Methods for pragmatic randomized clinical trials of pain therapies: IMMPACT statement.

ABSTRACT: Pragmatic, randomized, controlled trials hold the potential to directly inform clinical decision making and health policy regarding the treatment of people experiencing pain. Pragmatic trials are designed to replicate or are embedded within routine clinical care and are increasingly valued to bridge the gap between trial research and clinical practice, especially in multidimensional conditions, such as pain and in nonpharmacological intervention research. To maximize the potential of pragmatic trials in pain research, the careful consideration of each methodological decision is required. Trials aligned with routine practice pose several challenges, such as determining and enrolling appropriate study participants, deciding on the appropriate level of flexibility in treatment delivery, integrating information on concomitant treatments and adherence, and choosing comparator conditions and outcome measures. Ensuring data quality in real-world clinical settings is another challenging goal. Furthermore, current trials in the field would benefit from analysis methods that allow for a differentiated understanding of effects across patient subgroups and improved reporting of methods and context, which is required to assess the generalizability of findings. At the same time, a range of novel methodological approaches provide opportunities for enhanced efficiency and relevance of pragmatic trials to stakeholders and clinical decision making. In this study, best-practice considerations for these and other concerns in pragmatic trials of pain treatments are offered and a number of promising solutions discussed. The basis of these recommendations was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks.

Mindfulness in Facilitating Pelvic Floor Botulinum Toxin Injection in Women with Chronic Pelvic Pain.

Botulinum toxin (BoNT) injection can safely be done as an office-based procedure, but can be painful itself, especially when injecting pelvic floor muscles to treat chronic pelvic pain (CPP). Mindfulness interventions may reduce procedure-associated acute anxiety and pain. We applied mindfulness techniques to increase the tolerability of office-based pelvic floor BoNT injections in women with CPP. Women enrolled in a clinical trial of BoNT for endometriosis-associated CPP were offered a brief, guided mindfulness session before and/or after transvaginal injection. Anxiety, pain, and dysphoria were rated on a 0-10 numerical rating scale (NRS) before and after each mindfulness session. Eight women underwent mindfulness sessions. Five participants had a session before and two after the transvaginal injection. One participant had two sessions: one before and one after separate injections. All six women completing a session prior to injection had at least moderate anxiety, which lessened after the mindfulness session (median NRS change: -3.3/10). All three women reporting injection-associated pain experienced less intense pain following the post-injection session (median NRS change: -3/10). Three women experiencing dysphoria improved after the session (median NRS change: -3/10). A brief, guided mindfulness session may lessen acute pain, anxiety, and dysphoria associated with office-based transvaginal BoNT injection.

Developing consensus on core outcome sets of domains for acute, the transition from acute to chronic, recurrent/episodic, and chronic pain: results of the INTEGRATE-pain Delphi process.

Background: Pain is the leading cause of disability worldwide among adults and effective treatment options remain elusive. Data harmonization efforts, such as through core outcome sets (COS), could improve care by highlighting cross-cutting pain mechanisms and treatments. Existing pain-related COS often focus on specific conditions, which can hamper data harmonization across various pain states. Methods: Our objective was to develop four overarching COS of domains/subdomains (i.e., what to measure) that transcend pain conditions within different pain categories. We hosted a meeting to assess the need for these four COS in pain research and clinical practice. Potential COS domains/subdomains were identified via a systematic literature review (SLR), meeting attendees, and Delphi participants. We conducted an online, three step Delphi process to reach a consensus on domains to be included in the four final COS. Survey respondents were identified from the SLR and pain-related social networks, including multidisciplinary health care professionals, researchers, and people with lived experience (PWLE) of pain. Advisory boards consisting of COS experts and PWLE provided advice throughout the process. Findings: Domains in final COS were generally related to aspects of pain, quality of life, and physical function/activity limitations, with some differences among pain categories. This effort was the first to generate four separate, overarching COS to encourage international data harmonization within and across different pain categories. Interpretation: The adoption of the COS in research and clinical practice will facilitate comparisons and data integration around the world and across pain studies to optimize resources, expedite therapeutic discovery, and improve pain care. Funding: Innovative Medicines Initiative 2 Join Undertaking; European Union Horizon 2020 research innovation program, European Federation of Pharmaceutical Industries and Associations (EFPIA) provided funding for IMI-PainCare. RDT acknowledges grants from Esteve and TEVA.

Pain management research from the NIH HEAL Initiative.

This article presents an overview of the pain research programs within the National Institutes of Health (NIH) Helping to End Addiction Long-term® Initiative, or NIH HEAL Initiative®. Launched in 2018 to address the opioid crisis, the NIH HEAL Initiative supports research on addiction prevention and treatment. A key component of addiction prevention is the development of new, effective, non-addictive treatments for acute and chronic pain. HEAL's innovate research portfolio spans the spectrum from therapeutic discovery and development through clinical trials and into clinical practice.

An Autopsy Series of Seven Cases of VPS13A Disease (Chorea-Acanthocytosis).

BACKGROUND: Vacuolar protein sorting 13 homolog A (VPS13A) disease, historically known as chorea-acanthocytosis, is a rare neurodegenerative disorder caused by biallelic mutations in VPS13A, usually resulting in reduced or absent levels of its protein product, VPS13A. VPS13A localizes to contact sites between subcellular organelles, consistent with its recently identified role in lipid transfer between membranes. Mutations are associated with neuronal loss in the striatum, most prominently in the caudate nucleus, and associated marked astrogliosis. There are no other known disease-specific cellular changes (eg, protein aggregation), but autopsy reports to date have been limited, often lacking genetic or biochemical diagnostic confirmation. OBJECTIVE: The goal of this study was to characterize neuropathological findings in the brains of seven patients with VPS13A disease (chorea-acanthocytosis). METHODS: In this study, we collected brain tissues and clinical data from seven cases of VPS13A for neuropathological analysis. The clinical diagnosis was confirmed by the presence of VPS13A mutations and/or immunoblot showing the loss or reduction of VPS13A protein. Tissues underwent routine, special, and immunohistochemical staining focused on neurodegeneration. Electron microscopy was performed in one case. RESULTS: Gross examination showed severe striatal atrophy. Microscopically, there was neuronal loss and astrogliosis in affected regions. Luxol fast blue staining showed variable lipid accumulation with diverse morphology, which was further characterized by electron microscopy. In some cases, rare degenerating p62- and ubiquitin-positive cells were present in affected regions. Calcifications were present in four cases, being extensive in one. CONCLUSIONS: We present the largest autopsy series of biochemically and genetically confirmed VPS13A disease and identify novel histopathological findings implicating abnormal lipid accumulation. © 2023 International Parkinson and Movement Disorder Society.

Sphingolipid and Phospholipid Levels Are Altered in Human Brain in Chorea-Acanthocytosis.

BACKGROUND: Chorea-acanthocytosis (ChAc) is associated with mutations of VPS13A, which encodes for chorein, a protein implicated in lipid transport at intracellular membrane contact sites. OBJECTIVES: The goal of this study was to establish the lipidomic profile of patients with ChAc. METHODS: We analyzed 593 lipid species in the caudate nucleus (CN), putamen, and dorsolateral prefrontal cortex (DLPFC) from postmortem tissues of four patients with ChAc and six patients without ChAc. RESULTS: We found increased levels of bis(monoacylglycerol)phosphate, sulfatide, lysophosphatidylserine, and phosphatidylcholine ether in the CN and putamen, but not in the DLPFC, of patients with ChAc. Phosphatidylserine and monoacylglycerol were increased in the CN and N-acyl phosphatidylserine in the putamen. N-acyl serine was decreased in the CN and DLPFC, whereas lysophosphatidylinositol was decreased in the DLPFC. CONCLUSIONS: We present the first evidence of altered sphingolipid and phospholipid levels in the brains of patients with ChAc. Our observations are congruent with recent findings in cellular and animal models, and implicate defects of lipid processing in VPS13A disease pathophysiology. © 2023 International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Applications of botulinum toxin to the female pelvic floor: Botulinum toxin for genito-pelvic pain penetration disorder and chronic pelvic pain in women.

Chronic pain conditions like genito-pelvic pain penetration disorder and chronic pelvic pain cause significant morbidity in women worldwide and yet are underdiagnosed and undertreated. While the use of botulinum toxin for pain conditions has expanded, there are few randomized controlled studies of botulinum toxin for pelvic pain conditions in women. This paper provides an update on the current status and context for considering botulinum toxin treatment for these conditions to complement and expand currently available approaches. High quality clinical trials to evaluate safety and efficacy and to determine optimal doses and approaches to injection are urgently needed.

Endometriosis-associated chronic pelvic pain.

Endometriosis is a heterogeneous disease where neurogenic sensitization can lead to chronic pain within and beyond the pelvis. Coincident pain and comorbidities merit specific attention. We discuss the causes, comorbidities, and management of endometriosis-associated chronic pelvic pain, advocating for a multidisciplinary approach to develop more effective treatments.

Research objectives and general considerations for pragmatic clinical trials of pain treatments: IMMPACT statement.

ABSTRACT: Many questions regarding the clinical management of people experiencing pain and related health policy decision-making may best be answered by pragmatic controlled trials. To generate clinically relevant and widely applicable findings, such trials aim to reproduce elements of routine clinical care or are embedded within clinical workflows. In contrast with traditional efficacy trials, pragmatic trials are intended to address a broader set of external validity questions critical for stakeholders (clinicians, healthcare leaders, policymakers, insurers, and patients) in considering the adoption and use of evidence-based treatments in daily clinical care. This article summarizes methodological considerations for pragmatic trials, mainly concerning methods of fundamental importance to the internal validity of trials. The relationship between these methods and common pragmatic trials methods and goals is considered, recognizing that the resulting trial designs are highly dependent on the specific research question under investigation. The basis of this statement was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) systematic review of methods and a consensus meeting. The meeting was organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership. The consensus process was informed by expert presentations, panel and consensus discussions, and a preparatory systematic review. In the context of pragmatic trials of pain treatments, we present fundamental considerations for the planning phase of pragmatic trials, including the specification of trial objectives, the selection of adequate designs, and methods to enhance internal validity while maintaining the ability to answer pragmatic research questions.

Comparison of Ultrasound and Electrical Stimulation Guidance for Onabotulinum Toxin-A Injections: A Randomized Crossover Study.

Background: Botulinum neurotoxin (BoNT) injection is an established therapy for limb spasticity and focal limb dystonia. Comparative benefits of injection guidance procedures have not been rigorously studied. Objectives: We compared 2 targeting techniques for onabotulinumtoxin-A (onabotA) injection for the treatment of focal hand dystonia and upper limb spasticity: electrophysiologic guidance using electrical stimulation (E-stim) and ultrasound (US). Methods: This was a 2-center, randomized, crossover, assessor-blinded trial. Participants with focal hand dystonia or upper limb spasticity, on stable onabotA therapy for at least 2 previous injection cycles, were randomly assigned to either E-stim or US with crossover at 3 months. The primary outcome was improvement in dystonia or spasticity severity on a visual analog scale (VAS; 0-100) measured 1 month after each injection. The secondary outcome was participant discomfort assessed on a VAS. Repeated-measures analysis of covariance was used with linear mixed-model covariate selection. Results: A total of 19 participants (13 men) completed the study, 10 with upper limb spasticity and 9 with dystonia. Benefit was equivalent between the 2 techniques (VAS least-square mean [LSmean] 51.5 mm with US and 53.1 with E-stim). E-stim was perceived as more uncomfortable by participants (VAS LSmean 34.5 vs. 19.9 for E-stim and US, respectively). Procedure duration was similar with the 2 procedures. There were no serious adverse events related to either approach. Conclusions: US and E-Stim localization guidance techniques provide equivalent efficacy in onabotA injections for spasticity and dystonia. US guidance injections are more comfortable for participants. Both techniques are effective guidance methods, with US potentially preferable based on participant comfort.

The Human Cost: Patient Contribution to Clinical Trials in Neurology.

Drug development abounds with corporate pharmaceutical capital investment and expenditure costs for new therapeutics. However, there is little data on the human investment, in particular, the number of participants required or the potential burden on and cost to individual trial participants so instrumental to this endeavor. Indeed, the human participant burden in clinical trials is poorly, if at all, described in the literature and we could identify no reports that have detailed the participant burden unique to neurology trials. The cost of clinical trials to participants, including the unique circumstances affecting enrollment of diverse participant populations, has only begun to be reflected in the wider clinical trial literature. Additionally, details of the indirect costs, including time commitment, out-of-pocket expenses, emotional expenditure, and potential loss of enrollment into a more successful trial by participants in trials that fail - the majority in the field - is also particularly striking in the lack of representation in the literature. Even in successful clinical trials, participants in the placebo group face both an emotional burden and medical risk of morbidity and mortality without potential offsetting therapeutic benefit.

American Indian and Alaska Native Enrollment in Clinical Studies in the National Institutes of Health's Intramural Research Program.

Clinical studies conducted by the National Institutes of Health's Intramural Research Program (NIH-IRP) provide eligible individuals with access to innovative research treatments that may not otherwise be available. The NIH-IRP's mission is to include all Americans, including American Indians and Alaska Natives, in its clinical research. This study is the first to provide data about inclusion of American Indians/Alaska Natives in NIH-IRP clinical studies. We analyzed data from the more than 1,800 NIH-IRP protocols active in 2014 and 2017. We found that the absolute number of American Indian/Alaska Native enrollees increased between 2014 and 2017 but remained at 1% of all participants, a disproportionately low level. The number of clinical studies that enrolled American Indian/Alaska Native individuals similarly did not change. NIH efforts to expand participation of American Indians/Alaska Natives in clinical studies has often focused on research within their communities or on health needs specific to these groups. Those efforts should expand to include processes and protections for the proportionate and ethical inclusion of American Indians and Alaska Natives who individually enroll in studies that are not specific to American Indians, Alaska Natives, or their tribal nations.

Widespread myofascial dysfunction and sensitisation in women with endometriosis-associated chronic pelvic pain: A cross-sectional study.

BACKGROUND: Chronic pelvic pain persists in some women with endometriosis even after lesion removal and optimized hormonal treatment. OBJECTIVE: Characterize the presence and distribution of pain, myofascial dysfunction and sensitisation beyond the pelvis in women with endometriosis-associated chronic pelvic pain. METHODS: Cross-sectional study of 30 women prior to participation in a clinical trial. Evaluation included pain-focused abdominopelvic gynaecologic examination with the identification of pelvic floor muscle spasm. Neuro-musculoskeletal examination assessed paraspinal allodynia and hyperalgesia bilaterally and myofascial trigger points in 13 paired muscles. Pressure-pain thresholds were measured over interspinous ligaments and trigger points. Women completed the body territories element of the Body Pain Index. RESULTS: All women had a pelvic floor muscle spasm that they self-identified as a major focus of pain. Twenty of 30 women described their pelvic pain as focal. However, all demonstrated widespread myofascial dysfunction with low pressure-pain thresholds and trigger points in over two-thirds of 26 assessed regions. Widespread spinal segmental sensitisation was present in 17/30, thoracic in 21/30 and lumbosacral/pelvic in 18/30. Cervical sensitisation manifested as low pressure-pain thresholds with 23/30 also reporting recurrent, severe headaches and 21/30 experiencing orofacial pain. Those reporting diffuse pelvic pain were more likely to have widespread (p = .024) and lumbosacral/pelvic (p = .036) sensitisation and report over 10 painful body areas (p = .009). CONCLUSIONS: Women with endometriosis-associated chronic pelvic pain often have myofascial dysfunction and sensitisation beyond the pelvic region that may be initiated or maintained by on-going pelvic floor spasm. These myofascial and nervous system manifestations warrant consideration when managing pain in this population. Clinicaltrials.gov identifier: NCT01553201. SIGNIFICANCE: Women with endometriosis often have pelvic pain persisting after surgery despite hormonal therapies and these women have regional pelvic sensitisation and myofascial dysfunction. Pelvic floor muscle spasm is a major pain focus in this population. Sensitisation and myofascial dysfunction are widespread, beyond the pelvic region. On-going pelvic floor spasm may initiate or maintain sensitisation. Myofascial/sensitisation manifestations warrant consideration when managing pain in this population.

Management of Anterocapitis and Anterocollis: A Novel Ultrasound Guided Approach Combined with Electromyography for Botulinum Toxin Injection of Longus Colli and Longus Capitis.

Chemodenervation of cervical musculature using botulinum neurotoxin (BoNT) is established as the gold standard or treatment of choice for management of Cervical Dystonia (CD). The success of BoNT procedures is measured by improved symptomology while minimizing side effects and is dependent upon many factors including: clinical pattern recognition, identifying contributory muscles, BoNT dosage, and locating and safely injecting target muscles. In patients with CD, treatment of anterocollis (forward flexion of the neck) and anterocaput (anterocapitis) (forward flexion of the head) are inarguably challenging. The longus Colli (LoCol) and longus capitis (LoCap) muscles, two deep cervical spine and head flexor muscles, frequently contribute to these patterns. Localizing and safely injecting these muscles is particularly challenging owing to their deep location and the complex regional anatomy which includes critical neurovascular and other structures. Ultrasound (US) guidance provides direct visualization of the LoCol, LoCap, other cervical muscles and adjacent structures reducing the risks and side effects while improving the clinical outcome of BoNT for these conditions. The addition of electromyography (EMG) provides confirmation of muscle activity within the target muscle. Within this manuscript, we present a technical description of a novel US guided approach (combined with EMG) for BoNT injection into the LoCol and LoCap muscles for the management of anterocollis and anterocaput in patients with CD.

Self-reported benefit and weakness after botulinum toxin in dystonia.

With this retrospective, single center, chart review study, we investigate the self-reported benefit and weakness after botulinum toxin injections in three different types of dystonia: focal hand dystonia (FHD), blepharospasm and cervical dystonia. We found that the benefit lasts significantly longer in FHD compared to the other two groups.

Critical NIH Resources to Advance Therapies for Pain: Preclinical Screening Program and Phase II Human Clinical Trial Network.

Opioid-related death and overdose have now reached epidemic proportions. In response to this public health crisis, the National Institutes of Health (NIH) launched the Helping to End Addiction Long-term InitiativeSM, or NIH HEAL InitiativeSM, an aggressive, trans-agency effort to speed scientific solutions to stem the national opioid public health crisis. Herein, we describe two NIH HEAL Initiative programs to accelerate development of non-opioid, non-addictive pain treatments: The Preclinical Screening Platform for Pain (PSPP) and Early Phase Pain Investigation Clinical Network (EPPIC-Net). These resources are provided at no cost to investigators, whether in academia or industry and whether within the USA or internationally. Both programs consider small molecules, biologics, devices, and natural products for acute and chronic pain, including repurposed and combination drugs. Importantly, confidentiality and intellectual property are protected. The PSPP provides a rigorous platform to identify and profile non-opioid, non-addictive therapeutics for pain. Accepted assets are evaluated in in vitro functional assays to rule out opioid receptor activity and to assess abuse liability. In vivo pharmacokinetic studies measure plasma and brain exposure to guide the dose range and pretreatment times for the side effect profile, efficacy, and abuse liability. Studies are conducted in accordance with published rigor criteria. EPPIC-Net provides academic and industry investigators with expert infrastructure for phase II testing of pain therapeutics across populations and the lifespan. For assets accepted after a rigorous, objective scientific review process, EPPIC-Net provides clinical trial design, management, implementation, and analysis.

Botulinum toxin for chronic pelvic pain in women with endometriosis: a cohort study of a pain-focused treatment.

BACKGROUND AND OBJECTIVES: Many women with endometriosis continue to have pelvic pain despite optimal surgical and hormonal treatment; some also have palpable pelvic floor muscle spasm. We describe changes in pain, spasm, and disability after pelvic muscle onabotulinumtoxinA injection in women with endometriosis-associated pelvic pain, a specific population not addressed in prior pelvic pain studies on botulinum toxin. METHODS: We present an open-label proof-of-concept case series of women with surgically diagnosed endometriosis. Under conscious sedation and with topical anesthetic, 100 units of onabotulinumtoxinA was injected transvaginally into pelvic floor muscle spasm areas under electromyography guidance. Changes in pain intensity, muscle spasm, disability, and pain medication use were assessed at periodic visits for up to 1 year after injection. RESULTS: Thirteen women underwent botulinum toxin injection and were followed for at least 4 months. Before injection, 11 of the 13 women had spasm in >4/6 assessed pelvic muscles and reported moderate pain (median visual analog scale (VAS): 5/10; range: 2-7). By 4-8 weeks after injection, spasm was absent/less widespread (≤3 muscles) in all (p=0.0005). Eleven rated their postinjection pain as absent/mild (median VAS: 2; range: 0-5; p<0.0001); 7/13 reduced pain medication. Disability decreased in 6/8 women with at least moderate preinjection disability (p=0.0033). Relief lasted 5-11 months in 7 of the 11 patients followed for up to 1 year. Adverse events were mild and transient. CONCLUSIONS: These findings suggest pelvic floor spasm may be a major contributor to endometriosis-associated pelvic pain. Botulinum toxin injection may provide meaningful relief of pain and associated disability. TRIAL REGISTRATION NUMBER: NCT01553201.

Botulinum toxin and occupational therapy for Writer's cramp.

BACKGROUND: Writer's cramp (WC) is a form of focal hand dystonia, for which focal botulinum neurotoxin (BoNT) injections are the current best therapy. Past studies have shown that some types of rehabilitative therapy can be useful. We hypothesized that BoNT together with a specific type of occupational therapy would be better than BoNT alone for treating WC patients comparing the effects with a patient-rated subjective scale. METHODS: Twelve WC patients were randomized to two groups. Six received only BoNT therapy and 6 received BoNT & occupational therapy. The occupational therapy involved specific exercises of finger movements in the direction opposite to the dystonic movements during writing. BoNT was injected by movement disorders neurologists in the affected muscles under electromyography-guidance. The primary outcome was the patient-rated subjective scale at 20 weeks. Secondary exploratory outcomes included the writer's cramp rating scale (WCRS), writer's cramp impairment scale (WCIS), the writer's cramp disability scale (WCDS), handgrip strength and kinetic parameters. RESULTS: The patient-rated subjective scale scores at 20 weeks were not significantly different between the two groups. Significant objective improvement was noted in the BoNT & occupational therapy group, as noted by the decrease (28%) in WCIS scores. CONCLUSIONS: Improvement of the primary outcome measure, the patient-rated subjective scale, was not achieved. However, significant improvement was found in the BoNT & occupational therapy group in a secondary measure of impairment. Our hypothesis-driven study results are likely limited by small sample size, and further large-scale studies of occupational therapy methods to improve the efficacy of BoNT seems worthwhile.

Methodological approaches to botulinum toxin for the treatment of chronic pelvic pain, vaginismus, and vulvar pain disorders.

INTRODUCTION AND HYPOTHESIS: Botulinum toxin (BoNT) is increasingly used for pain, especially with muscle spasm. We describe our methodology for BoNT treatment of chronic pelvic pain (CPP) in women and place it in the context of the literature on techniques for this use. METHODS: Databases were searched using terms "botulinum toxin," "pelvic pain," and "vaginismus." Reports on vaginismus/vulvodynia/vestibulodynia (included if pelvic floor muscles were injected) were grouped as "vaginismus/vulvar pain disorders" (V/VPD). We analyzed the type of report, condition, toxin serotype/brand, dose/dilution, muscle selection, guidance technique, and anesthesia. Publications from the same authors without unique information were combined for specific analyses. RESULTS: Thirty-eight reports had analyzable information; many lacked complete information. Most were open-label prospective reports; there were four technical reports, one randomized comparison of doses and one placebo-controlled study of efficacy. Pelvic floor muscles were approached transvaginally, transperineally or transgluteally. BoNT brand/dose/dilution varied widely. Muscle localization techniques included anatomical landmarks only, electromyography, electrical stimulation with/without ultrasound, and fluoroscopy/CT scanning. Papers discussing analgesia utilized general anesthesia, conscious sedation with/without topical/local anesthesia, topical/local agent alone or pudendal block before or after injection. Cumulatively, 58-100% of patients with CPP and 71-100% of those with V/VPD improved. Serious adverse events (transient fecal incontinence/constipation, urinary incontinence/retention) were more frequent with higher doses. CONCLUSIONS: BoNT can be safely and tolerably injected into pelvic floor muscles in women as an out-patient procedure. This study identifies methodological factors to be considered in future studies and the critical need for high-quality clinical trials for this emerging treatment.