Introduction
Method
Study design
Settings
Participants
Inclusion criteria | 1) Age over 18 years old diagnosed with advanced cancer undergoing active anticancer treatment 2) Patients diagnosed with any type of cancer except CNS tumor, hormone-sensitive cancers, or pheochromocytoma 3) CRF diagnosis based on the International Classification of Diseases 10th Edition (ICD-10) 4) Reporting of moderate to severe fatigue in the last week (score ≥ 4 on a scale of 0 to 10) 5) Hemoglobin level higher than 9 g/dL in 2 weeks before enrollment 6) Ability to swallow and absorb medications 7) In case of the possibility of getting pregnant during the treatment and up to 6 weeks after, willingness to use effective contraceptive methods 8) Ability to read and write |
Exclusion criteria | 1) Presence of a known fatigue disorder not related to cancer 2) Presence of cognitive disorders, mental disorders (severe anxiety, major depression, schizophrenia, bipolar syndrome), neurological or brain disorders (dementia, delirium, Tourette syndrome, motor tics, epilepsy, history of stroke, aneurysm), diabetes, untreated severe anemia or anemia that requires blood transfusion, severe and uncontrolled pain and insomnia, serious cardiac disorders, uncontrolled arrhythmia or hypertension, history of long QT syndrome, glaucoma, intestinal obstruction, uncontrolled hypothyroidism, respiratory disorders that limit participation, autoimmune diseases, bleeding disorders 3) Abnormal function of the liver (high ALT or AST) and kidney (abnormal Cr or GFR less than 50) 4) History of major surgery in 1 month before enrollment 5) Taking erythropoietin, psychostimulants, antidepressants, food supplements, or other drugs to control fatigue currently or in the 4 weeks before participating in the study 6) Simultaneous use of drugs (including warfarin, anticonvulsants, tricyclic antidepressants, antipsychotics, monoamine oxidase inhibitors, clonidine, theophylline, caffeine and pseudoephedrine) 7) Major dose change (more than 25%) of opioids in 48 h before enrollment 8) Hypersensitivity to sympathomimetic amines 9) Planned surgery within 2 months of screening 10) History of sensitivity to or intolerance of the medications under study 11) Pregnant or lactating women 12) History of drug or alcohol abuse in the past year 13) Involvement in other clinical trials |
Withdrawal (discontinuation) criteria | 1) Voluntary withdrawal of the trial by the patient for any reason 2) Significant deterioration in the patient’s clinical condition 3) Occurrence of severe/serious adverse event(s) 4) The need to take erythropoietin during the study period 5) Patient or doctor recognition that stopping the medications is in the patient’s best interest |
Intervention
Pharmacological agents
Pharmacological agents | Description |
---|---|
Methylphenidate | Methylphenidate is a psychostimulant which has been frequently studied and is widely prescribed for the medical management of patients with attention deficit hyperactivity disorder [3, 32]. Methylphenidate is considered as one of the promising pharmacological options in improving CRF, which is well tolerated by patients, although the results about its efficacy are mixed [29]. Both NCCN and ASCO recommend psychostimulant drugs (such as methylphenidate) as pharmacological options in active treatment patients, although they note that clinical evidence is limited [33] |
Bupropion | Bupropion is a non-serotonergic antidepressant that may be useful in the treatment of CRF. Bupropion is widely available as a generic drug with an excellent safety profile, and there have been frequent requests to investigate bupropion as a pharmacological agent for the treatment of CRF [13]. Bupropion is an antidepressant with a dual effect on the neurotransmitter systems of norepinephrine and dopamine, so psychopharmacologically it shares a wide range of actions with psychostimulants [25] |
Ginseng | Thanks to its various pharmacological effects, ginseng is one of the most valuable herbs in herbal medicine. Ginseng is widely used in the United States and other countries, based on the belief that it improves energy levels, and relieves stress and mental and physical fatigue [34]. Panax Ginseng extract has a direct effect on the central nervous system, and the ability to modulate inflammatory cytokines. Despite its frequent use, evidence for its effect on the improvement of CRF is limited [35]. Ginseng is a good treatment option, especially in patients who want to use herbal medicines |
Amantadine | Amantadine is a drug approved by the Food and Drug Administration for the prevention of influenza and the symptomatic treatment of Parkinson’s disease, and it is the most widely studied drug for fatigue associated with multiple sclerosis [36]. It is unclear which pharmacological effect may be responsible for the possible anti-fatigue properties of amantadine [37]. According to a Cochrane systematic review study, amantadine appears to be promising in improving fatigue in other chronic conditions, but whether or not it relieves fatigue in cancer patients has not been shown, and should be investigated [15] |
Outcomes and data collection
Trial handling
Recruitment
Assignment and blinding
Individuals | Information withheld | Method of blinding | Considerations |
---|---|---|---|
Participants | Group assignment and study hypotheses | Similar appearance and packaging of medications | Participants will be unblinded through email after the trial is closed |
Principal investigators | Group assignment | - Concealed allocation schedule - Similar medications and packaging | They will be blinded until the end of the data analysis |
Randomization provider | Not blinded | - | She will not be involved in the rest of the trial |
Research assistants assigning participants | Group assignment, purposes and hypotheses of the study, and participant characteristics | - Concealed allocation schedule | They will not be involved in the rest of the trial |
Pharmacist | Not blinded | - | The pharmacist will not have a role in data analysis |
Statistician | Group assignment, participant, and group identities | Codes are given to participants and groups | - |
Nurses who make contact with participants | Group assignment, study hypotheses, and participant characteristics | - Concealed allocation schedule - Participants are given numerical identifiers | They will not have any role in data analysis or manuscript writing |
Data collectors | Not applicable | - | The data are patient-reported outcomes |
Manuscript writers | Not applicable | - | - |
Data and Safety Monitoring Committee (DSMC) | Group assignment | - Concealed allocation schedule | They can request to break the code for any participant at any time if needed |
Participant timeline
Study period | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|
Enrolment | Allocation | Intervention (Post-allocation) | Follow-up (Post-allocation) | |||||||
Timepoint | − t1 | 0 | Week 1 | Week 2 | Week 3 | Week 4 | Week 5 | Week 6 | Week 7 | Week 8 (Close-out) |
Enrolment | ||||||||||
- Eligibility screen | X | |||||||||
- Informed consent | X | |||||||||
- Random allocation | X | |||||||||
Interventions: | ||||||||||
- Pharmaceutical groups | X | X | X | X | ||||||
- Placebo group | X | X | X | X | ||||||
Assessments: | ||||||||||
- Baseline data collection | X | |||||||||
- Main outcome (fatigue level) | X | X | X | X | X | X | X | |||
- Secondary outcome (PRO-CTCAE questionnaire for adverse events) | X | X | X | X | X | |||||
- Nurse phone calls | X | X | X | X | X | X | ||||
- In-person visits | X | X | X |