Efficacy of Individualized Homeopathic Medicinal Products in LM Potencies in Cancer-Related Fatigue: Protocol for a Series of N-of-1 Trials, with Meta-analysis of Individual Patient Data

Abstract

Background

Cancer-related fatigue (CRF) poses a significant challenge in cancer care and affects the quality of life of many patients. Despite the prevalence and impact of the condition, identifying effective therapies remains a challenge. Non-pharmacological remedies, such as complementary therapies including homeopathy, are under-researched. A clinical trial with n-of-1 design has therefore been planned to evaluate the potential of individualized homeopathic medicinal products (IHMPs) in the management of CRF.

Methods

A series of double-blind, randomized, placebo-controlled, n-of-1 trials will be conducted. Each participant will undergo three rounds of two intervention phases in a randomly determined order. The study will be performed at the Oncology Outpatient Department of D. N. De Homoeopathic Medical College and Hospital. Participants with CRF who meet pre-defined eligibility requirements will be enrolled. The FACIT-F sub-scale is the primary outcome measure; Short Form-36 and the Wu Cancer Fatigue Scale are the secondary outcomes. All outcomes will be measured at baseline, on day 7 and then every 10 days for 2 months. The sample size will be the number of patients who can be recruited during the 18-month period of the trial. The Numerical Rating Scale (0–10) measuring fatigue severity will be used in screening and preliminary evaluation of the degree of fatigue. Comprehensive blood tests to evaluate various physiological factors related to CRF will also be performed. An assessment of the effect of the IHMPs will be obtained per individual and by aggregating the data of all participants via meta-analysis.

Conclusion

The results of our study will clarify the possible therapeutic effects of IHMPs for patients with CRF, as well as improve our understanding of the n-of-1 study design as it is applied to homeopathy research.

Trial Registration

Clinical Trials Registry—India: CTRI/2024/03/064438.

Keywords

cancer - fatigue - homeopathy - placebo - n-of-1 trial

Authors' Contributions

S.G., M.S., K.C., R.K.P., S.M.A., I.H., S.C. contributed to the literature search and study concept. S.G., M.S., A.M. and S.S. contributed to the study design, statistical analysis plan and drafting of the manuscript. All the authors reviewed and approved the final manuscript for submission.

Publication History

Received: 05 December 2024

Accepted: 27 February 2025

Article published online:
17 June 2025

• References

• 1 Jankowski C, Berger A, Aranha O. et al. NCCN Guidelines Version 2. 2022: Cancer-Related Fatigue. NCCN, 2022 https://www.nccn.org/guidelines/guidelines-detail?category=3&id=1424
• 2 Soones T, Ombres R, Escalante C. An update on cancer-related fatigue in older adults: a narrative review. J Geriatr Oncol 2022; 13: 125-131
• 3 Santos JC, Pyter LM. Neuroimmunology of behavioral comorbidities associated with cancer and cancer treatments. Front Immunol 2018; 9: 1195
• 4 Nugusse T, Lemlem SB, Deressa J, Kisa S. Prevalence of fatigue and associated factors among cancer patients attending Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia. Cancer Manag Res 2021; 13: 1909-1916
• 5 Agarwal S, Garg R, Minhas V. et al. To assess the prevalence and predictors of cancer-related fatigue and its impact on quality of life in advanced cancer patients receiving palliative care in a tertiary care hospital: a cross-sectional descriptive study. Indian J Palliat Care 2020; 26: 523-527
• 6 Al Maqbali M, Al Sinani M, Al Naamani Z, Al Badi K, Tanash MI. Prevalence of fatigue in patients with cancer: a systematic review and meta-analysis. J Pain Symptom Manage 2021; 61: 167-189.e14
• 7 Lipsett A, Barrett S, Haruna F, Mustian K, O'Donovan A. The impact of exercise during adjuvant radiotherapy for breast cancer on fatigue and quality of life: a systematic review and meta-analysis. Breast 2017; 32: 144-155
• 8 Whisenant M, Wong B, Mitchell SA, Beck SL, Mooney K. Distinct trajectories of fatigue and sleep disturbance in women receiving chemotherapy for breast cancer. Oncol Nurs Forum 2017; 44: 739-750
• 9 Schmidt ME, Wiskemann J, Schneeweiss A, Potthoff K, Ulrich CM, Steindorf K. Determinants of physical, affective, and cognitive fatigue during breast cancer therapy and 12 months follow-up. Int J Cancer 2018; 142: 1148-1157
• 10 Fox P, Darley A, Furlong E. et al. The assessment and management of chemotherapy-related toxicities in patients with breast cancer, colorectal cancer, and Hodgkin's and non-Hodgkin's lymphomas: a scoping review. Eur J Oncol Nurs 2017; 26: 63-82
• 11 Pillai RN, Behera M, Owonikoko TK. et al. Comparison of the toxicity profile of PD-1 versus PD-L1 inhibitors in non-small cell lung cancer: a systematic analysis of the literature. Cancer 2018; 124: 271-277
• 12 Jones JM, Olson K, Catton P. et al. Cancer-related fatigue and associated disability in post-treatment cancer survivors. J Cancer Surviv 2016; 10: 51-61
• 13 Davidson KW, Silverstein M, Cheung K, Paluch RA, Epstein LH. Experimental designs to optimize treatments for individuals: personalized N-of-1 trials. JAMA Pediatr 2021; 175: 404-409
• 14 Ulbrich-Zürni S, Teut M, Roll S, Mathie RT. The N-of-1 clinical trial: a timely research opportunity in homeopathy. Homeopathy 2018; 107: 10-18
• 15 West HJ. Complementary and alternative medicine in cancer care. JAMA Oncol 2018; 4: 139
• 16 Fabi A, Bhargava R, Fatigoni S. et al. Cancer-related fatigue: ESMO Clinical Practice Guidelines for diagnosis and treatment. Ann Oncol 2020; 31: 713-723
• 17 Alappattu M, Harrington SE, Hill A, Roscow A, Jeffrey A. Oncology Section EDGE Task Force on Cancer: A systematic review of patient-reported measures for sexual dysfunction. Rehabil Oncol 2017; 35: 137-143
• 18 McNeely J, Wu LT, Subramaniam G. et al. Performance of the tobacco, alcohol, prescription medication, and other substance use (TAPS) tool for substance use screening in primary care patients. Ann Intern Med 2016; 165: 690-699
• 19 Hahnemann CFS. Organon of Medicine, 5th & 6th ed. New Delhi: B. Jain Publishers Pvt. Ltd.; 2002
• 20 Adler UC, Adler MS, Cesar AT. et al. Homeopathy for major depressive disorder: protocol for N-of-1 studies. Complement Med Res 2023; 30: 332-339
• 21 Lin PJ, Kleckner I, Loh K. et al. Influence of yoga therapy on cancer-related fatigue and meditational relationships between changes in sleep and cancer-related fatigue: a nationwide, multicenter randomized controlled trial of yoga in cancer survivor. Integr Cancer Ther 2019; 18: 1-11
• 22 Rau KM, Shun SC, Chiou TJ. et al. A nationwide survey of fatigue in cancer patients in Taiwan: an unmet need. Jpn J Clin Oncol 2020; 50: 693-700
• 23 Ware Jr JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992; 30: 473-483
• 24 Butt Z, Lai JS, Rao D, Heinemann AW, Bill A, Cella D. Measurement of fatigue in cancer, stroke, and HIV using the Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) scale. J Psychosom Res 2013; 74: 64-68
• 25 Brazier JE, Harper R, Jones NM. et al. Validating the SF-36 health survey questionnaire: new outcome measure for primary care. BMJ 1992; 305: 160-164
• 26 Wu HS, Wyrwich KW, McSweeney M. Assessing fatigue in persons with cancer: further validation of the Wu Cancer Fatigue Scale. J Pain Symptom Manage 2006; 32: 255-265
• 27 Zucker DR, Schmid CH, McIntosh MW, D'Agostino RB, Selker HP, Lau J. Combining single patient (N-of-1) trials to estimate population treatment effects and to evaluate individual patient responses to treatment. J Clin Epidemiol 1997; 50: 401-410
• 28 Schluter PJ, Ware RS. Single patient (n-of-1) trials with binary treatment preference. Stat Med 2005; 24: 2625-2636
• 29 Porcino AJ, Shamseer L, Chan A-W. et al. SPIRIT extension and elaboration for n-of-1 trials: SPENT 2019 checklist. BMJ 2020; 368: m122
• 30 Shamseer L, Sampson M, Bukutu C. et al. CONSORT extension for reporting N-of-1 trials (CENT) 2015: explanation and elaboration. BMJ 2015; 350: h1793
• 31 Dean ME, Coulter MK, Fisher P, Jobst K, Walach H. Reporting data on homeopathic treatments (RedHot): a supplement to CONSORT. Homeopathy 2007; 96: 42-45
• 32 Gaertner K, Hahn RG, Razlog R. et al. Critical appraisal tool for homeopathic intervention studies – CATHIS. Complement Med Res 2025; 12: 1-20
• 33 World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 2013; 310: 2191-2194
• 34 Zucker DR, Ruthazer R, Schmid CH. Individual (N-of-1) trials can be combined to give population comparative treatment effect estimates: methodologic considerations. J Clin Epidemiol 2010; 63: 1312-1323
• 35 Lillie EO, Patay B, Diamant J, Issell B, Topol EJ, Schork NJ. The n-of-1 clinical trial: the ultimate strategy for individualizing medicine?. Per Med 2011; 8: 161-173
• 36 Minton O, Richardson A, Sharpe M, Hotopf M, Stone P. A systematic review and meta-analysis of the pharmacological treatment of cancer-related fatigue. J Natl Cancer Inst 2008; 100: 1155-1166
• 37 Mustian KM, Alfano CM, Heckler C. et al. Comparison of pharmaceutical, psychological, and exercise treatments for cancer-related fatigue: a meta-analysis. JAMA Oncol 2017; 3: 961-968
• 38 Hilfiker R, Meichtry A, Eicher M. et al. Exercise and other non-pharmaceutical interventions for cancer-related fatigue in patients during or after cancer treatment: a systematic review incorporating an indirect-comparisons meta-analysis. Br J Sports Med 2018; 52: 651-658
• 39 Tangelloju A, Chakravarti R, Singh R. et al. A review on the current status of homeopathy in the clinical management of cancer. Curr Drug Targets 2022; 23: 1252-1260
• 40 Medioni J, Scimeca D, Marquez YL. et al. Benefits of homeopathic complementary treatment in patients with breast cancer: a retrospective cohort study based on the French Nationwide Healthcare Database. Clin Breast Cancer 2023; 23: 60-70
• 41 Bagot JL. Improving tolerance and compliance of new targeted therapies with homeopathy: a major challenge in oncology. OBM Integr Compliment Med 2022; 7: 26
• 42 Bagot JL, Theunissen I, Serral A. Perceptions of homeopathy in supportive cancer care among oncologists and general practitioners in France. Support Care Cancer 2021; 29: 5873-5881
• 43 Frass M, Lechleitner P, Gründling C. et al. Homeopathic treatment as an add-on therapy may improve quality of life and prolong survival in patients with non-small cell lung cancer: a prospective, randomized, placebo-controlled, double-blind, three-arm, multicenter study. Oncologist 2020; 25: e1930-e1955
• 44 Rostock M, Naumann J, Guethlin C, Guenther L, Bartsch HH, Walach H. Classical homeopathy in the treatment of cancer patients – a prospective observational study of two independent cohorts. BMC Cancer 2011; 11: 19
• 45 David A, Hausner D, Frenkel M. Cancer-related fatigue – is there a role for complementary and integrative medicine?. Curr Oncol Rep 2021; 23: 145