Trial Design and Oversight

In this double-blind trial conducted at eight international centers, we randomly assigned patients in a 3:1 ratio to undergo focused ultrasound thalamotomy or a sham procedure in which no acoustic energy was delivered. The primary study end point was the change in tremor from baseline to 3 months, analyzed on the basis of videotaped assessments. After 3 months, patients in the sham-procedure group could cross over to active treatment (Fig. S2 in the Supplementary Appendix).

Representatives of the manufacturer of the focused ultrasound system used in the study (InSightec) provided study oversight and technical support and obtained national regulatory permissions. Independent institutional approval of the study was obtained by the research team at each participating center, and all patients gave written informed consent. Clinical oversight of the trial was provided by the principal investigator and an independent data and safety monitoring board. The authors vouch for the veracity and completeness of the data and data analyses. The first author wrote the first draft of the manuscript, and all authors made the decision to submit the manuscript for publication. The study was conducted with fidelity to the study protocol, which is available at NEJM.org.

Patients

Patients with essential tremor, diagnosed by a neurologist specializing in movement disorders, were enrolled on the basis of eligibility criteria that have been described previously.24 Briefly, patients were eligible if they had a postural or intention tremor of the hand that was moderate to severe (defined by a score of ≥2 on the Clinical Rating Scale for Tremor26 [CRST; scores range from 0 to 4 per component assessed and higher scores indicate more severe tremor]) and disabling (defined by a score of ≥2 on any of the eight items in the disability subsection of the CRST [scores range from 0 to 4 per item, and higher scores indicate greater disability]). Additional eligibility criteria were tremor that was refractory to at least two trials of medical therapy, including at least one first-line agent (propranolol or primidone). For patients receiving concurrent medical therapy, medication doses had to be stable for 30 days before randomization. Patients were excluded if they had a neurodegenerative condition, unstable cardiac disease, coagulopathy, risk factors for deep-vein thrombosis, severe depression (defined by a score ≥20 on Patient Health Questionnaire 9 [scores range from 0 to 27, with higher scores indicating more severe depression]), or cognitive impairment (defined by a score of <24 on the Mini–Mental State Examination [scores range from 0 to 30, with lower values indicating greater impairment]) or if they had undergone a previous brain procedure (transcranial magnetic stimulation, deep-brain stimulation, stereotactic lesioning, or electroconvulsive therapy). A skull density ratio (the ratio of cortical to cancellous bone) of 0.45 or more was required from the screening computed tomographic (CT) scan.

From August 2013 through September 2014, we enrolled 81 patients and randomly assigned them to a study group. Five of these patients were excluded before undergoing the assigned procedure because they met exclusionary criteria, as detailed in Fig. S2 in the Supplementary Appendix. As predefined in the protocol and statistical analysis plan, only the 76 patients in whom the study procedure was attempted or completed were included in the modified intention-to-treat analysis.

Focused Ultrasound Thalamotomy

The details of focused ultrasound thalamotomy have been described previously.23-25 Briefly, patients were placed in a stereotactic head frame that was coupled to an MRI-compatible ultrasound transducer. After stereotactic targeting with the use of MRI, acoustic energy was sequentially titrated to temperatures sufficient for tissue ablation (approximately 55 to 60°C). Each brief sonication was monitored with magnetic resonance thermometry, and the patient was clinically assessed for tremor reduction and adverse effects (for details, see the description in the Supplementary Appendix).

For patients randomly assigned to undergo a sham procedure, an identical procedure was performed with a randomized number of sonications for which the acoustic power was disengaged so that no acoustic energy was delivered to the brain. Only the treatment team was aware of the group assignments; patients and assessors were unaware of the assignments.

Outcome Assessments

Tremor assessments, based on the CRST,26 were performed at each site by a movement-disorder specialist, and functional status was determined on the basis of the rating for the disability subsection (Part C) of the CRST, as well as the disease-specific, self-reported Quality of Life in Essential Tremor Questionnaire (QUEST).27 Tremor evaluations were videotaped for primary analysis by an independent core group of neurologists (Tremor Research Group) at baseline and at 1, 3, 6, and 12 months after treatment.

The primary efficacy outcome measure was defined as the change from baseline to 3 months in the tremor score for the hand in the thalamotomy group as compared with the sham-procedure group. The tremor score (on a scale ranging from 0 to 32, with higher scores indicating more severe tremor) was derived from the CRST, Part A (three items: resting, postural, and action or intention components of hand tremor), and the CRST, Part B (five tasks involving handwriting, drawing, and pouring), in the hand contralateral to the thalamotomy.

The three prespecified secondary efficacy measures were functional limitations in daily activities, measured according to eight items in the disability subsection of the CRST (maximum overall score, 32; higher scores indicate greater disability); quality of life, assessed with the QUEST at 3 months; and the durability of the reduction in hand tremor at 12 months. We also performed a post hoc analysis of total tremor scores (maximum overall score for the most severe tremor, 152 points without supine assessments). Safety was assessed throughout the study on the basis of reported adverse events. MRI was performed immediately after the study procedure and at 12 months.

Blinding

The study participants and the neurologist at each site were unaware of the treatment assignments throughout the first 3 months, and the primary assessors of the videotaped tremor evaluations were not involved in the study treatments and were unaware of the treatment assignments and the side that was treated (left vs. right). Since the patients’ heads were not covered, the assessors could see whether the videotapes showed preoperative or postoperative tremor evaluations; however, they could not determine whether the videotapes were taken 1, 3, 6, or 12 months after treatment.

Statistical Analysis

We calculated the sample size from pilot-study observations, accounting for a potential dropout rate of 20%. The null hypothesis was that thalamotomy would be either the same as or inferior to the sham procedure with respect to the percentage improvement in the primary end point. The alternative hypothesis was that thalamotomy would be superior to the sham procedure. Given a sample of at least 60 patients, the study had almost 100% power to show the primary efficacy of thalamotomy, assuming, on the basis of historical results, average improvements of 78% and 4% in the thalamotomy and sham-procedure groups, respectively (standard deviation, 25%). Power calculations were performed with the use of an independent-groups t-test, with a randomization ratio of 3:1 for assignment to thalamotomy versus the sham procedure. The probability of detecting an adverse event rate of 1% was 0.45, and the probability of a 5% rate was 0.95. The statistical analysis was planned and conducted with the assistance of the biostatistics team at TechnoSTAT. The statistical analysis plan (see the study protocol) was approved by the Food and Drug Administration (FDA).

We used a hierarchical testing design to control for multiple comparisons across the one primary and three prespecified secondary end points. The primary efficacy analysis was confirmed at an alpha level of 0.05, and then each of the three secondary efficacy end points was tested at an alpha level of 0.05. No confirmatory statements were made about other end points. Thus, type 1 error was controlled across all end points tested in this study.

A sensitivity analysis with multiple imputation was planned, but in the primary analysis, only two patients had missing data. Since worst-case and best-case scenarios yielded such similar results, additional imputation was not carried out. A second sensitivity analysis, performed because five patients were found to meet exclusion criteria after randomization, confirmed that their exclusion had no effect on the results of the primary outcome analysis (see the Supplementary Appendix). The data reported here were locked on September 17, 2015, and the report was finalized on October 14, 2015.