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

Primary Purpose

Chronic Fatigue Syndrome (CFS), Myalgic Encephalomyelitis (ME)

Status
Completed
Phase
Phase 2
Locations
Norway
Study Type
Interventional
Intervention
Cyclophosphamide
Sponsored by
Haukeland University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Fatigue Syndrome (CFS) focused on measuring Chronic Fatigue Syndrome, Myalgic Encephalomyelitis (ME), Cyclophosphamide, Immunomodulatory treatment, CFS

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Dept. of Oncology, Haukeland University Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Cyclophosphamide

Arm Description

Cyclophosphamide, intravenous infusions four weeks apart. Six infusions in total. First infusion: 600 mg/m2. Infusions 2 to 6: 700 mg/m2

Outcomes

Primary Outcome Measures

Fatigue score, selfreported
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
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)
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)
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
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
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
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
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
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
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.

Full Information

First Posted
March 25, 2015
Last Updated
May 10, 2021
Sponsor
Haukeland University Hospital
Collaborators
The Kavli Foundation, Oslo University Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT02444091
Brief Title
Cyclophosphamide in Myalgic Encephalopathy/ Chronic Fatigue Syndrome (ME/CFS)
Acronym
CycloME
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 Type
Interventional

2. Study Status

Record Verification Date
December 2019
Overall Recruitment Status
Completed
Study Start Date
March 2015 (Actual)
Primary Completion Date
December 6, 2019 (Actual)
Study Completion Date
December 6, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Haukeland University Hospital
Collaborators
The Kavli Foundation, Oslo University Hospital

4. Oversight

Data Monitoring Committee
Yes

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Fatigue Syndrome (CFS), Myalgic Encephalomyelitis (ME)
Keywords
Chronic Fatigue Syndrome, Myalgic Encephalomyelitis (ME), Cyclophosphamide, Immunomodulatory treatment, CFS

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
40 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cyclophosphamide
Arm Type
Experimental
Arm Description
Cyclophosphamide, intravenous infusions four weeks apart. Six infusions in total. First infusion: 600 mg/m2. Infusions 2 to 6: 700 mg/m2
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Intervention Description
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.
Primary Outcome Measure Information:
Title
Fatigue score, selfreported
Description
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.
Time Frame
Within 12 months follow-up
Title
Overall response
Description
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.
Time Frame
Within 12 months follow-up
Secondary Outcome Measure Information:
Title
Short Form-36 (SF-36)
Description
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.
Time Frame
Recorded at baseline, and at 3, 6, 9 and 12 months follow-up.
Title
Physical activity (Sensewear armband)
Description
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.
Time Frame
Recorded at baseline, at 7-9 months, and at 11-12 months
Title
Cardiopulmonary exercise tests for two following days
Description
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.
Time Frame
At baseline, and repeated at 7-9 months, and 11-12 months
Title
Self-recorded Function level
Description
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.
Time Frame
At baseline, and at 3, 6, 9 and 12 months follow-up
Title
Fatigue Severity Scale
Description
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.
Time Frame
Baseline, 3, 6, 9 and 12 months
Title
Longest continuous response duration
Description
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.
Time Frame
Within 12 months follow-up
Title
Sustained clinical response at 12 months
Description
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.
Time Frame
Assessment at end of follow-up (12 months)
Title
Safety and tolerability
Description
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.
Time Frame
Continuously within the study period of 12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mella Olav, MD, PhD
Organizational Affiliation
Haukeland University Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Øystein Fluge, MD, PhD
Organizational Affiliation
Haukeland University Hospital
Official's Role
Study Director
Facility Information:
Facility Name
Dept. of Oncology, Haukeland University Hospital
City
Bergen
ZIP/Postal Code
N-5021
Country
Norway

12. IPD Sharing Statement

Citations:
PubMed Identifier
22039471
Citation
Fluge O, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, Naess H, Dahl O, Nyland H, Mella O. Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study. PLoS One. 2011;6(10):e26358. doi: 10.1371/journal.pone.0026358. Epub 2011 Oct 19.
Results Reference
background
PubMed Identifier
19566965
Citation
Fluge O, Mella O. Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series. BMC Neurol. 2009 Jul 1;9:28. doi: 10.1186/1471-2377-9-28.
Results Reference
background
PubMed Identifier
32411717
Citation
Rekeland IG, Fossa A, Lande A, Ktoridou-Valen I, Sorland K, Holsen M, Tronstad KJ, Risa K, Alme K, Viken MK, Lie BA, Dahl O, Mella O, Fluge O. Intravenous Cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An Open-Label Phase II Study. Front Med (Lausanne). 2020 Apr 29;7:162. doi: 10.3389/fmed.2020.00162. eCollection 2020.
Results Reference
derived

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

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