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Cyclophosphamide in Myalgic Encephalopathy/ Chronic Fatigue Syndrome (ME/CFS) (CycloME)

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ClinicalTrials.gov Identifier: NCT02444091
Recruitment Status : Active, not recruiting
First Posted : May 14, 2015
Last Update Posted : April 12, 2016
Sponsor:
Collaborators:
Information provided by (Responsible Party):

Study Description
Brief Summary:

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 or disease Intervention/treatment Phase
Chronic Fatigue Syndrome (CFS) Myalgic Encephalomyelitis (ME) Drug: Cyclophosphamide Phase 2

Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Masking: None (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
Study Start Date : March 2015
Estimated Primary Completion Date : January 2017
Estimated Study Completion Date : January 2017

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
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.


Outcome Measures

Primary Outcome Measures :
  1. Fatigue score, selfreported [ Time Frame: Within 12 months follow-up ]

    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.


  2. Overall response [ Time Frame: Within 12 months follow-up ]

    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 :
  1. Short Form-36 (SF-36) [ Time Frame: Recorded at baseline, and at 3, 6, 9 and 12 months follow-up. ]
    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.

  2. Physical activity (Sensewear armband) [ Time Frame: Recorded at baseline, at 7-9 months, and at 11-12 months ]
    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.

  3. Cardiopulmonary exercise tests for two following days [ Time Frame: At baseline, and repeated at 7-9 months, and 11-12 months ]
    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.

  4. Self-recorded Function level [ Time Frame: At baseline, and at 3, 6, 9 and 12 months follow-up ]

    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.


  5. Fatigue Severity Scale [ Time Frame: Baseline, 3, 6, 9 and 12 months ]

    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.


  6. Longest continuous response duration [ Time Frame: Within 12 months follow-up ]

    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.


  7. Sustained clinical response at 12 months [ Time Frame: Assessment at end of follow-up (12 months) ]

    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.


  8. Safety and tolerability [ Time Frame: Continuously within the study period of 12 months ]

    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.



Eligibility Criteria

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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
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
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02444091


Locations
Norway
Dept. of Oncology, Haukeland University Hospital
Bergen, Norway, N-5021
Sponsors and Collaborators
Haukeland University Hospital
The Kavli Foundation
Oslo University Hospital
Investigators
Principal Investigator: Mella Olav, MD, PhD Haukeland University Hospital
Study Director: Øystein Fluge, MD, PhD Haukeland University Hospital
More Information

Publications:
Responsible Party: Haukeland University Hospital
ClinicalTrials.gov Identifier: NCT02444091     History of Changes
Other Study ID Numbers: KTS-7-2015
2014-004029-41 ( EudraCT Number )
First Posted: May 14, 2015    Key Record Dates
Last Update Posted: April 12, 2016
Last Verified: April 2016

Keywords provided by Haukeland University Hospital:
Chronic Fatigue Syndrome
Myalgic Encephalomyelitis (ME)
Cyclophosphamide
Immunomodulatory treatment
CFS

Additional relevant MeSH terms:
Syndrome
Fatigue
Brain Diseases
Fatigue Syndrome, Chronic
Encephalomyelitis
Myalgia
Disease
Pathologic Processes
Signs and Symptoms
Central Nervous System Diseases
Nervous System Diseases
Virus Diseases
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Diseases
Central Nervous System Infections
Musculoskeletal Pain
Pain
Neurologic Manifestations
Cyclophosphamide
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists