Cyclophosphamide in ME/CFS Part A:an Open Label Phase-II Study With Six Intravenous Cyclophosphamide

deleder2k

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The trial "CycloME" is now underway in Norway. The official name is:


Cyclophosphamide in Myalgic Encephalopathy/ Chronic Fatigue Syndrome (ME/CFS). Part A: an Open Label Phase-II Study With Six Intravenous Cyclophosphamide Infusions Four Weeks Apart, and Follow-up for 12 Months

It seems that the study is due to be finished in November 2016. That means we probably will have results approximately 1 year before the Rituximab phase 3 is published.

Here is the information posted on clinicaltrials.gov:

Significant clinical improvements of ME/CFS symptoms were observed in two patients with long-standing ME/CFS who received adjuvant chemotherapy including cyclophosphamide for breast cancer, also in one ME/CFS patient who received chemotherapy including iphosphamide for Hodgkin lymphoma.

Three pilot ME/CFS patients were thereafter treated with six intravenous infusions four weeks apart, in two of these with a significant clinical response.

The hypothesis is that a subset of ME/CFS patients have an activated immune system, and that ME/CFS symptoms may be alleviated by treatment with cyclophosphamide as intravenous pulse infusions four weeks apart, six infusions in total.


The purpose of the present study is to treat ME/CFS patients with cyclophosphamide as intravenous pulse infusions four weeks apart, six infusions in total. The effects on ME/CFS symptoms and tolerability/side effects during 12 months follow-up will be registered, and additional tests will be performed to objectively register changes in physical ability during follow-up. Studies to investigate possible large vessel endothelial dysfunction and skin microvascular dysfunction will be performed before start of intervention and during follow-up.


Condition Intervention Phase
Chronic Fatigue Syndrome (CFS)
Myalgic Encephalomyelitis (ME)
Drug: Cyclophosphamide
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Cyclophosphamide in Myalgic Encephalopathy/ Chronic Fatigue Syndrome (ME/CFS). Part A: an Open Label Phase-II Study With Six Intravenous Cyclophosphamide Infusions Four Weeks Apart, and Follow-up for 12 Months

Resource links provided by NLM:

MedlinePlus related topics: Chronic Fatigue Syndrome Fatigue
Drug Information available for: Cyclophosphamide
U.S. FDA Resources
Further study details as provided by Haukeland University Hospital:

Primary Outcome Measures:
  • Fatigue score, selfreported [ Time Frame: Within 12 months follow-up ] [ Designated as safety issue: No ]
    Selfreported Fatigue score is registered every second week, always compared to baseline, as the mean of the four symptoms: "Post-exertional malaise", "Fatigue", "Need for rest", Daily functioning" (scale 0-6, in which 3 is unchanged from baseline). Mean Fatigue scores for the time intervals 0-3, 3-6, 6-9 and 9-12 months are recorded for each patient. Changes in selfreported Fatigue scores from baseline to the mean values in each of the time intervals 0-3, 3-6, 6-9 and 9-12 months follow up, will constitute the primary endpoint.


    Responses for the primary endpoint will be recorded separately for the group of (at least) 25 ME/CFS patients not given rituximab previously, for the group with previous rituximab intervention for ME/CFS with no clinical response and for the group with previous rituximab intervention with clinical response but later relapse, and also for all 40 included patients together.

  • Overall response [ Time Frame: Within 12 months follow-up ] [ Designated as safety issue: No ]
    Overall response is recorded as the effect on ME/CFS symptoms during 12 months follow-up. The overall response is not predefined to a specific time interval during follow-up, but is defined as mean Fatigue score at least 4.5 for at least 6 consecutive weeks for moderate response, and mean Fatigue score at least 5.0 for at least 6 consecutive weeks for major response. Single response periods and the sum of response periods during 12 months follow-up will be recorded.


    Overall response will be recorded separately for the group of (at least) 25 ME/CFS patients not given rituximab previously, for the group with previous rituximab intervention for ME/CFS with no clinical response and for the group with previous rituximab intervention with clinical response but later relapse, and also for all 40 included patients together.

Secondary Outcome Measures:
  • Short Form-36 (SF-36) [ Time Frame: Recorded at baseline, and at 3, 6, 9 and 12 months follow-up. ] [ Designated as safety issue: No ]
    SF-36 (ver 1.2) is completed by patients at baseline, and at 3, 6, 9, 12 months follow-up. Changes in Physical health summary score, Physical function, and "Mean of five subdimensions" (Physical function, Bodily pain, Vitality, Social function, General health) from baseline to each of the time points 3, 6, 9 and 12 months follow-up are recorded and constitute secondary endpoints. Secondary endpoints will be recorded separately for the group of (at least) 25 ME/CFS patients not given rituximab previously, for the group with previous rituximab intervention for ME/CFS with no clinical response and for the group with previous rituximab intervention with clinical response but later relapse, and also for all 40 included patients together.
  • Physical activity (Sensewear armband) [ Time Frame: Recorded at baseline, at 7-9 months, and at 11-12 months ] [ Designated as safety issue: No ]
    The patients' physical activity level, in a home setting for 7 consecutive days, is recorded using Sensewear armbands, with registration at baseline and repeated in the time interval 7-9 months follow-up, and in the interval 11-12 months. Changes from baseline to analysis during the time intervals 7-9 months and 11-12 months, for mean number of steps per 24h, maximum number of steps per 24h, mean duration per 24h with activity level at least 3.5 METs, max duration per 24h with activity level at least 3.5 METs, are recorded. Changes in Physical activity will be recorded separately for the group of (at least) 25 ME/CFS patients not given rituximab previously, for the group with previous rituximab intervention for ME/CFS with no clinical response and for the group with previous rituximab intervention with clinical response but later relapse, and also for all 40 included patients together.
  • Cardiopulmonary exercise tests for two following days [ Time Frame: At baseline, and repeated at 7-9 months, and 11-12 months ] [ Designated as safety issue: No ]
    For patients who can tolerate exercise, cardiopulmonary exercise tests will be performed for two consecutive days, at baseline, and repeated in the time intervals 7-9 months, and 11-12 months. A programmed ramp-protocol is used. Oxygen-uptake and work load (Watt) day 2, at maximum effort and at anaerobic threshold, will be recorded and used for comparison to oxygen-uptake and work load with repeated tests after 7-9 and 11-12 months. Changes from baseline to repeated exercise tests after 7-9 and 11-12 months will be analyzed.
  • Self-recorded Function level [ Time Frame: At baseline, and at 3, 6, 9 and 12 months follow-up ] [ Designated as safety issue: No ]
    Self-recorded "Function level" (scale 0-100, compared to healthy state, according to a set of examples) are registered every second week. Mean "Function level" for the time intervals 0-3, 3-6, 6-9, 9-12 months are calculated. The changes in selfreported "Function level", from baseline to the mean value during each of the the time intervals 0-3, 3-6, 6-9, 9-12 months constitute secondary endpoints.

    Changes in Self-reported Function level will be recorded separately for the group of (at least) 25 ME/CFS patients not given rituximab previously, for the group with previous rituximab intervention for ME/CFS with no clinical response and for the group with previous rituximab intervention with clinical response but later relapse, and also for all 40 included patients together.

  • Fatigue Severity Scale [ Time Frame: Baseline, 3, 6, 9 and 12 months ] [ Designated as safety issue: No ]
    Fatigue Severity Scale (FSS) is completed by patients at baseline and at 3, 6, 9, 12 months. The changes in FSS from baseline to 3, 6, 9 and 12 months constitute secondary endpoints.


    Changes in Fatigue severity scale will be recorded separately for the group of (at least) 25 ME/CFS patients not given rituximab previously, for the group with previous rituximab intervention for ME/CFS with no clinical response and for the group with previous rituximab intervention with clinical response but later relapse, and also for all 40 included patients together.

  • Longest continuous response duration [ Time Frame: Within 12 months follow-up ] [ Designated as safety issue: No ]
    The longest duration of continuous self-reported Fatigue score ≥ 4,5 (for at least 6 consecutive weeks) within 12 months follow-up.


    The longest response duration will be recorded separately for the group of (at least) 25 ME/CFS patients not given rituximab previously, for the group with previous rituximab intervention for ME/CFS with no clinical response and for the group with previous rituximab intervention with clinical response but later relapse, and also for all 40 included patients together.

  • Sustained clinical response at 12 months [ Time Frame: Assessment at end of follow-up (12 months) ] [ Designated as safety issue: No ]
    The fraction of patients with sustained clinical response (defined as Fatigue score of at least 4.5) at 12 months, constitute a secondary endpoint.


    Sustained clinical response at 12 months will be recorded separately for the group of (at least) 25 ME/CFS patients not given rituximab previously, for the group with previous rituximab intervention for ME/CFS with no clinical response, and for the group with previous rituximab intervention with clinical response but later relapse, and for all included patients together.

  • Safety and tolerability [ Time Frame: Continuously within the study period of 12 months ] [ Designated as safety issue: Yes ]
    Safety will be assessed by interim history, physical examination, and laboratory assessments every four weeks the first six months, thereafter at 6, 9 and 12 months follow-up. Adverse events will be graded according to the Common Toxicity Criteria for Adverse Effects (NCI-CTCAE, version 4.0). Number of patients with any grade, or severe (≥ grade 3 NCI-CTCAE version 4.0) toxicity will be reported, as a measure of tolerability and safety.


    Adverse Events may include include hair loss, vomiting, diarrhea, jaundice, leukopenia, anemia, thrombocytopenia, infections, allergic reactions and hemorrhagic cystitis, disturbed ovarian function. The investigators will also collect information on possible toxicity after the formal 12 months study period.

Estimated Enrollment: 40
Study Start Date: March 2015
Estimated Study Completion Date: November 2016
Estimated Primary Completion Date: November 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cyclophosphamide
Cyclophosphamide, intravenous infusions four weeks apart. Six infusions in total. First infusion: 600 mg/m2. Infusions 2 to 6: 700 mg/m2
Drug: Cyclophosphamide
Cyclophosphamide intravenous infusions four weeks apart, in total six infusions. First infusion: cyclophosphamide 600mg/m2. Infusions 2 to 6: cyclophosphamide 700 mg/m2 . Follow-up for 12 months.

Eligibility

Ages Eligible for Study: 18 Years to 65 Years
Genders Eligible for Study: Both
Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:

  • Patients with ME/CFS according to "Canadian" criteria (2003)
  • Duration of ME/CFS at least 2 years
  • Mild/Moderate, Moderate, Moderate/Severe and Severe ME/CFS may be included
  • Age 18-65 years
  • Signed informed consent
Exclusion Criteria:

  • Patients with fatigue who do not comply by the diagnostic "Canadian" criteria (2003) for ME/CFS
  • Duration of ME/CFS less than 2 years
  • Mild ME/CFS
  • Very severe ME/CFS (bedridden requiring help for all tasks)
  • Patients where the workup uncovers other pathology as possible cause of symptoms
  • Pregnancy or breast feeding
  • Previous malignant disease (except basal cell carcinoma of skin and cervical carcinoma in situ/dysplasia)
  • Previous long-term systemic treatment with immunosuppressive agents (e.g. azathioprine, ciclosporin, mycophenolate mofetil). Except steroid treatment for e.g. obstructive lung disease or autoimmune diseases such as e.g. ulcerative colitis
  • Serious endogenous depression
  • Lack of ability to complete the study including follow-up
  • Reduced renal function (creatinine > 1.5 x UNL)
  • Reduced liver function (bilirubin or transaminases > 1.5 x UNL)
  • Known hypersensitivity to cyclophosphamide or metabolites
  • Reduced bone marrow function
  • Ongoing cystitis or urinary tract obstruction
  • Known HIV positivity, previous hepatitis B or hepatitis C, or reason to suspect other ongoing and clinically relevant infection
 
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Bob

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Interesting to note that the Canadian Criteria are being used and at least two years duration of illness:
Inclusion Criteria:
  • Patients with ME/CFS according to "Canadian" criteria (2003)
  • Duration of ME/CFS at least 2 years
  • Mild/Moderate, Moderate, Moderate/Severe and Severe ME/CFS may be included
  • Age 18-65 years
  • Signed informed consent
 

Bob

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Yikes, Cyclophosphamide seems to be a heavy-duty chemotherapy drug, with potential for very severe side effects especially at higher doses. It's not for the faint hearted. But I don't know how dose size for autoimmunity compares with dose size for cancer - perhaps lower doses might make a significant difference for the side-effect profile and potential for adverse events.
http://en.wikipedia.org/wiki/Cyclophosphamide

I'm not familiar with the drug or its mechanism of action but it is used to treat severe autoimmune conditions including rheumatoid arthritis, and seems to have a mechanism of action via T cells. (Perhaps we've discussed this before? I can't remember):
http://en.wikipedia.org/wiki/Cyclophosphamide#Mechanism_of_action
 
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deleder2k

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They use 600-700mg/m2. I think that is common for breast cancer (a long with several other medicines at the same time). I heard somewhere that 600-700mg/m2 is safer once in a while than having a low dose often.

In cancer they can give up to 3-4 g/m2 if I am not mistaken.
 

Marky90

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Yikes, Cyclophosphamide seems to be a heavy-duty chemotherapy drug, with potential for very severe side effects especially at higher doses. It's not for the faint hearted. But I don't know how dose size for autoimmunity compares with dose size for cancer - perhaps lower doses might make a significant difference for the side-effect profile and potential for adverse events.
http://en.wikipedia.org/wiki/Cyclophosphamide

I'm not familiar with the drug or its mechanism of action but it is used to treat severe autoimmune conditions including rheumatoid arthritis, and seems to have a mechanism of action via T cells. (Perhaps we've discussed this before? I can't remember):
http://en.wikipedia.org/wiki/Cyclophosphamide#Mechanism_of_action
Yep! Not a walk in the park-drug by any means, but it doesnt seem too bad either with regards to the actual chances of getting serious side effects "Myeloproliferative neoplasms, including acute leukemia, non-Hodgkin lymphoma, and multiple myeloma, occurred in 5 of 119 rheumatoid arthritis patients within the first decade after receiving cyclophosphamide, compared with one case of chronic lymphocytic leukemia in 119 rheumatoid arthritis patients without a history of cyclophosphamide use."

However - Acute leukemia, e.g, is a very very serious diagnosis indeed.
In other words - not a drug to take in a heartbeat!
 

Marky90

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cyclo-risk.png

From the study comments: "Because lymphoma is a cancer arising from lymphocytes, it is not surprising that diseases characterized by immune system dysregulation (including RA, among others) are associated with malignant transformation of lymphocytes. Similarly, T-cell large granular lymphocyte leukemia is a disorder often associated with autoimmune disorders, especially RA, and particularly in patients with Felty syndrome. This malignancy of cytotoxic T cells is characterized by dysregulated apoptosis and may be antigen driven.20 Controversy continues, however, as to how much of the total risk of hematologic malignant neoplasms in RA is related to the disease process itself vs to immunosuppressive medications; recent data suggest both aspects are likely important.13 Immunosuppressive drugs have been linked to the development of both leukemia and lymphomas, and immunodeficiency, whether innate or acquired, is a strong risk factor for certain lymphomas. In many cases, this association relates to the emergence of Epstein-Barr virus–driven malignant proliferations; however, in RA, this does not seem to be the only driving force.13 Impaired immune surveillance can prevent the deletion of abnormal cells, a phenomenon that may have been magnified in our study design, which focused on an older cohort."
 

Bob

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Yep! Not a walk in the park-drug by any means, but it doesnt seem too bad either with regards to the actual chances of getting serious side effects "Myeloproliferative neoplasms, including acute leukemia, non-Hodgkin lymphoma, and multiple myeloma, occurred in 5 of 119 rheumatoid arthritis patients within the first decade after receiving cyclophosphamide, compared with one case of chronic lymphocytic leukemia in 119 rheumatoid arthritis patients without a history of cyclophosphamide use."

However - Acute leukemia, e.g, is a very very serious diagnosis indeed.
In other words - not a drug to take in a heartbeat!
Yep, if you're one of the unlucky 5 in 119 who gets lymphoma or leukaemia then it's definitely not a walk in the park. I can't see me wanting to take this drug. But if it were to have a guaranteed and substantial benefit then I should imagine that it would be something that very severely affected patients may potentially consider.
 
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Marky90

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Have one or more objective measurements as primary outcomes instead of secondary, and move the fatigue questionnaires into secondary outcomes. The current set up allows them to say the treatment is a success if "fatigue" answers improve, even if actual disability stays the same or worsens.
I see your point.

But as far as i can tell that is accounted for with "fatigue" just being one of the 4 symptoms ("Post-exertional malaise", "Need for rest", "daily functioning")

I see the biggest problem being patients not being completely honest.
 

Marky90

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Yep, if you're one of the unlucky 5 in 119 who gets lymphoma or leukaemia then it's definitely not a walk in the park. I can't see me wanting to take this drug. But if it were to have a guaranteed and substantial benefit then I should imagine that it would be something that very severely affected patients may consider.
I agree. However, a fair point is that we probably got a fair chance of getting b-cell related cancer in the first place with ME. So if you got the approx same chance of attaining some other cancer, with cyclo, but your healthy.. Well then it kinda makes sense to go for it if all else fails?
 

Bob

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I agree. However, a fair point is that we probably got a fair chance of getting b-cell related cancer in the first place with ME. So if you got the approx same chance of attaining some other cancer, with cyclo, but your healthy.. Well then it kinda makes sense to go for it if all else fails?
I think the decision to take cyclo would be a very personal choice and would depend on the severity of ME/CFS and on whether cyclo guarantees a substantial and sustained improvement in every patient it is prescribed to. If you were to get no benefit from it, or short-term benefit, but you developed cancer a few years down the line then it's not a good deal.

I'm not convinced by your assertion that we "probably got a fair chance of getting b-cell related cancer in the first place with ME." We do have an increased risk of developing certain specific cancers, but I'm not sure there is robust data for this, and I'm pretty sure it's not anywhere near as high as 5 in 119 for leukaemia and lymphoma etc over a ten year period? As far as I remember, it's a substantially increased rate, compared to the general population, but the rates are still very low. If it were as high as 10% over a ten year period, then I think we'd know a lot of forum members who had developed cancer over the past few years. (Note that the cancer rates that you've posted are for a ten year period, and not lifetime.)
 
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Marky90

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"CFS was associated with diffuse large B cell lymphoma (OR = 1.34, 95% CI = 1.12-1.61), marginal zone lymphoma (OR = 1.88, 95% CI = 1.38-2.57), and B cell NHL not otherwise specified (OR = 1.51, 95% CI = 1.03-2.23)."

Source: http://www.prohealth.com/library/showarticle.cfm?libid=17017

Not too good in statistics, could anyone explain in laymans terms?:)

Edit: The authors caution that; the study was limited to people aged 66 years and older, so that the findings may not be generalisable to younger (non-elderly) populations. Furthermore, they warn against any direct interpretation or application of these results in a clinical setting; as they say, “We could not estimate the absolute risk of non-Hodgkin lymphoma associated with CFS, but the risk is likely too small to affect the clinical management of patients”.

Second edit: In other words you are probably right Bob!
 
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