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N-of-1 within-patient trials to improve the rational use of therapeutic drugs: Evaluation of their contribution in personalizing the treatment of chronic pain

English title N-of-1 within-patient trials to improve the rational use of therapeutic drugs: Evaluation of their contribution in personalizing the treatment of chronic pain
Applicant Buclin Thierry
Number 173539
Funding scheme Investigator Initiated Clinical Trials (IICT)
Research institution Division de Pharmacologie clinique Biomédecine, Département des Laboratoires Centre Hospitalier Universitaire Vaudois
Institution of higher education University of Lausanne - LA
Main discipline Internal Medicine
Start/End 01.06.2017 - 28.02.2021
Approved amount 499'400.00
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All Disciplines (4)

Discipline
Internal Medicine
Methods of Epidemiology and Preventive Medicine
Neurology, Psychiatry
Pharmacology, Pharmacy

Keywords (5)

N-of-1 trials; Chronic pain; Precision Medicine; Evidence-based Medicine; Treatment individualization

Lay Summary (German)

Lead
Als personalisierte Nutzenbewertung könnten „N-of-1-Trials“ die Betreuung von Patienten mit chronischen Schmerzen verbessern.
Lay summary

Zusammenfassung und Ziel:

Chronische Schmerzen sind eine medizinische Herausforderung. Verschiedene Behandlungsmodalitäten haben unabsehbare, stark unterschiedliche Wirkungen. Hinzu kommt, dass psychologische, zwischenmenschliche, soziale und kontextspezifische Faktoren jegliche objektive Bewertung beinträchtigen.

„N-of-1-Trials“ sind therapeutische, an einzigen Patienten durchgeführte klinische Versuche. Spezifische Behandlungsmodalitäten werden abwechselnd, doppelblind mit Placebo verabreicht, gemäss im Voraus festgelegten, randomisierten Zeitabschnitten. So wird die Wirksamkeit der je angewandten Behandlungsmethode objektiv evaluiert. Und so kann man auch erkennen, welche Patienten non-responders sind, was sie in der Zukunft vor unwirksamen Massnahmen schützen kann. Die Förderung der Patientensicherheit und deren aktive Teilnahme an ihrer Betreuung sind weitere Vorteile.

Unsere Studie wird die Nützlichkeit von „N-of-1-Trials“ in Patienten mit chronischen Schmerzen evaluieren. Eine Gruppe von 120 Patienten wird im Rahmen von „N-of-1-Trial“ behandelt und mit einer Gruppe von üblich behandelten Patienten verglichen.

Bedeutung:

Der Einsatz von „N-of-1-Trials“ könnte sich auch in anderen Bereichen als nützlich erweisen. Ein breiteres Ziel unserer Studie ist, solche Untersuchungsmethoden der medizinischen Gemeinschaft und der Öffentlichkeit bekannt zu machen. Diese Evidenzbasierte Medizin und Präzisionsmedizin zusammenführende Methoden sind nämlich von grossem Interesse im Sinne vom rationalisierten Arzneimittelgebrauch, einschliesslich Risikominderung und Kostenkontrolle. 

 

Direct link to Lay Summary Last update: 05.07.2017

Lay Summary (French)

Lead
Les « N-of-1 trials » offrent une évaluation personnalisée de la réponse thérapeutique et pourraient améliorer la prise en charge des douleurs chroniques.
Lay summary

Résumé et Objectifs : 
Les traitements des douleurs chroniques sont complexes et leur efficacité varie fortement entre individus. La réponse d’un patient à un traitement donné est difficile à prédire. De plus, des facteurs psychologiques, relationnels, sociaux et contextuels rendent son évaluation objective délicate.
Les « N-of-1 trials » sont des essais thérapeutiques réalisés chez un seul patient : ils comparent un traitement à un placebo durant plusieurs périodes alternées au hasard. L’analyse des mesures d’effet recueillies en aveugle permet d’évaluer objectivement l’efficacité du traitement et d’éviter chez les non-répondeurs les risques liés aux prescriptions inefficaces. Ce type de test favorise la sécurité des patients, tout en leur proposant une participation active à leur prise en charge. 
Notre étude vise à déterminer l’utilité des « N-of-1 trials » dans les douleurs chroniques pour sélectionner les traitements efficaces et dé-prescrire les inefficaces. Un groupe de 120 patients avec une prise en charge incluant un « N-of-1 trial » sera comparé à un groupe suivi de manière standard. 

Perspectives : 
La douleur chronique n’est qu’un des multiples domaines d’application des « N-of-1 trials ». Cette étude vise indirectement à populariser ces tests dans la communauté médicale et le public. Réalisant la jonction entre Médecine factuelle et Médecine de précision, cette approche contribuera à améliorer la pertinence thérapeutique, à diminuer les risques médicamenteux et à réduire les coûts de la santé.
 
Direct link to Lay Summary Last update: 05.07.2017

Lay Summary (English)

Lead
N-of-1 trials, as personalized assessment of therapeutic response, could improve the management of chronic pain patients.
Lay summary

Summary and goals:
Drug management in chronic pain is complex and treatment efficacy varies between individuals, making the response of a given patient to a given treatment poorly predictable. Moreover, its objective assessment is difficult, due to contributions of psychological, relational, social and contextual factors.

N-of-1 trials are therapeutic trials performed in a single patient, comparing a treatment to a placebo during several randomly alternated periods. The analysis of effect measurements blindly collected provides an objective evaluation of effectiveness and helps preventing unnecessary risks in non-responders. This type of test therefore promotes patients’ safety, while stimulating their active participation in their medical care.

Our study aims at evaluating the usefulness of N-of-1 trials in chronic pain management to select effective drugs and to support de-prescription of ineffective ones. A group of 120 patients offered a N-of-1 trial will be compared to a group followed according to standard of care.

Prospects:
Chronic pain is only one among many areas where N-of-1 trials could be beneficial. This study also indirectly aims at popularizing this type of test throughout the medical community and the public. While connecting Evidence-based medicine with Precision medicine, this approach could contribute to improve the relevance of medicinal treatments, to decrease drug-associated risks and to control health system costs.

Direct link to Lay Summary Last update: 05.07.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
N-of-1 trials ou essais thérapeutiques individuels: un test probant pour diagnostiquer l’efficacité thérapeutique
Diezi Léonore, Buclin Thierry, N-of-1 trials ou essais thérapeutiques individuels: un test probant pour diagnostiquer l’efficacité thérapeutique, in Revue Médicale Suisse , (in press).

Associated projects

Number Title Start Funding scheme
159615 Activity-dependent plasticity in pathological pain 01.04.2015 Project funding (Div. I-III)

Abstract

Background: A “N-of-1 trial” is a randomized double-blind multi-period crossover trial conducted in a single patient to assess treatment effectiveness or tolerability in chronic/relapsing conditions. Such tests represent the reference method for “diagnosing the therapeutic response” at the individual level. A rigorous methodology has been established for their performance. Many authors recommend them to support difficult treatment decisions, e.g. involving costly drugs, off-label indications, uncertain efficacy, questionable tolerability... Despite their potential for improving patient management, N-of-1 trials are still poorly adopted by the medical community. Clinical Pharmacology units might contribute to optimize drug use in selected situations by offering this service. This study addresses the usefulness of this approach in an illustrative condition. Chronic pain, of all causes, affects many adults and represents a therapeutic challenge. A wide choice of treatments is available, but their efficacy is variable and poorly predictable. Even when overall efficacy has been proven by randomised controlled trials, interindividual variability makes a given patient’s response difficult to predict, not to mention side effects or induction of misuse. Empirical tryouts of analgesics produce uncertain results that can mislead both patients and physicians.An evidence-based method to assess individual effectiveness and thereby withdraw useless/risky prescriptions in non-responders would thus be a valuable tool for practitioners treating chronic pain patients.Objective: This multicentre, prospective, parallel group, open label, randomized controlled trial will evaluate the potential of within-patient N-of-1 trials, compared to standard practice, to reduce the number of ineffective prescriptions while confirming the efficacy of beneficial ones. Design:The trial will recruit 240 adult chronic pain patients over Romandie pain centers, in whom the efficacy of a specific background treatment is questioned either before or after initiation (stratification criterion). Rather than concentrating on one medication in particular, the trial will include any long-term supportive medication (e.g. antiepileptics, antidepressants, cannabinoids, opiates, NSAIDs).Half of the patients (intervention group) will be proposed a N-of-1 trial to evaluate treatment efficacy in double blind. The test will typically consist in 6 periods of 2 weeks of either active drug or placebo, allocated 3:3 in random sequence (the duration of periods may vary in function of the drug’s properties). During each period, active treatment/placebo doses will be titrated up if necessary. Pain (VAS) and tolerance will be recorded in a patient’s diary. At test end, the treatment code will be opened, the data analyzed and the results shared with the patient and the practitioner, who will decide on upcoming prescription. The patients randomized to the control group will receive usual care. In both groups, adjunctive self-help approach will be offered by a psychologist during 6 therapy sessions, so that all study subjects benefit from their inclusion and have the same number of encounters with the study team. The main study endpoint will consist in a composite including the number of pain medications and the average level of pain over 2 weeks. The difference in these values between the inclusion and the end-of-study (at 6 months) will allow a separation of the participants according to either outcomes: success defined by deprescription or sizeable diminution of pain level (by at least 30% in VAS level), versus failure defined by prescription and no sizeable difference in pain level. Success rates will be compared between the N-of-1 group and the control group. Secondary outcomes will be quality of life (Short Form Health Survey), patient’s satisfaction and treatment cost. Prospect: Rather than assessing the global efficacy of a particular pain medication, this study aims at evaluating the medical usefulness of N-of-1 trials as a tool for chronic pain management. Formal N-of-1 trials deserve better attention from the medical community, as a promising approach for the personalized evaluation of therapeutic response in selected situations, when sensitive medical decisions require a high confidence.
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