Medical Policy

Policy Num:      02.001.104
Policy Name:    Desensitization Treatment for Peanut Allergies
Policy ID:          [02.001.104]  [Ac / B / M- / P-]  [5.01.36]

Last Review:      July 10, 2024
Next Review:      July 20, 2025
 

Related Policies: None

Desensitization Treatment for Peanut Allergies

Summary

Description

While peanut allergy is the most common cause of food allergy among children in the United States, deaths from accidental peanut exposure are rare. Approximately 80% of individuals who develop peanut allergy early in childhood do not outgrow their allergy and over half of them suffer from additional food allergies. Diagnosis of peanut allergy is made with an unequivocal history of an immediate allergic reaction following peanut ingestion, use of a skin prick test, and peanut specific IgE levels. Strict allergen avoidance is the standard of care. Peanut (Arachis hypogaea) allergen powder-dnfp is a defatted, slightly roasted peanut flour with a characterized peanut allergen profile and gradually increasing doses are given orally to desensitize patients.

Summary of Evidence

For individuals who are peanut-allergic children and adolescents ages 4 to 17 who receive peanut (Arachis hypogaea) allergen powder-dnfp, the evidence includes 2 pivotal double-blind, randomized, placebo-controlled trials (PALISADE and ARTEMIS), and an open-label extension study of the PALISADE trial. Relevant outcomes are symptoms, quality of life, hospitalizations, medication use, and treatment-related mortality and morbidity. In the PALISADE trial, 555 patients aged 4 to 55 years were randomized to peanut (Arachis hypogaea) allergen powder-dnfp (n=416) or placebo (n=139). A subset of 499 patients 4 to 17 years of age were used for the primary analysis. The primary outcome was the difference in the proportion of participants who could ingest 600 mg or more of peanut protein without dose-limiting symptoms in a food challenge after approximately 1-year follow-up between the treatment and placebo arm. The percentage of patients who met the primary endpoint at exit food challenge test was 67.2% versus 4.0% (difference 63.2%; 95% CI, 53.0 to 73.3; p<.001) in the treatment arm versus placebo, respectively. Adverse events occurred with greater frequency and severity in peanut (Arachis hypogaea) allergen powder-dnfp treated individuals versus placebo: serious adverse events (2.2% vs. 0.8%), systemic allergic reactions (14.2% vs. 3.2%), use of epinephrine outside of the food challenge test (14.0% vs. 6.5%), withdrawal due to adverse events (11.6% vs. 2.4%), and overall withdrawal rate (21.0% vs. 7.3%). In the ARTEMIS trial, similar results revealed that peanut (Arachis hypogaea) allergen powder-dnfp significantly increased the percentage of patients who could tolerate an even higher dose of peanut protein of 1000 mg as compared to placebo (58% vs. 2%, p<.0001). Additionally, 99% of patients in the peanut (Arachis hypogaea) allergen powder-dnfp group and 98% of patients in the placebo group experienced 1 or more treatment-emergent adverse events, with the majority of events being mild or moderate in severity. Gastrointestinal disorders occurred more frequently among the peanut (Arachis hypogaea) allergen powder-dnfp participants as compared to placebo (91% vs. 77%). Additionally, certain subjects in the peanut (Arachis hypogaea) allergen powder-dnfp group reported quality of life improvements that exceeded the minimum clinically important difference between the 2 groups across various domains. Notable study relevance limitations included the intended use for the population was unclear, key health outcomes were not addressed, insufficient assessment of harms, and the existence of an insufficient duration for the evaluation of benefits and harms. Key limitations in study design and conduct included the potential for partial unblinding due to adverse events (outcome assessed by treating physician).The RAMSES phase 3 trial was designed to evaluate the safety and tolerability of peanut allergen powder-dnfp in patients who had not undergone a screening food challenge in order to demonstrate a more "real world" setting than the ARTEMIS and PALISADE trials that required a positive screening food challenge for inclusion. The RAMSES trial found safety results similar to the ARTEMIS and PALISADE trials; however, the follow-up period is limited and long-term safety and efficacy results are lacking. There is need for more data to demonstrate that desensitization leads to reduced reactions to accidental exposure to peanuts and improved quality of life. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to assess whether desensitization treatment for peanut allergies improves the net health outcome in patients with peanut allergy.

Policy Statements

The use of peanut (Arachis hypogaea) allergen powder-dnfp is considered investigational for all indications.

Policy Guidelines

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Peanut Allergy

Peanut allergy is the most common food allergy in the United States (U.S.) with an estimated 1.6 million children and teens affected.^1, It is the most common allergen implicated in cases of death due to food allergy among teens.^2, However, death from accidental peanut exposure is rare; estimated rates of fatal anaphylaxis due to accidental peanut exposure range from 0.73 to 4.25 deaths per 1,000,000 patient years, depending on community prevalence.^3,

Allergic reactions can range from mild cutaneous symptoms to gastrointestinal symptoms such as abdominal pain, nausea, vomiting, and diarrhea, and severe reactions such as anaphylaxis.^4,5, Approximately 80% of individuals who develop peanut allergy early in childhood do not outgrow their food allergy in adulthood,^4,6, and over half of them suffer from additional food allergies.^7,8,

Diagnosis

Double-blind, placebo-controlled, oral food challenges are the gold standard for the diagnosis of food allergy including peanut. However, food challenge tests for peanut allergy are not performed routinely in a clinical setting due to the high-risk of precipitating severe symptoms including anaphylaxis. The diagnosis and management of peanut allergy in clinical practice rely on an unequivocal history of an immediate reaction consisting of typical allergic symptoms following the isolated ingestion of a peanut. After establishing the pretest probability of the diagnosis based on a positive clinical history, clinicians measure allergen sensitization with a skin prick test, allergen specific IgE, or both to establish the post‑test probability of peanut allergy.^9,8, The predictive power of such tests to confirm clinical history has been based on observational studies.^9, Food challenge tests may be required if the history and IgE test results do not clearly indicate an allergy.

Current Treatment

The current standard of care for peanut allergy is strict avoidance of peanut-containing food products and timely administration of epinephrine, antihistamines, beta-blockers, and steroids in case of an allergic reaction upon accidental exposure. Up to 4 out of 10 individuals with a peanut allergy may experience an accidental exposure with an annual incidence ranging from 5% to 20%.^10,11,12, Neuman-Sunshine et al (2012) retrospectively analyzed records of 572 individuals with peanut allergy. The median age at initial observation was 1.4 years; the median duration of follow-up was 5.3 years. The rate of post-diagnosis peanut exposure was 4.7%/year, the rate of severe reactions was 1.6%/year, and the use of epinephrine was 1.1%/year. Of the 685 exposures analyzed, 75.9% were due to ingestion, 13.6% due to contact, and 4.5% were airborne.^11, Patients and patient representatives report that strict avoidance of allergen results in an increased burden of day-to-day living, limitation on social activity and independence, missed time from work, negative impact on quality of life, and negative emotional impact. Further, affected persons and their family lifestyles are heavily impacted by fear and anxiety, and an important goal for patients is to be able to live and eat more freely.

Oral immunotherapy is practiced in the U.S. either under clinical trial protocols at tertiary centers or at unregulated private clinics. The extent of their use is not known and non-reimbursable. According to the Institute for Clinical and Economic Review in 2019, the majority of allergists do not offer oral immunotherapy. As a result, patients who pursue it often pay out of pocket, which can limit access to those who can afford it. There have been many studies of oral immunotherapy for peanut allergy using different peanut preparations, different dose escalation strategies, different maintenance doses (125 mg to 5000 mg peanut protein per day), different primary outcomes, and different target populations.^{13,14,15,16,17,18,} Selected published randomized controlled trials for oral immunotherapy for peanut allergies included in a systematic review published in 2019^19, are summarized in Table 1.

Table 1. Study Characteristics of Selected Published Randomized Controlled Trials for Peanut Allergy

Adapted from Chu et al, 201919,OFC: oral food challenges; OIT; oral immunotherapy; SIT; subcutaneous immunotherapy.

Regulatory Status

On January 31, 2020, Palforzia^® [Peanut (Arachis hypogaea) Allergen Powder-dnfp] was approved by the U.S. Food and Drug Administration for the mitigation of allergic reactions, including anaphylaxis, that may occur with accidental exposure to peanut. Palforzia is approved for use in patients with a confirmed diagnosis of peanut allergy. Initial dose escalation may be administered to patients aged 4 through 17 years. Up-dosing and maintenance may be continued in patients 4 years of age and older. Palforzia is to be used in conjunction with a peanut-avoidant diet.

Rationale

This evidence review was created in April 2020 with a search of the PubMed database. The most recent literature update was performed through April 29, 2024.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Peanut (Arachis hypogaea) Allergen Powder-dnfp

Clinical Context and Therapy Purpose

The purpose of peanut (Arachis hypogaea) allergen powder-dnfp in individuals who have peanut allergy is to provide a treatment option that is an improvement on existing therapies. Potential benefits of this therapy may include the following:

• Treatment offers a standardized dose of allergen that may allow successful treatment of many patients for whom other available treatments were not available or not reimbursed (such as unregulated oral immunotherapy).

• Successful treatment may reduce the potential for morbidity and mortality and improve quality of life.

Peanut (Arachis hypogaea) allergen powder-dnfp is not a curative therapy.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals ages 4 to 17 years with a diagnosis of peanut allergy.

Interventions

The therapy being considered is peanut (Arachis hypogaea) allergen powder-dnfp (defatted, slightly roasted peanut flour with a characterized peanut allergen profile). The oral desensitization immunotherapy approach uses gradually increasing doses of peanut-derived allergen or protein given orally to desensitize patients to peanut over a period of about 6 months. Afterward, patients would continue to take maintenance doses in order to maintain desensitization.

Comparators

The following practice is currently being used to treat peanut allergy: allergen avoidance and medical management in case of exposure.

Outcomes

The general outcomes of interest are symptoms, quality of life, hospitalization, medication use, treatment-related mortality, and treatment-related morbidity. Details of these outcome measures are summarized in Table 2.

The primary efficacy outcome measure used in trials was the proportion of patients who were desensitized based on the oral food challenge (OFC) test at the entry and exit of the study. While the precise definition of desensitization was different in different trials, desensitization implies that patients who elicited an allergic response (subjective or objective) to a lower dose at study entry did not elicit an allergic response at a higher threshold at study exit. In order to maintain desensitization, individuals must continue ongoing therapy with a maintenance dose of peanut allergen indefinitely. There is no standard eliciting or tolerated dose that defines desensitization. Tolerance is defined when an individual no longer has allergic symptoms when eating peanut-containing food or during an OFC, months to years after any treatment has stopped.

Desensitization is an intermediate outcome measure. While it can be hypothesized that a desensitized individual may be less likely to react to accidental exposure to peanut protein with ongoing treatment, it is not yet definitively known whether desensitization can protect patients from real-world accidental exposures (e.g. prevent allergic reactions, hospitalization, or death). Direct evidence linking desensitization thresholds to precise clinical outcomes is not available and it is not known whether increasing the eliciting threshold in a graded OFC results in a reduction in peanut-induced allergic reactions. The pivotal trial for peanut (Arachis hypogaea) allergen powder-dnfp has a total follow-up of 1 year from dose initiation to assess the rates of desensitization. To fully assess the impact of desensitization on precise clinical outcomes, patients need to be followed up for a period of 3 to 5 years in real-world settings.

Table 2. Health Outcome Measures Relevant to Treatment for Peanut Allergy

ER: emergency room.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

The clinical development program of peanut (Arachis hypogaea) allergen powder-dnfp for individuals with peanut allergy includes multiple RCTs and open-label double- and single-arm trials that are summarized in Table 3. Results of 2 pivotal phase 3 RCTs [Peanut Allergy Oral Immunotherapy Study for Desensitization (PALISADE) and AR101 Trial in Europe Measuring Oral Immunotherapy Success (ARTEMIS)], the phase 3 Real-World AR101 Market-Supporting Experience Study (RAMSES), 1 phase 2 RCT (ARC001), 1 long-term efficacy and safety follow-on study (ARC004), and 1 subgroup analysis of the follow-on study have been published. In addition, 2 studies combining safety data from multiple clinical development program trials have been published.

Table 3. Summary of the Clinical Development Program for Peanut (Arachis hypogaea) Allergen Powder-dnfp

DBRCT: double-blind randomized controlled trial; NCT: national clinical trial.

Randomized Controlled Trials

Trial characteristics and results of the pivotal phase 3 PALISADE and ARTEMIS trials as well as the RAMSES phase 3 trial are summarized in Tables 4 to 6, respectively. The primary outcome of the PALISADE trial was the proportion of participants 4 to 17 years of age who could ingest 600 mg or more of peanut protein without dose-limiting symptoms in a food challenge after approximately 1-year follow-up (referred to as desensitization earlier). Note that the 600 mg dose is an exception from the practical allergy (PRACTALL) OFC dose escalation protocol, which increases as follows: 3, 10, 30, 100, 300, 1000, and 3000 mg. The PRACTALL OFC dose escalation protocol is a standardized protocol developed by the American Academy of Allergy, Asthma & Immunology and the European Academy of Allergy and Clinical Immunology.^33, The trial protocol encouraged participants to take their maintenance dose with a meal at roughly the same time each day (within a 4-hour period), to refrain from activities that can increase allergic reactivity (exercise, hot showers, or baths) within 3 hours of taking the dose, and not to go to sleep within 2 hours of taking the dose. The primary outcome was the proportion of participants who could ingest 600 mg or more of peanut protein without dose-limiting symptoms in a food challenge referred to as desensitization. At the end of 1-year follow-up, 67.2% of the peanut (Arachis hypogaea) allergen powder-dnfp treated patients met the desensitization criteria compared to 4.0% in the placebo group (between-group difference 63.2%, 95% confidence interval [CI] 53.0% to 73.3%, p<.001). The median overall exposure was 330.5 days (range, 1 to 485 days) for the peanut (Arachis hypogaea) allergen powder-dnfp group and 328.0 days (range, 1 to 414 days) for the placebo.

Adverse events were graded using the National Cancer Institute Common Toxicity Criteria. Treatment with peanut (Arachis hypogaea) allergen powder-dnfp was associated with adverse events that occurred with greater frequency and severity. The rates of serious adverse events (2.2% vs. 0.8%), systemic allergic reactions (14.2% vs. 3.2%), and use of epinephrine outside of a food challenge test (14.0% vs. 6.5%) were more common in the peanut (Arachis hypogaea) allergen powder-dnfp group versus placebo. Use of epinephrine was based on the discretion of the patient or caregiver. In the peanut (Arachis hypogaea) allergen powder-dnfp group, 67% of epinephrine doses were administered at home. Withdrawal due to adverse events was more common in the active treatment group (11.6% vs. 2.4%) as was the overall withdrawal rate from the study (21.0% vs. 7.3%). Adverse event rates during the maintenance phase, which may reflect rates during long-term follow-up, remained high. For example, abdominal pain (15% peanut [Arachis hypogaea] allergen powder-dnfp vs. 6%), and vomiting (16% peanut [Arachis hypogaea] allergen powder-dnfp vs. 12%) remained common and higher in the peanut (Arachis hypogaea) allergen powder-dnfp group. This was also true for systemic allergic reactions (8.7% peanut [Arachis hypogaea] allergen powder-dnfp vs. 1.7%) during the maintenance phase.

The primary outcome of the ARTEMIS trial was the proportion of patients 4 to 17 years of age who tolerated 1000 mg peanut protein as a single dose with no dose-limiting symptoms at the exit food challenge.^32, Compared with PALISADE, the ARTEMIS trial had a shorter treatment duration and a higher primary outcome, with the intent to examine desensitization to peanut over a shorter time course, with a more inclusive patient population. Results revealed that 58% of patients in the peanut (Arachis hypogaea) allergen powder-dnfp group met the primary endpoint versus 2% of patients in the placebo group (between-group difference 56%, 95% CI 44.1% to 65.2%, p<.0001) in an intention to treat analysis. The cumulative exposure to the trial regimen was 89.78 years in the peanut (Arachis hypogaea) allergen powder-dnfp group and 31.07 years in the placebo group. In the safety analysis, 130 (99%) of 132 patients in the peanut (Arachis hypogaea) allergen powder-dnfp group and 42 (98%) of 43 patients in the placebo group had 1 or more treatment-emergent adverse events during the intervention period, with nearly all events mild or moderate in severity. No patient had an unexpected serious adverse reaction or an adverse event that was fatal or considered to be life-threatening. Gastrointestinal disorders occurred more frequently among participants in the peanut (Arachis hypogaea) allergen powder-dnfp group as compared to placebo (91% vs. 77%). No cases of eosinophilic esophagitis were reported in ARTEMIS, which is unlike previous trials involving food oral immunotherapy. However, patients with a history of eosinophilic gastrointestinal diseases, or chronic or recurrent gastrointestinal symptoms, were excluded from the ARTEMIS trial and no patient underwent an elective endoscopy. With regard to food allergy-related quality of life, certain subjects in the peanut (Arachis hypogaea) allergen powder-dnfp group reported improvements that exceeded the minimum clinically important difference between the 2 groups across all Food Allergy Quality of Life Questionnaire (FAQLQ) domains and Food Allergy Independent Measure (FAIM) domains related to the perceived likelihood and outcomes of a severe allergic reaction.

The RAMSES phase 3 trial was designed to evaluate the safety and tolerability of peanut allergen powder-dnfp in patients who had not undergone a screening food challenge in order to demonstrate a more "real world" setting than the ARTEMIS and PALISADE trials where a positive screening food challenge was required for inclusion.^31, The RAMSES trial, along with its open-label extension study (ARC011), found similar safety results as the ARTEMIS and PALISADE trials.

The phase 2 ARC001 RCT^26, enrolled a slightly different population and used a different primary outcome than reported in the PALISADE AND ARTEMIS trials. Therefore, detailed results of this trial are not summarized in this report. ARC001 enrolled 55 participants ages 4 to 26 years, but unlike the PALISADE trial there were no separate analyses reported for those age 4 to 17 years and the proportion of study participants over the age of 17 was not reported. The primary outcome in ARC001 was ability to tolerate at least 300 mg of peanut protein during a double-blind, placebo-controlled food challenge. This differs from the PALISADE and ARTEMIS trials, which required the ability to tolerate 600 and 1000 mg of peanut protein, respectively. In addition, in ARC001 the exit food challenge was performed after 2 weeks on the target daily maintenance dose of 300 mg of peanut protein rather than the 24 weeks of maintenance dosing in the PALISADE trial and 3 months in the ARTEMIS trial. Of the individuals treated with peanut (Arachis hypogaea) allergen powder-dnfp, 79% (23/29) were able to tolerate 300 mg of peanut protein compared with 19% (5/26) of participants randomized to placebo (oat protein).

Table 4. Summary of Trial Characteristics of Key Randomized Trials of Peanut (Arachis hypogaea) Allergen Powder-dnfp

DBPCFC: double-blind placebo-controlled food challenge; kUA: allergen specific unit; L: liter; psIgE: serum peanut-specific immunoglobulin E; SPT: peanut skin prick test.a Of a total of 555 patients randomized, primary analysis was conducted on 499 patients age 4 to 17 years of whom 3 were excluded because they did not receive any trial medications.b History of cardiovascular disease (including uncontrolled or inadequately controlled hypertension), severe or life-threatening episode of anaphylaxis or anaphylactic shock within 60 days of screening DBPCFC, eosinophilic esophagitis, other eosinophilic gastrointestinal disease, gastroesophageal reflux disease, or other gastrointestinal symptoms of undiagnosed etiology, unstable chronic disease (other than asthma, atopic dermatitis, or allergic rhinitis), mast cell disorder (including mastocytosis, urtictimes pigmentosa and hereditary or idiopathic angioedema); dose-limiting reactions to placebo part of screening DBPCFC.c With a characterized peanut allergen profile.d Any severe or life-threatening episodes of anaphylaxis within 60 days of the screening DBPCFC, severe or uncontrolled asthma, a history of eosinophilic esophagitis, or chronic, recurrent, or severe gastrointestinal symptoms with an undiagnosed cause.

Table 5. Summary of Efficacy Results of Key Randomized Trials of Peanut (Arachis hypogaea) Allergen Powder-dnfp

CI: confidence interval; IDE: initial dose escalation; NR: not reported; SAR: systemic allergic reaction.a Primary endpoint: ability to ingest a single dose of at least 600 mg of peanut protein (cumulative dose, ≥1043 mg) during the exit food challenge, with no dose-limiting symptoms, according to the judgment of the investigator.b Key secondary endpoints (reported here in hierarchical order): 1) % of participants who could tolerate single doses of 300 mg and 1000 mg at the exit food challenge; 2) Maximum severity of symptoms that occurred at any dose level of peanut protein during the exit food challenge.c Fewer patients in the placebo group versus peanut (Arachis hypogaea) allergen powder-dnfp tolerated more than 100 mg of peanut protein. The number of patients who attempted the 300 mg, 600 mg, and 1000 mg food challenge dose in the placebo arm was 33, 12, and 5 compared to 291, 285, and 250, respectively, in the peanut (Arachis hypogaea) allergen powder-dnfp group.d Primary endpoint: ability to ingest a single dose of 1000 mg of peanut protein (cumulative dose, ≥2043 mg) during the exit food challenge, with non dose-limiting symptoms.e Key secondary endpoints (reported here in hierarchical order): 1) % of participants who could tolerate single doses of 600 mg and 300 mg at the exit food challenge; 2) Maximum severity of symptoms that occurred at any dose level of peanut protein during the exit food challenge. f Complied RAMSES and ARC011 safety data.

Table 6. Summary of Anaphylaxis and Treatment Discontinuation in Key Randomized Trials of Peanut (Arachis hypogaea) Allergen Powder-dnfp

a Time to onset of anaphylaxis occurred within 2 hours after dosing in 70% of reactions, greater than 2 hours and up to 10 hours in 18% of reactions, and greater than 10 hours in 12% of reactions among peanut (Arachis hypogaea) allergen powder-dnfp treated subjects.

The purpose of the limitations tables (Tables 7 and 8) is to display notable limitations identified in each study. Key limitations in study relevance included the intended use for the population was unclear, key health outcomes were not addressed, and the existence of an insufficient duration for the evaluation of benefits and harms. Key limitations in study design and conduct included the potential for partial unblinding due to adverse events (selective outcomes such as safety, adherence, epinephrine use assessed/documented by the treating physician).

Patient-centric clinical and humanistic outcomes such as reduction in the frequency and/or severity of allergic or anaphylactic symptoms in day-to-day life, reduction in parental or patient time off from work/school, expanded activities for children, reduction in resource utilization and increased quality of life have not been reported. This is a critical limitation given that treatment imposes a significant time burden (requiring more than 12 office visits and restrictions on the timing of dose administration) and adverse events burden (higher overall withdrawal rate, withdrawal due to adverse events, systemic allergic reactions, and the use of epinephrine). Clinical utility of food challenge studies in predicting a patient’s future risk and frequency of allergic reactions to peanut outside the clinic setting has not been demonstrated.^35,36,19, Further, the severity of allergic reaction elicited during an OFC test does not predict the severity of the next.^37,38,36, Multiple organizations such as GRADE, the National Institute of Allergy and Infectious Diseases, U.S. Food and Drug Administration, and World Allergy Organization recommend evaluation of patient-centered outcomes, such as a risk and rate of allergic and anaphylactic reactions as primary measures to estimate health benefits and harms of interventions for IgE-mediated food allergies.^39,35,40,41,

Based on the current evidence, limited conclusions can be drawn regarding the long-term efficacy and safety of peanut (Arachis hypogaea) allergen powder-dnfp. The primary outcome of desensitization was evaluated after 6 months or less of the maintenance regimen. It is unclear if the high rates of desensitization observed in the PALISADE and ARTEMIS trials can be replicated in the real-world setting. Non-adherence to treatment can lead to diminished desensitization or being less careful about peanut avoidance, which can increase the potential for a serious allergic or anaphylactic reaction to therapy or accidental environmental exposure. Safety issues, particularly the incidence of gastrointestinal symptoms including eosinophilic esophagitis have also not been well characterized in the individual trials.

The limitation “intended use for population is unclear” incorporates the element of how generalizable the results of a clinical trial are to the real-world (external validity) as well as an assessment of the appropriateness of the patient population enrolled in the clinical trial. Individuals in the PALISADE and ARTEMIS trials were selected on the basis of their sensitivity in an OFC test. Oral food challenge studies for peanut are not routinely performed in a clinical setting because they are considered high-risk and can result in severe symptoms including anaphylaxis. Further, patients in the PALISADE trial were selected on the basis of their sensitivity to no more than 100 mg of peanut protein which may not be representative of persons with peanut allergy in the real-world, 50% of whom have a reaction to doses above 100 mg.^42, It is unclear if patients in the real-world will achieve the magnitude of desensitization observed in clinical trials as patient selection for treatment will not be based on the results of an OFC test but rather on the history of an allergic reaction, skin prick test, and serum peanut-specific IgE levels. The RAMSES trial intended to include a more "real world" population by excluding the oral food challenge as a requirement for inclusion; however, the follow-up period is limited and long-term safety and efficacy results are lacking.^31,

Table 7. Study Relevance Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other.c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 8. Study Design and Conduct Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other.b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other.c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other.d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other.e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other.f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.

PALISADE follow-on study (ARC004)

Vickery et al (2021) published results from an open-label follow-on study (ARC004) to the PALISADE trial that evaluated the safety and tolerability of daily and nondaily peanut (Arachis hypogaea) allergen powder-dnfp maintenance regimens, the efficacy of different regimens with a double-blind, placebo-controlled food challenge of up to a single 2000 mg dose (cumulative dose, 4034 mg) of peanut protein, and the long-term immunologic effects of peanut (Arachis hypogaea) allergen powder-dnfp.^29, Of the 409 subjects (4 to 17 years of age) who completed the PALISADE trial, 358 entered the ARC004 trial. Of these, 102 subjects were peanut (Arachis hypogaea) allergen powder-dnfp-naive and 256 continued peanut (Arachis hypogaea) allergen powder-dnfp treatment. Those patients who were continuing on active treatment from the PALISADE trial were assigned to receive daily or non-daily dosing regimens while those who were treatment-naive were escalated to a 300 mg/day dose of peanut (Arachis hypogaea) allergen powder-dnfp followed by maintenance dosing. Among those patients continuing on peanut (Arachis hypogaea) allergen powder-dnfp treatment, the exposure-adjusted event rates were 12.94 to 17.54/participant-year and 25.95 to 42.49/participant-year in daily and non-daily dosing cohorts, respectively. The vast majority of individuals experienced adverse events that were mild or moderate in severity. Desensitization rates appeared to be improved in those patients receiving daily versus non-daily peanut (Arachis hypogaea) allergen powder-dnfp dosing, with cohort 3A (daily dosing for approximately 56 weeks) having the highest desensitization rates. Additionally, ongoing immunomodulation with continued peanut (Arachis hypogaea) allergen powder-dnfp therapy was demonstrated by changes in immune markers. Peanut (Arachis hypogaea) allergen powder-dnfp-naive patients experienced outcomes mirroring those observed in the active arm of the PALISADE trial. The open-label design of this trial resulted in the study being underpowered to detect significant differences between groups or cohorts; data were evaluated using descriptive statistics only.

Fernandez-Rivas et al (2022) reported a subgroup analysis of ARC004 that included 142 study participants 4 to 17 years of age from the 300 mg daily dose cohorts and included some limited quality of life evidence.^43, Food allergy-related quality of life was assessed using FAQLQ and FAIM scales at time of entry into the PALISADE trial and at exit from the ARC004 study. Self-assessed FAQLQ scores generally decreased (indicating improvement) from PALISADE entry to ARC004 exit in 8 to 17 year old participants while changes in parent-assessed scores for children under age 8 were less consistent over time, as were changes in FAIM scores. The analysis of food allergy-related quality of life was exploratory and limited to a small subset of study participants; therefore, no definitive conclusions can be drawn regarding the the effect of peanut (Arachis hypogaea) allergen powder-dnfp on food allergy-related quality of life based on this evidence. Other measures of quality of life were not reported.

Adverse events

Adverse events and safety issues were not well characterized in the PALISADE and ARTEMIS trials. Brown et al (2022)^30, reported combined safety data from the PALISADE, ARTEMIS, and RAMSES (see Table 4) trials, and from the open-label ARC004 (PALISADES follow-on) and ARC011 (RAMSES extension) studies. Among 944 study participants age 4 to 17 years who received at least 1 dose of peanut (Arachis hypogaea) allergen powder-dnfp, 829 (87.8%) experienced a treatment-related adverse event, including 24 participants (2.5%) who experienced a serious treatment-related adverse event. Eighty participants (9.5%) discontinued treatment due to adverse events, and 10 participants (1.1%) experienced anaphylaxis. When compared with placebo, the adverse event rate was 11.8% (99/841) in the peanut (Arachis hypogaea) allergen powder-dnfp group and 2.4% (8/335) in the placebo group. Systemic allergic reactions requiring the use of epinephrine ranged from 3.7% to 6.1% in the peanut (Arachis hypogaea) allergen powder-dnfp arms and 0 to 2.7% in the placebo arms.

A case series by Nilsson et al (2021) reported the incidence of endoscopically-confirmed eosinophilic esophagitis among 1217 participants enrolled in the peanut (Arachis hypogaea) allergen powder-dnfp clinical development program.^27, Among the participants, there were 62 withdrawals due to gastrointestinal symptoms. Another 28 participants were referred for gastroenterology evaluation, and 17 participants underwent esophagogastroduodenoscopy. Eosinophilic esophagitis was confirmed in 12 of these participants, resulting in an incidence of 0.99%. All but one of the confirmed cases occurred in children and adolescents, all had comorbid allergic diseases (generally asthma and/or allergic rhinitis), and all received pharmacotherapy for treatment of eosinophilic esophagitis. Follow-up biopsy results were available for 7 participants, 5 of whom had endoscopic findings consistent with resolution of eosinophilic esophagitis.

Systematic Reviews

Systematic reviews that address important health outcomes not adequately addressed in the trials conducted as part of the peanut (Arachis hypogaea) allergen powder-dnfp clinical development program are discussed below. A limitation of this evidence is the inclusion of studies in the reviews that utilized different peanut oral immunotherapy preparations and treatment protocols than those used for the peanut (Arachis hypogaea) allergen powder-dnfp clinical development program.

Chu et al (2019) reported the findings of a systematic review that included 1041 participants (median age 8.7 years [interquartile range 5.9 to 11.2]) across 12 RCTs of peanut oral immunotherapy.^19, The review included results from the PALISADE trial, which accounted for about half of the total population and 4 of the included trials (including PALISADE) utilized proprietary immunotherapy preparations. Participants in the oral immunotherapy groups in these trials were given increasing doses of peanuts on a daily basis until they reached a maintenance dose. The median starting dose of peanut protein was 0.5 mg and the median maintenance dose was 2000 mg (equivalent to about 4 peanuts). A patient-centered endpoint of peanut-induced anaphylaxis that included events as a result of unplanned exposure to peanuts or as a result of oral immunotherapy itself was used. Anaphylaxis was defined as 2 or more organ system involvement after possible allergen exposure or isolated hypotension with known allergen exposure, per National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network criteria.^44, This endpoint potentially provides a better summary of a patient’s experience in day-to-day living compared to a single oral peanut challenge.^45, Results showed that oral immunotherapy increased the risk of anaphylaxis by 3-fold (relative risk 3.12 [95% CI 1.76 to 5.55]). This contrasts with passing an oral peanut challenge, which was much more probable with oral immunotherapy (relative risk 12.4 [95% CI 6.82 to 22.61]). In the meta-analysis, quality of life was not improved by oral immunotherapy in the 4 of 12 studies that reported assessments (relative risk 1.21 [95% CI 0.87 to 1.69]). As the meta-analysis pooled data from studies of heterogenous peanut oral immunotherapy preparations and treatment protocols, the characterization of safety endpoints remains incomplete.

Section Summary: Peanut (Arachis hypogaea) Allergen Powder-dnfp

The PALISADE trial demonstrated that peanut (Arachis hypogaea) allergen powder-dnfp increased the percentage of patients who could tolerate a 600 mg dose of peanut protein (the equivalent of approximately 2 whole peanut kernels) in a double-blind, placebo-controlled food challenge (67.2% vs. 4.0%, p<.001). All participants could tolerate no more than 30 mg of peanut protein (equivalent of one-tenth of 1 peanut kernel) prior to the treatment. However, there were significantly higher rates of gastrointestinal side effects, systemic allergic reactions, and epinephrine use in the peanut (Arachis hypogaea) allergen powder-dnfp group. Results from the ARTEMIS trial similarly revealed that peanut (Arachis hypogaea) allergen powder-dnfp significantly increased the percentage of patients who could tolerate an even higher dose of peanut protein of 1000 mg as compared to placebo (58% vs. 2%, p<.0001). Additionally, 99% of patients in the peanut (Arachis hypogaea) allergen powder-dnfp group and 98% of patients in the placebo group experienced 1 or more treatment-emergent adverse events; nearly all were mild or moderate in severity. Gastrointestinal disorders occurred more frequently among participants in the peanut (Arachis hypogaea) allergen powder-dnfp group as compared to placebo (91% vs. 77%). With regard to quality of life, certain subjects in the peanut (Arachis hypogaea) allergen powder-dnfp group reported improvements that exceeded the minimum clinically important difference between the 2 groups across various domains. Peanut (Arachis hypogaea) allergen powder-dnfp requires a substantial investment in time for patients (at least 12 office visits over the initial 24 weeks with in-office observation for at least 90 minutes) and continued consumption of peanut (Arachis hypogaea) allergen powder-dnfp to maintain desensitization. Notable limitations in study relevance included the intended use for the population was unclear, key health outcomes were not addressed, and the existence of an insufficient duration for the evaluation of benefits and harms. Key limitations in study design and conduct included the potential for partial unblinding due to adverse events, which can potentially bias outcomes such as safety, adherence, and epinephrine use, which were assessed/documented by the treating physician. The RAMSES phase 3 trial was designed to evaluate the safety and tolerability of peanut allergen powder-dnfp in patients who had not undergone a screening food challenge in order to demonstrate a more "real world" setting than the ARTEMIS and PALISADE trials where a positive screening food challenge was required for inclusion. The RAMSES trial found safety results similar to the ARTEMIS and PALISADE trials; however, the follow-up period is limited and long-term safety and efficacy results are lacking.

For individuals who are peanut-allergic children and adolescents ages 4 to 17 who receive peanut (Arachis hypogaea) allergen powder-dnfp, the evidence includes 2 pivotal double-blind, randomized, placebo-controlled trials (PALISADE and ARTEMIS), and an open-label extension study of the PALISADE trial. Relevant outcomes are symptoms, quality of life, hospitalizations, medication use, and treatment-related mortality and morbidity. In the PALISADE trial, 555 patients aged 4 to 55 years were randomized to peanut (Arachis hypogaea) allergen powder-dnfp (n=416) or placebo (n=139). A subset of 499 patients 4 to 17 years of age were used for the primary analysis. The primary outcome was the difference in the proportion of participants who could ingest 600 mg or more of peanut protein without dose-limiting symptoms in a food challenge after approximately 1-year follow-up between the treatment and placebo arm. The percentage of patients who met the primary endpoint at exit food challenge test was 67.2% versus 4.0% (difference 63.2%; 95% CI, 53.0 to 73.3; p<.001) in the treatment arm versus placebo, respectively. Adverse events occurred with greater frequency and severity in peanut (Arachis hypogaea) allergen powder-dnfp treated individuals versus placebo: serious adverse events (2.2% vs. 0.8%), systemic allergic reactions (14.2% vs. 3.2%), use of epinephrine outside of the food challenge test (14.0% vs. 6.5%), withdrawal due to adverse events (11.6% vs. 2.4%), and overall withdrawal rate (21.0% vs. 7.3%). In the ARTEMIS trial, similar results revealed that peanut (Arachis hypogaea) allergen powder-dnfp significantly increased the percentage of patients who could tolerate an even higher dose of peanut protein of 1000 mg as compared to placebo (58% vs. 2%, p<.0001). Additionally, 99% of patients in the peanut (Arachis hypogaea) allergen powder-dnfp group and 98% of patients in the placebo group experienced 1 or more treatment-emergent adverse events, with the majority of events being mild or moderate in severity. Gastrointestinal disorders occurred more frequently among the peanut (Arachis hypogaea) allergen powder-dnfp participants as compared to placebo (91% vs. 77%). Additionally, certain subjects in the peanut (Arachis hypogaea) allergen powder-dnfp group reported quality of life improvements that exceeded the minimum clinically important difference between the 2 groups across various domains. Notable study relevance limitations included the intended use for the population was unclear, key health outcomes were not addressed, insufficient assessment of harms, and the existence of an insufficient duration for the evaluation of benefits and harms. Key limitations in study design and conduct included the potential for partial unblinding due to adverse events (outcome assessed by treating physician).The RAMSES phase 3 trial was designed to evaluate the safety and tolerability of peanut allergen powder-dnfp in patients who had not undergone a screening food challenge in order to demonstrate a more "real world" setting than the ARTEMIS and PALISADE trials that required a positive screening food challenge for inclusion. The RAMSES trial found safety results similar to the ARTEMIS and PALISADE trials; however, the follow-up period is limited and long-term safety and efficacy results are lacking. There is need for more data to demonstrate that desensitization leads to reduced reactions to accidental exposure to peanuts and improved quality of life. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

Institute for Clinical and Economic Review

In 2019,the Institute for Clinical and Economic Review assessed the comparative clinical effectiveness and value of oral immunotherapy [peanut (Arachis hypogaea) allergen powder-dnfp] and Viaskin Peanut for peanut allergy.^46, The authors concluded, "The substantial increase in patients treated with peanut (Arachis hypogaea) allergen powder-dnfp who are able to tolerate 600 mg of peanut protein during an OFC compared with those treated with placebo (67.2% vs. 4.0%) is balanced by a significant increase in gastrointestinal symptoms, systemic allergic reactions, and epinephrine use. The net health benefits of peanut (Arachis hypogaea) allergen powder-dnfp will be driven by changes in quality of life and reductions in reactions to accidental exposure to peanuts, neither of which has been demonstrated. Thus, there is only moderate certainty of a comparable, small, or substantial net health benefit and a small (but non-zero) likelihood of a negative net health benefit for peanut (Arachis hypogaea) allergen powder-dnfp compared with strict avoidance and rapid use of epinephrine (P/I, promising, but inconclusive). Given the need for frequent visits to doctors during the dose escalation phase and the frequent adverse events, it will be important to ensure that patients receive adequate informed consent and that their preferences are carefully elicited prior to initiating desensitization therapy with peanut (Arachis hypogaea) allergen powder-dnfp".

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this review are listed in Table 9.

Table 9. Summary of Key Trials

NCT: national clinical trial.a Denotes industry-sponsored or cosponsored trial.

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Policy History