Pain Outcomes After Digital Amputation Using Tulavi Allay™ Nerve Cap

Pain Outcomes After Digital Amputation Using Tulavi Allay™ Nerve Cap: A Prospective Trial for Safety and Efficacy

In 2016, one in five individuals in the United States (US) experienced chronic pain, and approximately 40% of them suffered from neuropathic pain. The physical and emotional burden on patients results in costs of billions of dollars annually. Digital amputations affect over 23,000 people each year in the US and may lead to neuropathic pain and neuroma formation in the transected nerves. Previous studies have reported a 6.6% incidence of symptomatic neuroma, and more than 60% of these patients require surgery to reduce the negative impact on their daily living activities.

To minimize neuroma formation after digital amputation, various techniques have been described, such as traction neurectomies (TN) and dorsal transpositions (DT), with and without nerve coaptation. However, it remains unclear whether these techniques improve patient-reported outcome measures in individuals undergoing this type of procedure. Previously published studies are descriptive in nature, focus on a single surgical technique, or include patients with established symptomatic neuromas. The only prospective trial on this topic was published in 2000 and compared two conventional techniques that have since been modified to better minimize neuroma formation or to reduce mechanical pressure by transposing the nerve ends to the dorsal aspect of the hand. However, that study used different scales to measure outcomes and did not incorporate aspects of pain that affect patients' emotional and social well-being.

Currently, two randomized controlled trials are enrolling patients. One compares surgical techniques for the treatment of neuroma rather than its prevention. The other excludes digits with injuries located distal to the interphalangeal joints. Both studies focus on more complex surgical techniques.

Given the extent of this problem, there has been recent innovation aimed at preventing neuroma formation. One promising product is the Tulavi Allay™ Nerve Cap, which has demonstrated encouraging results in basic science studies and anecdotally in early clinical use cases. In this study, the investigators have designed a prospective trial to assess the efficacy of the Tulavi Allay™ Nerve Cap when used to prevent symptomatic digital nerve neuroma following traumatic digital amputation.

Background and Significance In 2016, one in five individuals in the United States (US) experienced chronic pain, and approximately 40% of them suffered from neuropathic pain. The physical and emotional burden on patients results in healthcare and societal costs of billions of dollars annually. Digital amputations affect over 23,000 people each year in the US and may lead to neuropathic pain and neuroma formation in the transected nerves. Previous studies have reported a 6.6% incidence of symptomatic neuroma, and more than 60% of these patients require surgery to reduce the negative impact on their daily activities.

To minimize neuroma formation after digital amputation, various techniques have been described, such as traction neurectomies (TN) and dorsal transpositions (DT), with and without nerve coaptation. However, it remains unclear whether these techniques improve patient-reported outcome measures in individuals undergoing this type of procedure. Previously published studies are largely descriptive, focus on a single surgical technique, or include patients with established symptomatic neuromas. The only prospective trial on this topic was published in 2000 and compared two conventional techniques that have since been modified to better minimize neuroma formation or reduce mechanical pressure by transposing nerve ends to the dorsal aspect of the hand. However, that study used heterogeneous outcome measures and did not assess the emotional and social impact of pain.

Currently, two randomized controlled trials (RCTs) are enrolling patients. One compares surgical techniques for the treatment of neuroma rather than its prevention. The other excludes patients with injuries to digits distal to the interphalangeal joint. Both studies focus on more complex surgical techniques.

Given the scope of this problem, there has been recent innovation aimed at preventing neuroma formation. One promising intervention is the Tulavi Allay™ Nerve Cap, which has demonstrated encouraging results in preclinical research and early clinical experience. In this study, the investigators have designed a prospective trial to assess the efficacy of the Tulavi Allay™ Nerve Cap in preventing symptomatic digital nerve neuroma following traumatic digital amputation.

General Description of Study Design This is a prospective trial. The investigators will enroll 20 patients. Questionnaires will be administered at the first post-operative appointment and again at 4-6 weeks, 3 months, 6 months, and 12 months post-operatively.

The following validated outcome measures will be used throughout patient participation:

Numerical Rating Scale (NRS): A standard 11-point pain scale (0 = no pain, 10 = worst possible pain). While no clinically significant change has been defined for digital amputation pain, studies on other chronic pain conditions have suggested that a reduction of 2 points represents a clinically meaningful difference.

Patient-Reported Outcomes Measurement Information System Pain Interference (PROMIS-PI): This instrument captures the impact of pain on emotional and social life. The investigators will use the PROMIS Pain Interference Computer-Adaptive Testing (PROMIS-PI CAT), which measures pain interference over the previous 7 days. PROMIS scores have a mean of 50 and a standard deviation (SD) of 10 in the reference population (US general population with pain).

Cold Intolerance Symptom Severity (CISS) Score: A six-item questionnaire (scored from 4-100), where each question ranges from 0 = no symptoms to 10 = most severe symptoms imaginable. The first question is not included in the final score. A score >50 is considered pathological cold intolerance.

Study Procedures

After surgery, patients who consent to participate will complete the following scales at five time points:

NRS pain score (0-10)

PROMIS-PI CAT (0-100)

CISS score (4-100)

These represent the primary quantitative outcomes and will be collected at:

First post-operative visit

1 month after surgery

3 months after surgery

6 months after surgery

12 months after surgery

Additional data will be collected at each visit using a custom questionnaire administered through REDCap (Research Electronic Data Capture):

Use of medication for neuropathic pain (Yes/No)

Engagement in desensitization physical therapy (Yes/No)

If patients are unable to attend an in-person visit or prefer remote follow-up, study staff will provide a REDCap survey link or administer the questionnaires by phone, depending on patient preference. Patients will have a two-week window to complete questionnaires. If questionnaires remain incomplete by the end of the two-week window, study staff will attempt contact for one additional week. After that, the data point will be marked as missing.

All enrolled patients will undergo surgery regardless of study participation. Remuneration is not applicable.

Study Termination Criteria:

Patient elects to withdraw from the study

Loss to follow-up (i.e., persistent missing data)

Regardless of study participation or withdrawal, patients will continue to receive standard clinical care. Physicians will remain accessible for consultation at all times.

Risks and Discomforts Surgical techniques for nerve stump management after digital amputation are currently selected based on surgeon preference, as there is no consensus on a superior method. All techniques aim to reduce the risk of symptomatic neuroma formation and related pain or discomfort.

The Tulavi Allay™ Nerve Cap has received De Novo classification by the U.S. Food and Drug Administration (FDA). Its use in this study does not expose patients to additional risk, as all patients already require nerve stump management as part of their surgical care.

While risks may vary depending on the cause of the amputation, potential implant-related risks include local tissue reaction or material failure. However, the hydrogel material used in the nerve cap is bioabsorbable. The product is provided as an in-kind research gift and will not result in additional cost to the patient.

Expected complications of both surgical techniques include: infection, injury to digital vessels, neuroma formation, hyperalgesia, cold intolerance, and neuropathic pain. No specific or unique complications related to the Tulavi Allay™ Nerve Cap have been reported.

A potential additional risk is the breach of confidentiality. To minimize this, all data will be collected electronically using REDCap, a secure, HIPAA (Health Insurance Portability and Accountability Act)-compliant, web-based platform hosted by Mass General Brigham (MGB) HealthCare Research Computing, through its Enterprise Research Infrastructure & Services (ERIS). Only study investigators and staff will have access to identifiable data. No paper-based records will be used. Once analysis is complete, all study data will be de-identified.

Benefits Currently, the most effective technique for preventing neuroma-particularly in terms of pain, cold intolerance, and pain interference-is not known. Therefore, there is no guaranteed individual benefit to participants. However, findings from this study may guide the development of future randomized controlled trials and improve neuroma management practices.

Statistical Analysis All statistical analyses will be conducted independently from Tulavi Therapeutics to avoid bias. The Principal Investigator (PI) has no financial conflict of interest.

A sample size of 20 patients has been established based on similar studies of other neuroma prevention techniques.

Data will be assessed for normality. Results will be reported as means and SDs for parametric data, medians and interquartile ranges for non-parametric data, and frequencies and percentages for categorical variables.

Relationships between explanatory variables and continuous outcomes will be assessed using simple linear regression and Pearson or Spearman correlation, as appropriate. For dichotomous explanatory variables, Mann-Whitney U or unpaired t-tests will be used. For categorical variables, Kruskal-Wallis and one-way ANOVA tests will be applied. In univariate analyses, statistical significance will be set at P ≤ 0.10.

Variables with statistically significant associations in univariate analysis will be included in a multivariable linear regression model to identify independent predictors of surgical outcomes, with significance set at P ≤ 0.05. If sample size limits the number of variables that can be included, the most clinically relevant and/or modifiable variables will be prioritized.

If imbalances between groups arise despite randomization, the investigators will consider stratification in the analysis. Based on existing literature and biological rationale, several variables may act as potential confounders or effect modifiers.

Inclusion Criteria:

• Patients undergoing traumatic amputation of a single or multiple digits at MGB
• English-speaking

Exclusion Criteria:

• Patients undergoing revision amputation or non-traumatic amputation
• Patients under 22 years old
• Patients who are pregnant and/or breastfeeding
• Unable or unwilling to participate in a trial study
• Patients with a known allergy to poly (ethylene glycol) (PEG) or the color additives FD&C Yellow No. 5 Dye (tartrazine) or FD&C Blue No. l Dye (brilliant blue FCF).