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

NCT02444091 | Completed Phase 2 DMC

• 2 other identifiers: KTS-7-20152014-004029-41
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

Chronic Fatigue Syndrome; Myalgic Encephalomyelitis (ME); Cyclophosphamide; Immunomodulatory treatment; CFS

Outcome Measures

Primary Outcomes (2)

• 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.

  Within 12 months follow-up

• 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.

  Within 12 months follow-up

Secondary Outcomes (8)

• Short Form-36 (SF-36)

  Recorded at baseline, and at 3, 6, 9 and 12 months follow-up.

• Physical activity (Sensewear armband)

  Recorded at baseline, at 7-9 months, and at 11-12 months

• Cardiopulmonary exercise tests for two following days

  At baseline, and repeated at 7-9 months, and 11-12 months

• Self-recorded Function level

  At baseline, and at 3, 6, 9 and 12 months follow-up

• Fatigue Severity Scale

  Baseline, 3, 6, 9 and 12 months

Study Arms (1)

Cyclophosphamide

EXPERIMENTAL

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

Drug: Cyclophosphamide

Interventions

Cyclophosphamide DRUG

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.

Cyclophosphamide

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Haukeland University Hospital: lead
• The Kavli Foundation: collaborator
• Oslo University Hospital: collaborator

Study Sites (1)

Dept. of Oncology, Haukeland University Hospital

Bergen, N-5021, Norway

Location

Related Publications (3)

• 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.

  PMID: 22039471 BACKGROUND

• 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.

  PMID: 19566965 BACKGROUND

• 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.

  PMID: 32411717 DERIVED

MeSH Terms

Conditions

Fatigue Syndrome, Chronic

Interventions

Cyclophosphamide

Condition Hierarchy (Ancestors)

Muscular Diseases; Musculoskeletal Diseases; Encephalomyelitis; Neuroinflammatory Diseases; Nervous System Diseases; Neuromuscular Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Mella Olav, MD, PhD

  Haukeland University Hospital

  PRINCIPAL INVESTIGATOR

• Øystein Fluge, MD, PhD

  Haukeland University Hospital

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 25, 2015
• First Posted: May 14, 2015
• Study Start: March 1, 2015
• Primary Completion: December 6, 2019
• Study Completion: December 6, 2019
• Last Updated: May 11, 2021

Record last verified: 2019-12

Locations

NO (1)