing chronic infections considering ocrelizumab may benefit by learning more about the protocol Dr. Wheldon used for his wife, in my unprofessional opinion, of course.

          I’m making no broad claims, merely stating the experience of one person. But a person having notable success, as noted by her neurologist, btw. Ought these cases be spoken of or silenced? Perhaps, we should charge headlong but not mindless into another new campaign to stop MS.
          Respectfully Yours

          • OK has anyone out their tried the Wheldon protocol and did not feel that it worked for them. I am sorry but anecdote is not evidence of value. We have been here so many times. $10,000,000 dollars and more were spent by the Cnadians discrediting CCSVI, the Italians probably also spent a large amount too. I am not dis-missing it, I am simply stating the scientific evidence is weak. If you look though the blog you will see that Dr Wheldon used to visit the blog. I am critical of armchair scientists who sit on their bum and do nothing to get the evidence needed for their ideas. You may say we have done nothing to get combination treatments going, so yes we know it is hard. But if you as a commuity believe this is the way forward put pressure on the MS Societies to investigate them.

    • Not all of us have slow disease progression. I strongly disagree with you that all the drug research is a waste of money. I’m more than willing to take the risk on infection because I definitely won’t have a long happy independent life without something to slow the disease. I can’t imagine where I would be without something to slow it down. And lifestyle changes aren’t going to cut it. I started out with about the cleanest lifestyle you can imagine including growing up on an organic farm.

    • Parasitic pharma? Am interested to hear if you have formulated that view from inside knowledge and experience or just repetition of received wisdom.

  • You need to monitor Immunoglobulins before each infusion not just annually. With rituximab the infections are low, although ocrevus is more potent so more infections. Speaking to an immunologist about when to give immunoglobulins in cases of hypogammaglobulinaemia is invaluable.

    • Re: “You need to monitor Immunoglobulins before each infusion not just annually…”

      Yes, in the HYPE study we suggest doing immunoglobulin levels 6-monthly. The problem is what protocol of HYPE-Ig-RT (immunoglobulin replacement therapy) do we use? This study is really about preventing infections, i.e. being proactive. When you look at the literature if patients on rituximab with hypogammaglobulinaemia and recurrent infections there are many different protocols. I suspect the HYPE-Ig-RT will have to be given at least every 2-months to keep Ig levels above a threshold that is associated with infections.

      • Two monthly HYPE-Ig-RT will be expensive. Who will pay for it? I suggest crossing that bridge when we have class 1 evidence that HYPE-Ig-RT works, i.e. derisks the problem at hand.

  • Are there other things like diet, exercise, the usual good lifestyle suspects that help reduce or negate the risk of hypogammaglobulinamiea (so?)? Alternatively, can the risk also be expressed by the presence of are other comorbidities like obesity, hypertension, and the usual suspects?

    Or…is the cause not something the individual can influence? If we)they/I can do something that roughly halves the risk then am all ears.

  • Regarding serious infections with MS DMTs… the Wheldon Protocol I referred to in earlier comments here is a prolonged treatment with antibiotics, not diet. Dr. David Wheldon developed this treatment for his wife with MS; it is commonly referred to as the Wheldon Protocol.
    Besides what Dr. Wheldon reported concerning his wife I know one person personally with MS who has achieved notable success using antibiotics rather than one of the approved DMTs. She chose the regimen outlined by the Wheldon protocol because of her health problems with recurring, serious infections and the MS DMTs she was put on seemed to increase the frequency and severity of those infections.
    Today, following Dr. Wheldon’s protocol, this lady lives a notably better life. Her MRIs are stable. This woman has not had a serious infection for 3 1/2 years and counting on the Wheldon Protocol using prolonged antibiotics. She has had no exacerbations of MS during that period and her quality of life has vastly, vastly improved. I speak with her daily so I know this to be accurate.
    I share skepticism about much of the nonsense floated regarding non-approved MS treatments. However, if I encounter someone achieving notable results outside approved DMTs and I can vouch for that person doing so, it is prudent to report on that person. Anecdotal cases may or may not turn out to be important but the first step is learning of their existence.
    I am not advocating; I’m reporting. If doing so does not fit prevailing bias, ignore it. I congratulate the woman. She accomplished more than her brilliant learned physicians.
    Wisdom is justified of her children.

    • Sorry for slip up, but as disease activity may be triggered by urinary and respiratory tract infections one could see how anti-biotics may be of benefit. This idea has its roots in Chlamdyia. However we have to base opinion on empirical evidence and without the evidence base we have to err on the side of the sceptic.

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