Wednesday, 12 November 2014

ASCEND Trial: why I think the natalizumab in SPMS trial will be negative

Will the natalizumab SPMS (ASCEND) trial be positive and disprove my hypothesis about progressive MS? #MSBlog  #MSResearch

What are the implication of the asynchronous progressive hypothesis for MSers? #MSBlog #MSResearch

"I recently did a post predicting that the fingolimod PPMS trial, or INFORMS trial, will be positive. Since then I have had a lot of discussions with MSers and colleagues the theoretical underpinnings of this prediction. If I am correct the same theoretical predictions should apply to SPMS; based on the theories of therapeutic lag and asynchronous progressive MS hypotheses the natalizumab in SPMS, or ASCEND,  trial should be negative."

"In the Barcelona study of interferon-beta-1b treatment in PPMS after 2-years of treatment there was no difference between PPMSers who had been treated with IFNbeta or placebo. The investigators' concluded that interferon-beta was ineffective in PPMS. However, when these patients were reassessed 5-years after the end of the study there were clear clinical and MRI features favouring interferon treatment. Based on this, and other observations, I have proposed that in progressive MS there is a lag between the onset of action of anti-inflammatory medication and its impact on the biology that underpins progression. The impact of anti-inflammatory medications in progressive MS will take several years to play out in the system that is already in the clinically progressive phase. In other words progression over the next 2 years is primed by focal inflammatory events that have occurred in the past. Therefore, suppressing inflammation today in progressive MS will have not have an impact over the next 2-years as the damage that has primed progression over the next 2 years has already occurred. I predict that all anti-inflammatory therapies will have a lag in terms of showing a treatment response in progressive MS."

"This diagram below illustrates the concept of the therapeutic lag. The bad news is that the natalizumab SPMS trials (ASCEND) is only 2-years in duration, compared to the fingolimod PPMS trial (INFORMS) in which most study subjects having been followed longer than 3 years with some over 5 years. Another factor favouring the INFORMS study is that it is an event driven study and the study will only be completed when enough events, or confirmed progressions occur, to give a definitive result. This is unlike the natalizumab in SPMS, or ASCEND, trial that is time locked and is being run over 96 weeks. Based on the therapeutic lag hypothesis this is not a long enough period of time to see a positive result."

"There is one caveat to the above prediction is the asynchronous progressive MS hypothesis, i.e. neurological systems to be affected first by progressive MS are those that have the longest, or most, wiring and hence more likely to be hit by multiple lesions. This is why the motor system to the legs, bladder and the cerebellar or balance system are typically affected first when progressive disease starts. The other systems (vision, motor system to the upper arms and face, sensory system, cognition, etc.) tend to be affected later by 'overt' progressive disease. I say overt because there is now good MRI evidence that the progressive component of MS is present from the start of the disease. The only reason we don't see it clinically is because the nervous system can compensate. However, once the compensatory systems fail in a particular pathway progressive MS ensues. What this means is that we may have different windows of opportunity to impact on the different functional systems. In other words there are multiple windows of therapeutic opportunity to act in MS and we should therefore shift our focus in progressive MS away from the system already in the clinically progressive phase to those systems that still have reserve capacity and not yet in the clinically progressive phase. Will natalizumab have enough time to act on these open windows of  therapeutic opportunity to give the ASCEND trial a chance of being positive?"

"In the natalizumab SPMS trial the the primary endpoint is the effect of natalizumab relative to placebo on delaying sustained disability progression, defined by 3 month sustained increase (>=20%) from baseline in the 25-foot timed walk test, or 9-hole peg test, or sustained increase in EDSS (0.5 or 1). The inclusion of an upper limb outcome measure makes in this composite, i.e. a system with reserve capacity in most SPMSers who are still walking, makes it much more likely that this trial will be positive in this domain. In addition, the 25-foot timed walk test is also more sensitive to change than the EDSS so there is a small chance that natalizumab may affect this outcome positively as well. However, I think it is unlikely that Natalizumab will have an impact on EDSS progression over 96-weeks. I hope I am wrong."

"The implications of the therapeutic lag and asynchronous progressive MS hypotheses is that we may have been designing, and doing, trials in progressive MS incorrectly. More importantly these concepts challenge the so called therapeutic window concept. It also means that instead of writing someone off  with progressive MS because their so called therapeutic window has closed is that we can now focus on the other therapeutic windows that are still open."

"It has never made sense to me not being able to prescribe a DMT to an MSer simply because they needed a wheelchair as a result of a devastating spinal cord relapse. What about their upper limb, cognitive and cerebellar function? Do we simply write these systems off because one, or two, long tract systems are severely damaged? I personally think the therapeutic lag and asynchronous progressive MS hypotheses gives MSers hope; hope for treatments that can at least preserve the function of pathways with reserve capacity, whilst the lab scientists work on remyelination and neurorestorative strategies. Buying time; spreading hope!"


Primary Outcome Measures:

Percentage of participants with confirmed progression of disability in one or more of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT) [Time Frame: Up to 96 weeks ] 

Confirmed disability progression is defined as one or more of the following criteria, confirmed at a second visit at least 6 months later and at Week 96: 

Confirmed progression in EDSS: EDSS score increased from baseline by at least 1 point if baseline EDSS ≤5.5 or by at least 0.5 points if baseline EDSS ≥6.

Or

Confirmed progression in T25FW: T25FW increased by at least 20% of the baseline walk. 

Or

Confirmed progression in 9HPT: 9HPT increased by at least 20% of the time taken at baseline. The progression in 9HPT can occur on either hand, but will have to be confirmed on the same hand. 


Eligibility
  • Ages Eligible for Study: 18 Years to 58 Years
  • Genders Eligible for Study: Both
  • Accepts Healthy Volunteers: No

Key Inclusion Criteria (Part 1):

  • Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local subject privacy regulations.
  • Secondary progressive multiple sclerosis (SPMS) defined as relapsing-remitting disease followed by progression of disability independent of or not explained by multiple sclerosis (MS) relapses for at least 2 years.
  • Expanded Disability Status Scale (EDSS) score of 3.0 to 6.5, inclusive.
  • Multiple Sclerosis Severity Score (MSSS) of 4 or higher.
  • Documented confirmed evidence of disease progression independent of clinical relapses over the 1 year prior to enrollment as defined in the Study Reference Guide.

Key Exclusion Criteria (Part 1):

  • Relapsing remitting multiple sclerosis (RRMS) or primary progressive multiple sclerosis (MS) as defined by the revised McDonald Committee criteria.
  • Clinical relapse (within 3 months) prior to randomization.
  • Timed 25-Foot Walk (T25FW) test of >30 seconds during the screening period.
  • Any value below the lower limit of normal for blood levels of leukocytes, lymphocytes, or neutrophils.
  • Considered by the Investigator to be immunocompromised based on medical history, physical examination, laboratory testing, or any other testing required by local guidelines, or due to prior immunosuppressive or immunomodulating treatment.
  • Subjects for whom magnetic resonance imaging (MRI) is contraindicated (i.e., have pacemakers or other contraindicated implanted metal devices, are allergic to gadolinium, or have claustrophobia that cannot be medically managed).
  • History of any clinically significant (as determined by the Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic (other than MS), dermatologic, psychiatric, and renal, or other major disease that would preclude participation in a clinical study.
  • History of malignant disease, including solid tumors and hematologic malignancies (with the exception of basal cell and squamous cell carcinomas of the skin that have been completely excised and are considered cured).
  • Known history of or positive test result for Human Immunodeficiency Virus (HIV).
  • Positive test result for hepatitis C virus (test for hepatitis C virus antibody [HCV Ab]) or hepatitis B virus (test for hepatitis B surface antigen [HBsAg] and/or hepatitis B core antibody [HBcAb]).
  • History of transplantation or any anti-rejection therapy.
  • Presence of any infectious disease (e.g., cellulitis, abscess, pneumonia, septicemia) within 30 days prior to screening.
  • History of progressive multifocal leukoencephalopathy (PML) or other opportunistic infections.
  • Treatment History 
  • Any prior treatment with cell-depleting therapies, including total lymphoid irradiation, cladribine, rituximab, alemtuzumab, or bone marrow ablation.
  • Any prior treatment with natalizumab.
  • Treatment with mitoxantrone, cyclophosphamide, cyclosporine, azathioprine, methotrexate, mycophenolate mofetil, T cell or T cell receptor vaccination, fingolimod, daclizumab, or cytapheresis within 6 months prior to randomization.
  • Treatment with intravenous or oral corticosteroids, intravenous immunoglobulin (IVIg), or plasmapheresis for treatment of multiple sclerosis within the 3 months prior to randomization.
  • Treatment with glatiramer acetate or any interferon beta preparations within 4 weeks prior to randomization.
  • Treatment with 4-aminopyridine within 30 days prior to randomization, unless a stable dose has been maintained for at least 30 days prior to randomization and will be continued for the course of this study.

Key Inclusion Criteria (part 2):
  • Subjects must have participated in and completed Part 1 per protocol, and have documented assessment attempts for Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT) prior to first open-label dosing.

Key Exclusion Criteria (Part 2):


  • Subjects with any significant change in clinical status, including laboratory tests that, in the opinion of the Investigator, would make them unsuitable to participate in this extension study. The Investigator must re-review the subject's medical fitness for participation and consider any diseases that would preclude treatment.
  • Subjects who discontinued study treatment in Part 1 OR had fewer than 20 infusions in Part 1 OR missed 2 or more consecutive infusions in Part 1.

CoI: multiple

6 comments:

  1. If the "therapeutic lag" hypothesis is correct, the length of the "lag period" may depend on the effectiveness of anti-inflammatory treatment

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    Replies
    1. Re: "If the "therapeutic lag" hypothesis is correct, the length of the "lag period" may depend on the effectiveness of anti-inflammatory treatment"

      Almost certainly and will be in proportion to how much reserve is left. The more reserve the shorter lag. Which is why natalizumab has a good chance in affecting upper limb function over 96 weeks and a lower chance of impacting lower limb function. All we have to wait is about 18 months and will have an answer. I think the last patient will out of the ASCEND trial in Aug 2015; 2-3 months for the data lock and 2-3 months for the analysis. It is a pit the trial didn;t have an interim analysis and 24 months, but could be run for 36-48 months.

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  2. Dear Diana from Minnisota

    Do not think us rude for not posting your comment but please do not add email addresses as you will no doubt get best friends you dontwant. However to answer your question. I am afraid you are too late for this trial it has now fully recruoted. However check out clinical trials.gov for trials to see what other trials are onging in your area. It lists the sites doing each study. Hope this is useful info

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  3. Great post. I'm on the trial and really hope it helps us all in the longer term.

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  4. "It has never made sense to me not being able to prescribe a DMT to an MSer simply because they needed a wheelchair as a result of a devastating spinal cord relapse."

    I don't think because disability shows up in areas such as bladder dysfunction is an indication of damage to the spinal cord. In my case, I lost bladder function and it was found that the demyelination occurred in the Pons. I'm currently on a DVD and all relapses and progression seemed to have been halted.

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  5. Re "the motor system to the legs, bladder and the cerebellar or balance system are typically affected first when progressive disease starts. The other systems (vision, motor system to the upper arms and face, sensory system, cognition, etc.) tend to be affected later by 'overt' progressive disease."

    I don't think my daughter follows this pattern. Legs and bladder are fine. Balance is not as good as before MS. Cognition is affected. But the most visible permanent damage seems to be in the functioning of her hands.

    ReplyDelete

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