Botulinum toxin type A for refractory upper‑limb resting tremor in Parkinson’s disease: a double‑blind, placebo‑controlled crossover trial

The primary objective is to evaluate the effect of intramuscular botulinum toxin type A on treatment‑refractory upper‑limb rest tremor in patients with Parkinson disease by comparing the Patient Global Impression‑Change (PGI‑C) score at six weeks post‑injection with placebo, providing a direct measure of patient‑perceived improvement in tremor severity. Secondary objectives include: - Assessment of tremor reduction using clinician‑rated scales (CGI‑C, CGI‑S) and the MDS‑UPDRS III amplitude items for resting (item 3.17) and postural (item 3.15) tremor, together with patient‑rated severity (PGI‑S) and global impression (PGI‑C); objective quantification via actimeter‑derived proportion of time with tremor, mean angular amplitude, and mean frequency measured by accelerometry. - Evaluation of patient‑reported outcomes, specifically changes in PDQ‑39 quality‑of‑life scores and activities of daily living as measured by MDS‑UPDRS part II. - Safety monitoring through changes in hand grip strength measured with a manual dynamometer, changes in muscle‑weakness severity (PGI‑S), and systematic collection of adverse events throughout the study.

The trial enrolled adult men and women aged 40 to 80 years who met the United Kingdom Parkinson’s Disease Society Brain Bank criteria for Parkinson disease and exhibited a treatment‑refractory resting tremor of the upper limb despite receiving at least two antiparkinsonian agents. Participants were required to have a Clinical Global Impression‑Severity score of ≥ 3 for tremor, stable antiparkinsonian medication for a minimum of four weeks prior to enrollment, and no prior exposure to botulinum toxin. Eligibility also required affiliation with a social security scheme and provision of informed written consent. The sponsor did not provide the total number of participants, and therefore the exact sample size is unavailable.

The trial is a randomized, double‑blind, placebo‑controlled cross‑over study evaluating the effect of botulinum toxin type A on refractory upper‑limb rest tremor in patients with Parkinson disease. Recruitment is planned from September 2026 to September 2029 (phase 4). After an initial screening visit confirming eligibility, participants are randomized to receive either Dysport 1500 U (botulinum toxin) or 3 mL NaCl (placebo) by intramuscular injection. Six weeks after the first injection a follow‑up visit assesses the primary Patient Global Impression‑Change score and secondary efficacy and safety measures. Participants then cross over to the alternate treatment, followed by a second 6‑week assessment. The final visit, occurring approximately 12 weeks after the first injection, serves as the end‑of‑study assessment. Total involvement for each participant is therefore about three months. Early termination may occur if a serious adverse event, lack of compliance, withdrawal of consent, or medical necessity arises.

The investigational product is Dysport 500 U, a powder for solution for injection supplied as a botulinum toxin type A‑haemagglutinin complex. The preparation is reconstituted to a solution for injection and administered intramuscularly at a total dose of 1500 U per treatment period. The injection is given as a single administration, with the study design employing a double‑blind, placebo‑controlled cross‑over schedule; the next injection, if required, occurs after an appropriate wash‑out interval.

The comparator is a placebo consisting of sterile normal saline (NaCl) administered by injection. Each placebo dose consists of 3 mL of isotonic saline delivered intramuscularly in the same manner and volume as the active drug to maintain blinding. The placebo is identified as placebo in the protocol and follows the identical dosing schedule as the experimental medication.

Entonox 50 %/50 % medicinal gas, a compressed mixture of nitrous oxide and oxygen, is provided as an auxiliary agent for inhalational analgesia during the injection procedure. The gas is supplied in a compressed cylinder delivering a total volume of 36 L per use. Administration is performed by inhalation immediately prior to the injection to ensure patient comfort. Compliance with the dosing regimen is monitored by study staff who document the time of administration, verify the volume of gas inhaled, and record any deviations from the protocol.

The primary efficacy assessment is the Patient Global Impression‑Change (PGI‑C) score, completed by the patient. Scores are obtained at baseline and at 6 weeks after each injection, and the change from baseline is compared between the botulinum toxin and placebo treatments.

Secondary efficacy assessments include:

• Change in the Clinician Global Impression‑Change (CGI‑C) score at 6 weeks post‑injection.
• Delta of the severity rating on the Clinician Global Impression‑Severity (CGI‑S) scale between baseline and 6 weeks.
• Delta of item 3.17 (amplitude) on the MDS‑UPDRS III investigator scale between baseline and 6 weeks.
• Change in the patient’s quality‑of‑life measured by the PDQ‑39 questionnaire between baseline and 6 weeks.
• Change in activities of daily living using the MDS‑UPDRS part two scale between baseline and 6 weeks.
• Delta of hand strength measured in Newtons with a manual dynamometer between baseline and 6 weeks.
• Delta of the severity of muscle weakness using the Patient Global Impression‑Severity (PGI‑S) scale between baseline and 6 weeks.
• Collection of adverse events throughout the study period.