Zavegepant intranasal spray for the Acute Treatment of Migraine : A Systematic Review and Meta-Analysis of Randomized Clinical Trials

doi:10.21203/rs.3.rs-3215981/v1

Download PDF

Systematic Review

Zavegepant intranasal spray for the Acute Treatment of Migraine : A Systematic Review and Meta-Analysis of Randomized Clinical Trials

https://doi.org/10.21203/rs.3.rs-3215981/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Migraine is a prevalent and debilitating primary headache disorder with significant socio-economic and personal impacts. This study aims to evaluate the safety and efficacy of zavegepant, a recently approved third-generation small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist nasal spray (BHV-3500), ), to be administered as a nasal spray in the acute treatment of migraine attacks. A search was conducted across multiple databases, to identify relevant randomized clinical trials (RCTs). After the study selection process, 2 RCTs (involving 2850 participants) and an additional trial for qualitative synthesis were included for analysis. The primary efficacy outcome assessed was freedom from pain at 2 hours post-dose, which showed a significantly higher likelihood in the zavegepant 10 mg group compared to the placebo group (RR 1.54, 95% CI 1.28 to 1.84). Additionally, zavegepant 10 mg demonstrated superior freedom from the most bothersome symptoms (MBS) at 2 hours post-dose compared to placebo (RR 1.26, 95% CI 1.13 to 1.42). Safety outcomes were evaluated based on adverse events (AEs), with the zavegepant 10 mg group experiencing a higher incidence of AEs compared to placebo (RR 1.78, 95% CI 1.5 to 2.12). Dysgeusia was the most commonly reported AE in the zavegepant group (RR 4.18, 95% CI 3.05 to 5.72). zavegepant effectively relieved pain and bothersome symptoms at 2 hours post-dose, however, it was associated with a higher incidence of adverse events, predominantly dysgeusia. In conclusion, while further research and clinical trials are needed to evaluate the long-term effectiveness and safety of zavegepant in diverse patient populations, the analyzed trials provide compelling evidence that zavegepant is a potentially effective acute treatment for migraine.

Neurology

Zavegepant

BHV-3500

Migraine

Acute migraine treatment

Intranasal

Nasal spray

Migraine is a chronic, inherited, and debilitating multi-phasic neurovascular disorder with distinct characteristics of moderate to severe headache, sensory disturbances, gastrointestinal symptoms, in addition to autonomic, cognitive, and other symptomatology. Numerous epidemiological studies have highlighted its widespread prevalence as well as the socio-economic and personal ramifications (1). In the Global Burden of Disease Study 2019 (GBD2019), migraine was responsible for 42.1 million years lost to disability, or 4.8% of total years lost to disability in 2019. Migraine headache makes up 88.2% of the burden of headache disorders (2) and impacts usual daily activities including work, school, or social activities as individuals with migraine might be severely impaired during an acute attack (3).

The discovery of the important role calcitonin gene-related peptide (CGRP) plays in the pathophysiology of migraine (4–6) has led to novel advances in migraine specific acute and preventive pharmacological interventions. Several research studies have shown that the activation of the trigeminovascular system is characterized by an elevation of CGRP in the jugular venous blood (4, 5). This elevation in CGRP typically returns to normal upon successful treatment (6). As a result of these observations, the development of CGRP receptor antagonists, known as gepants has been pursued as a therapeutic approach for migraine. While several earlier compounds have been halted in development, such as telcagepant, large, multi-site, randomized placebo-controlled clinical trials support the efficacy and safety of both ubrogepant and rimegepant for the acute treatment of migraine attacks (7). Zavegepant, a third generation small-molecule CGRP receptor antagonist, is the first intranasally administered option and was recently approved by the FDA. This highly selective and potent competitive CGRP receptor antagonist possesses remarkable aqueous solubility, making it suitable for nasal delivery, and demonstrates excellent oxidative stability (8). The primary efficacy outcomes of interest include pain freedom and freedom from the most bothersome symptom, both measured after 2 hours of treatment. Secondary outcomes will focus on pain relief, the ability to function normally, freedom from photophobia, phonophobia, and nausea. Safety outcomes will be evaluated in terms of Adverse Events (AE). The findings of this review will provide clinicians, researchers, and policymakers with valuable insights into the clinical effectiveness of zavegepant intranasal spray in the acute treatment of migraine.

Search strategy

A careful search was conducted in multiple electronic databases, including PubMed, EMBASE, Scopus, Cochrane, and the US National Library of Medicine Clinical Trials (clinicaltrials.gov) from the earliest available date to 26/06/2023. The search strategy employed consistent and predefined terms to identify relevant studies. The query/terms used were as follows: ((Zavegepant) OR (BHV-3500)) AND (Migraine) (Supplementary Table 1). The search strategy was peer review according to the Peer Review of Electronic Search Strategies checklist (9).

Study selection

Only randomized clinical trials (RCTs) were included in the meta-analysis to ensure robustness and strength of the evidence. Studies eligible for inclusion reported the efficacy and safety profile of zavegepant specifically in individuals with migraine (with and without aura) according to the International Classification of Headache Disorders, 3rd edition (10). Animal studies and other non-RCT study designs were excluded from the analysis.

Two independent reviewers screened the articles, and extracted data. Any conflicts or disagreements were resolved by a third reviewer. Throughout the study selection process, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed (Fig. 1) and was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42023440683. After the study selection phase, relevant information regarding the safety and efficacy outcomes of zavegepant in the acute treatment of migraines was extracted in a spreadsheet for analysis. A total of 20 abstracts were screened and 3 articles were examined in their entirety to be included in the systematic review after meeting the pre-established inclusion criteria.

The co-primary outcomes of interest included the efficacy of zavegepant nasal spray in ameliorating symptoms of migraine as measured by freedom from pain at 2 hours post dose administration and freedom from the most bothersome symptom (MBS) at 2 hours post dose (12,13 ). Pain freedom was assessed using a four point Likert scale (0 = none, 1 = mild, 2 = moderate, 3 = severe). Freedom from most bothersome symptom was assessed using a binary scale (0 = absent, 1 = present). Subjects were asked to identify their currently most bothersome symptom before taking the study medication. The target study population included male and female subjects with at least a one-year history of migraines (with or without aura), consistent with a diagnosis according to the International Classification of Headache Disorders, 3rd edition, including an age of onset before 50, migraine attacks that lasted 4 to 72 hours, not more than 8 attacks of moderate or severe intensity per month within the last 3 months and not less than 2 attacks per month, willing to give written informed consent and are able to read either English or Spanish. Croop et al. randomized subjects in 3:1 ratio between zavegepant and matching placebo (11), whereas Lipton et al. randomized subjects in 1:1 ratio between the two treatment groups (12). The treatment setting for the subjects included clinics, institutions or private office practices. Subjects were also recruited through a variety of sources, including referrals from physicians and other health care professionals. The treatment phase lasted up to 45 days and subjects who had headache pain reduced to a mild intensity or pain free intensity level were considered to have achieved pain relief.

Tabulations of demographic and baseline characteristics were made. Both co-primary endpoints were evaluated using Cochran-Mantel Haenszel methodology to estimate the common risk difference, and stratified by the use of prophylactic migraine medication (yes or no). These tests were conducted using the mITT (modified Intention to Treat) subjects, with missing data at two hours imputed to be failure (12, 13).

Data analysis

Data analysis was done using the R software (Version 4.3.0). A fixed effects or random effects model was used depending on the heterogeneity among the included studies, the Random Effects Model or the Common Effects Model was primarily employed. Relative risks were calculated using the raw event data extracted from the trials. Forest plots were generated to visualize and summarize the relative risks of the outcomes of interest. Heterogeneity was assessed using I², and tau-squared. Publication bias could not be assessed due to less studies.

Risk of Bias Assessment:

The potential risk of bias in the included trials was evaluated using the RoB 2.0 tool developed by the Cochrane Collaboration (Supplementary Table 2) (Supplementary Fig. 1). This tool provides a structured approach to evaluate the risk of bias across multiple domains. Two authors independently assessed the methodological quality of the included trials to determine any risk of bias and any discrepancies were resolved through discussion.

Study selection

Following a preliminary search across several databases, 171 records in total were retrieved. After eliminating 83 duplicates, we screened 88 articles for title and abstract. 30 papers were selected for full-text screening from the initial set of articles. Following the exclusion of the 23 articles for the various reasons indicated in the PRISMA flow chart, only 3 papers remained, where 2 trials were included for quantitative analysis and 1 for qualitative description (11–13). Both the studies were randomized clinical trials (RCTs) (11, 12). The details of the PRISMA flow chart are given in (Fig. 1).

Study population

A total of 2850 participants were involved in the included studies. They were split into two groups, one receiving the medication zavegepant and the other a placebo. The female participants (2403, 84.32% vs 447, 15.68%) constituted the majority of the population. Croop et al. (11) divided the participants receiving zavegepant in terms of the dose (5mg, 10 mg, and 20 mg) whereas Lipton et al. (12) conducted the study with those receiving only 10 mg of zavegepant. The consolidated mean age across the included studies was 40.81 ± 12.96 years (Supplementary Table 3).

Across three trials assessing zavegepant, demographic and population characteristics were recorded, with particular attention given to 10 mg dosage groups. All studies were predominantly composed of female participants, ranging from 81–86%. Racial makeup was mainly white across all studies, with a range of 75.7–83.3%. Black or African American representation was around 15% in each trial, with other races minimally included.

The average participant age was consistently in the early 40s across all studies. Mean heights ranged from 165.3 cm to 166.7 cm, and mean weights from 74.8 kg to 76.5 kg. Body Mass Index (BMI) was comparably consistent, averaging approximately 27 kg/m2 across the studies.

The trials also recorded the use of preventive migraine medication, with the majority of participants (ranging from 86–87.2%) not using such medication. In the study by Lipton et al., 2023, participants recorded a median of 4 moderate to severe migraine attacks per month (12).

Efficacy outcomes

The primary endpoint for the efficacy included freedom from pain at 2 hours post-dose. The pain freedom at 2 hours post-dose was achieved in 23.18% (235/1014) in the zavegepant 10 mg group and 15.10% (158/1047) in the placebo group (Fig. 2). From the pooled data, the zavegepant 10 mg group had a greater likelihood of experiencing pain freedom two hours after the treatment dose (RR 1.54, 95% CI 1.28 to 1.84; n = 2061; I² = 0%) as shown in (Fig. 2). Likewise, after the 2 hours of treatment dose, the zavegepant 10 mg group achieved more freedom from the most bothersome symptoms (MBS) than the placebo group [40.53% (411/1014) vs 32.10% (336/1047), RR 1.26, 95% CI 1.13 to 1.42; n = 2061; I² = 0%] as shown in (Fig. 2)(Table 1).

Table 1

Efficacy outcomes
Outcome	RR	CI	tau²	I²
Pain freedom, 2 h	1.54	1.28–1.84	0	0%
Freedom from MBS, 2 h	1.26	1.13–1.42	0	0%
Pain relief, 2 h	1.16	1.07–1.26	0	0%
Ability to function normally, 2 h	1.34	1.17–1.54	0	0%
Sustained pain relief, 2–24 h	1.22	1.09–1.36	0	0%
Sustained pain relief, 2–48 h	1.22	1.08–1.37	0	0%
Sustained pain freedom, 2–24 h	1.56	1.23–1.99	0	0%
Sustained pain freedom, 2–48 h	1.57	1.22–2.04	0	0%
Freedom from phonophobia, 2 h	1.28	1.11–1.47	0	0%
Freedom from photophobia, 2 h	1.25	1.09–1.42	0	0%
Pain relief, 60 min	1.14	1.03–1.26	0	0%
Ability to function normally, 60 min	1.22	1.01–1.48	0	0%
Pain relief, 30 min	1.38	1.19–1.6	0.01	50%
Ability to function normally, 30 min	1.62	1.17–2.23	0	0%
No rescue medication within 24 h	1.06	1–1.12	0	38%
Freedom from nausea, 2 h	1.04	0.94–1.16	0	0%
No pain relapse, 2–48 h (RE)	1.09	0.75–1.58	0.06	78%
CI: Confidence interval, h: hour, RE: random effects model, RR: Risk ratio

In terms of most other secondary endpoints regarding the efficacy outcomes, the zavegepant 10 mg group was significantly better than the placebo group as shown in Table 1 (Fig. 3–5).

Safety outcomes

The safety outcomes were measured in terms of the adverse events (AE) of the drug (zavegepant) and placebo. Among the participants treated with zavegepant 10 mg and placebo, the common adverse events were dysgeusia (17.79% vs 4.26%), nausea (3.52% vs 0.85%), nasal discomfort (2.74% vs 0.57%), vomiting (1.56% vs 0.28%), and throat irritation (1.17% vs 0.095%). The participants with any AE were more with the zavegepant 10 mg group [ 27.66% (283/1023) vs 15.53% (164/1056, RR 1.78, 95% CI 1.5 to 2.12; n = 2079; I² = 0%] as shown in Table 2. Dysgeusia was the most commonly found adverse event in the zavegepant 10 mg group as compared to the placebo group [17.79% (182/1023) vs 4.26% (45/1056), RR 4.18, 95% CI 3.05 to 5.72; n = 2079; I² = 0%] as shown in Table 2 (Fig. 6). However, the serious AE was similar in both the groups (0.0976% (1/1023) vs 0.0947 (1/1056), RR 1.02, 95% CI 0.06 to 16.3; n = 2079]. The only serious AE reported were thrombosis and vestibular migraine in the zavegepant 10 mg and placebo groups, respectively. In the trial NCT04408794 (13), zavegepant 10 mg was administered. Dysgeusia [39.14% (236/603)], Nasal discomfort [10.28% (62/603)], Nasal congestion [5.47% (33/603)], Throat irritation [5.47% (33/603)], Nausea [6.14% (37/603)] and Back pain [5.47% (33/603)] were the most reported adverse events (Table 2).

Table 2

Safety outcomes
Outcome	RR	CI	tau²	I²
Any AE	1.78	1.5–2.12	0	0%
Serious AE	1.02	0.06–16.3	-	-
Dysgeusia	4.18	3.05–5.72	0	0%
Nausea	4.13	2–8.54	0.14	27%
Nasal discomfort	4.83	2.01–11.61	0	0%
Vomiting	5.51	1.61–18.85	0	0%
Throat irritation	8.61	1.59–46.72	0	0%
CI: Confidence interval, RR: Risk ratio

Risk of bias analysis

Among the trials included, the two RCTs by Croop et al. and Lipton et al. exhibited low risk of bias based on the assessment using the RoB 2.0 tool. These trials demonstrated robust methodological quality, with careful consideration of potential sources of bias throughout the study design and execution. In contrast, the risk of bias assessment for the third trial included in the review resulted in an unclear classification. Insufficient information was available to make a definitive judgment regarding the risk of bias in this trial. Further details of the assessment of the risk of bias is provided in the (Supplementary Table 2).

This systematic review and meta analysis was performed to analyze the efficacy and safety of Zavegepant nasal spray for the treatment of acute attacks of migraine. In assessing patient populations in the three large randomized placebo controlled studies, demographics were predominantly composed of white, female participants in their early 40s. The average body mass index consistently hovered around the upper limit of the normal range. The studies had a low prevalence of preventive migraine medication usage, indicating a population with a more modest migraine history.

In our analysis, we found a statistically significant improvement in the primary efficacy endpoints, including pain freedom and relief from the most bothersome symptom within 2 hours of treatment initiation. The benefits of zavegepant use continue to manifest in the patients' ability to regain normal functioning within the same period. These results demonstrate the rapid-acting nature of the drug. Moreover, the efficacy of zavegepant extends beyond immediate relief, as indicated by sustained pain relief and pain freedom within 24 and 48 hours post-administration, thereby highlighting the drug's potential for long-term migraine control. Although the relief of nausea within 2 hours did not reach statistical significance, indicating a potential limitation of zavegepant, the absence of pain relapse within 2–48 hours, despite high heterogeneity, suggests its sustained efficacy.

While, the results highlight a notable degree of heterogeneity in certain parameters, such as pain relief and functional restoration within 30 minutes, and a lack of rescue medication use within 24 hours, the absence of significant heterogeneity in the majority of the studied parameters confirms the consistency of zavegepant's effects. However, this may warrant further investigation. Our analysis included trials by Croop et al. and Lipton et al., where the zavegepant 10 mg dose showcased superior efficacy in alleviating migraine symptoms, especially compared to lower dosages and placebos (11, 12).

When evaluating safety outcomes, we see a significant increase in risk of experiencing any adverse event, with a significant occurrence of specific events like dysgeusia, nausea, nasal discomfort, vomiting, and throat irritation (11–13). Nevertheless, the risk of serious adverse events was not found to be significant. Numerous other studies have also shown that 10 mg nasal spray has a favorable side effect profile in terms of serious and other adverse events (13, 14). The drug also had no clinically significant effect on the QT interval (15) and did not cause hepatotoxicity (16).

Moreover, use of the zavegepant's 10 mg dose emerged was well-tolerated in all the individual studies. Adverse events, though present, were predominantly minor and manageable. Expected instances of dysgeusia and nasal discomfort associated with the intranasal route were recorded by all the three studies (11–13). Moreover, the systemic side effects were surprisingly low, and the open-label trial (NCT04408794) provided additional reassurance, with adverse event rates well within acceptable bounds, further cementing zavegepant's strong safety position (13).

As evaluated by Croop et al. (14) zavegepant exhibits a distinct dose-response relationship when administered as a single dose. At a dose of 10mg, the maximum concentration in the plasma reached was approximately 13.4 ng/mL (14). The time to reach this maximum concentration was approximately half an hour (14). The total amount in the plasma from the time of administration until the last detectable concentration was approximately 26.19 ng.hr/mL and until infinity was approximately 28.52ng.hr/mL (14). Further, observational trends point to increased plasma concentrations, larger area under the curve, and variable time to maximum concentration with higher doses. It was also discovered that zavegepant nasal spray had an approximate bioavailability of 5% (17), that it underwent minimal metabolism (18), and that the primary route of elimination was through the biliary system (18, 19). Consequently, these encouraging pharmacokinetic properties highlight zavegepant's potential for use in intranasal migraine therapy. Notably, the drug's fast onset of action, reaching maximum plasma concentration within approximately 32 minutes, positions it as a suitable alternative for acute migraine treatment.

The gepants initially approved by the FDA, for the acute treatment of migraine were ubrogepant (20), an oral tablet and rimegepant (21), an orally disintegrating tablet. zavegepant was only recently approved by the FDA, and with a 2-hour pain freedom rate of 22.5%. Although there are no head to head comparator studies, gepants are comparable in efficacy (21.2–25.5% for 100 mg oral Ubrogepant, 19.6–21% for 75 mg oral Rimegepant and 22.5% for 10 mg intranasal Zavegepant) as shown in a systematic review by Tajti J. et al (24). Discrepancies in adverse event profiles among the gepants, highlighted by higher incidences of nausea in ubrogepant (4–6.9%, 100 mg oral dose) than zavegepant (4.1% in 10 mg intranasal dose) and rimegepant (1.8–2%, 75 mg oral dose), and unique side effects such as dysgeusia and nasal discomfort in zavegepant, suggests a differential impact of administration routes on safety profiles.

Consequently, this comparative review reflects the necessity of a tailored approach in migraine management, considering both the efficacy and safety of gepants, facilitated by the understanding of their distinct pharmacokinetic and pharmacodynamic properties. Taken together, the fast onset action and non-oral administration should be considered as first line for patients with severe pain at onset, prominent nausea and vomiting, and for those with contraindications to standard acute migraine treatments.

Our systematic review and meta-analysis confirms the superior efficacy of zavegepant over placebo in the management of migraine attacks, as demonstrated by a variety of measures, including rapid and sustained pain relief, functional improvements, and a reduction in migraine-related symptoms such as phonophobia and photophobia. These effects were observed as early as 30 minutes post-administration, enduring for up to 48 hours. Additionally, zavegepant-treated patients exhibited less reliance on rescue medication, pointing towards enhanced overall migraine control. On the downside, zavegepant was associated with an increase in adverse events, most of which were related to its manner of administration, such as dysgeusia, nasal discomfort, and throat irritation. Nevertheless, these events were non-serious and the prevalence of serious adverse events was comparable with the placebo group. The minor decrease in pain relapse rate and an inconclusive effect on relieving nausea do not significantly impact the robust positive overall trend. However, these factors, alongside the increased occurrence of nausea and vomiting, deserve further exploration, particularly their influence on patient adherence, to fully contextualize the overall therapeutic advantage of zavegepant.

The inclusion of only RCTs in the analysis and the pooled data synthesis from the available studies were the review's strengths, allowing us to draw conclusions from a larger sample size. This improves the statistical power and generalizability of the findings. However, the limitation was that only two RCTs could be identified. Both these studies used a single attack design and were limited to a placebo comparison rather than an active comparator. In addition, limitations of our analysis are due to the unavailability of comprehensive data across all studies. Future research could compare zavegepant to currently available treatment options. Populations who may benefit from the drug should be studied further, such as those who are unable to tolerate triptans and those who may require non-oral formulations but do not prefer injections. Furthermore, considering its lower risk ratios and superior efficacy compared to placebos, zavegepant has the potential to improve migraine treatment protocols, influence policies, and advocate for public health strategies prioritizing effective and safe migraine interventions. Additionally, its alternative mode of administration offers promise for optimizing patient care and outcomes.

Our study adds to the existing literature by providing evidence of the efficacy and safety of zavegepant compared to a placebo in relieving pain and reducing bothersome symptoms. The findings suggest that zavegepant (10mg) nasal spray may be an effective intervention for acute migraine attacks. Further studies are needed to determine efficacy in those already taken CGRP inhibitors preventively, in addition to individuals with higher degrees of migraine burden in real world settings.

PROSPERO Registration number: CRD42023440683 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=440683)

Acknowledgements: None

Conflict of Interest: None Declared

Funding - None

Arnold M. Headache classification committee of the international headache society (IHS) the international classification of headache disorders. Cephalalgia. 2018;38(1):1–211.
Institute for Health Metrics and Evaluation [Internet]. 2020 [cited 2023 Jul 12]. Migraine — Level 4 cause. Available from: https://www.healthdata.org/results/gbd_summaries/2019/migraine-level-4-cause
Buse D, Manack A, Serrano D, Reed M, Varon S, Turkel C, et al. Headache impact of chronic and episodic migraine: results from the American Migraine Prevalence and Prevention study. Headache: The Journal of Head and Face Pain. 2012;52(1):3–17.
Goadsby P, Edvinsson L, Ekman R. Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society. 1988;23(2):193–6.
Goadsby P, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society. 1990;28(2):183–7.
Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society. 1993;33(1):48–56.
Holland PR, Goadsby PJ. Targeted CGRP Small Molecule Antagonists for Acute Migraine Therapy. Neurotherapeutics. 2018 Apr;15(2):304–12.
Chaturvedula PV, Mercer SE, Pin SS, Thalody G, Xu C, Conway CM, et al. Discovery of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)-1-oxopropan-2-yl)-4-(2-oxo-1, 2-dihydroquinolin-3-yl) piperidine-1-carboxamide (BMS-742413): a potent human CGRP antagonist with superior safety profile for the treatment of migraine through intranasal delivery. Bioorganic & medicinal chemistry letters. 2013;23(11):3157–61.
McGowan J, Sampson M, Salzwedel DM, Cogo E, Foerster V, Lefebvre C. PRESS Peer Review of Electronic Search Strategies: 2015 Guideline Statement. J Clin Epidemiol. 2016 Jul;75:40–6.
Olesen J. International Classification of Headache Disorders. The Lancet Neurology. 2018 May;17(5):396–7.
Croop R, Madonia J, Stock DA, Thiry A, Forshaw M, Murphy A, et al. Zavegepant nasal spray for the acute treatment of migraine: A Phase 2/3 double‐blind, randomized, placebo‐controlled, dose‐ranging trial. Headache. 2022 Oct;62(9):1153–63.
Lipton RB, Croop R, Stock DA, Madonia J, Forshaw M, Lovegren M, et al. Safety, tolerability, and efficacy of zavegepant 10 mg nasal spray for the acute treatment of migraine in the USA: a phase 3, double-blind, randomised, placebo-controlled multicentre trial. The Lancet Neurology. 2023 Mar;22(3):209–17.
Study Record | Beta ClinicalTrials.gov [Internet]. [cited 2023 Jul 12]. Available from: https://clinicaltrials.gov/study/NCT04408794?intr=NCT04408794
Bertz R, Donohue M, Madonia J, Bhardwaj R, Stringfellow J, Anderson M, et al. Safety, tolerability, and pharmacokinetics of single and multiple ascending doses of zavegepant nasal spray in healthy adults. In WILEY 111 RIVER ST, HOBOKEN 07030-5774, NJ USA; 2022. p. 122–122.
Bertz R, Stringfellow J, Bhardwaj R, Donohue M, Madonia J, Anderson M, et al. Concentration QT Interval Modeling of Intranasally Administered Zavegepant in Healthy Subjects (P9-12.004). 2023;
Siler SQ, Woodhead J, Howell B, Conway C, Watkins PB. ADVANCING CALCITONIN GENE-RELATED PEPTIDE RECEPTOR (CGRP) ANTAGONISTS USING QUANTITATIVE SYSTEMS TOXICOLOGY MODELING TO CHARACTERIZE NEXT-IN-CLASS COMPOUNDS COMPARED TO THE HEPATOTOXIC FIRST IN CLASS TELCAGEPANT. In WILEY 111 RIVER ST, HOBOKEN 07030-5774, NJ USA; 2021. p. 719A-719A.
Comisar CM, Francis J, Bhardwaj R, Croop R, Coric V, Bertz R. Pharmacometric Analysis of Zavegepant for Treatment of Migraine. In SAGE PUBLICATIONS LTD 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND; 2022. p. 53–4.
Bhardwaj R, Donohue M, Stringfellow J, Madonia J, Anderson M, Stock D, et al. Absorption, distribution, metabolism, and elimination of 5 mg [14C]-zavegepant in healthy male subjects after a single intravenous infusion dose. In WILEY 111 RIVER ST, HOBOKEN 07030-5774, NJ USA; 2022. p. 101–2.
Bhardwaj R, Donohue M, Madonia J, Stringfellow J, Morris B, Stock DA, et al. Pharmacokinetics of Zavegepant Nasal Spray 10 mg in Subjects With Moderate Hepatic Impairment. In SAGE PUBLICATIONS LTD 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND; 2022. p. 92–3.
Scott LJ. Ubrogepant: first approval. Drugs. 2020;80(3):323–8.
Scott LJ. Rimegepant: first approval. Drugs. 2020;80(7):741–6.

SupplementaryMaterial2.docx
Supplementary Figure 1: Results from Risk of Bias analysis Supplementary Table 1. The adjusted search terms as per searched electronic databases [as of 26.06.2023] Supplementary Table 2. Results from Risk of Bias analysis Supplementary Table 3: Baseline characteristics of the included studies.

Download PDF

Version 1

posted

You are reading this latest preprint version

Zavegepant intranasal spray for the Acute Treatment of Migraine : A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Status:

Version 1

Abstract

Figures

Introduction

Methodology

Search strategy

Study selection

Data analysis

Risk of Bias Assessment:

Results

Study selection

Study population

Efficacy outcomes

Safety outcomes

Risk of bias analysis

Discussion

Conclusion

Declarations

References

Supplementary Files

Status:

Version 1