Galcanezumab in episodic migraine: the phase 3, randomized, double-blind, placebo-controlled PERSIST study

Study design and treatment

This was a phase 3 study conducted at 40 centers in China (n = 26), India (n = 10), and Russia (n = 4). The study comprised five periods: initial screening and washout of all excluded medications or migraine preventive treatments taken prior to study entry (3–45 days); a prospective baseline period to determine patient eligibility based on daily entries into an electronic patient-reported outcomes (ePRO) system (30–40 days); a 3-month, randomized, double-blind, placebo-controlled treatment period; a 3-month open-label extension; and a 4-month post-treatment phase to observe the washout of the study drug (Fig. 1). Here, we report the results of the double-blind period; the database lock was August 2021. Results from the open-label and post-treatment periods will be reported separately.

Fig. 1figure 1

Study design. aEligibility period determined between a minimum of 30 days and a maximum of 40 days. bPatients randomized to galcanezumab 120 mg received a loading dose of 240 mg at the first injection only (Visit 3). cTelephone visits. dAt Visit 7, patients randomized to placebo who entered the open-label extension received galcanezumab at a loading dose of 240 mg, while patients randomized to galcanezumab 120 mg continued treatment at the 120 mg dose. SP, study period; X indicates when dosing occurred

During the double-blind treatment period, patients were randomized 1:1 to receive monthly subcutaneous injections of galcanezumab 120 mg (with a loading dose of 240 mg) or placebo during an office visit. Patients could continue to take the following acute migraine medications: acetaminophen (paracetamol), non-steroidal anti-inflammatory drugs, triptans, ergotamine and derivatives, isometheptene mucate, dichloralphenazone and acetaminophen combination (Midrin), or combinations thereof. Assignment to treatment was via a computer-generated random sequence using an interactive web-response system. Randomization was stratified by country and baseline migraine frequency (< 8 MHDs vs. ≥ 8 MHDs per month). To preserve blinding, patients received two injections at the beginning of the randomized period (two galcanezumab 120 mg injections or two placebo injections). Galcanezumab and placebo (excipients only) were supplied as visually indistinguishable 1-ml, single-dose, prefilled, disposable manual syringes with study-specific labels.

Patients

Eligible patients were aged 18 to 65 years at the time of screening, with a diagnosis of episodic migraine as defined by the third edition of the International Classification of Headache Disorders (ICHD-3; 1.1 or 1.2) [21], a history of migraines for ≥ 1 year prior to Visit 1, and migraine onset before 50 years of age. Patients were required to have a history of 4–14 MHDs and ≥ 2 migraine attacks per month on average within the 3 months prior to Visit 1, and a frequency of 4–14 MHDs and ≥ 2 migraine attacks during the prospective baseline period. To avoid bias, patients were not told the number of MHDs on which study qualification was based. Patients had to be at least 80% compliant with ePRO daily diary entries during the prospective baseline period.

Patients were excluded if they had failed to respond to three or more classes of migraine preventive treatments, were currently receiving treatment for migraine prevention, or were taking or expected to take therapeutic antibodies during the study. Other key exclusion criteria were prior exposure to galcanezumab or another CGRP antibody, known hypersensitivity to multiple drugs, serious or unstable psychiatric conditions, history of stroke, risk for acute cardiovascular events based on medical history or electrocardiogram findings, and body mass index ≥ 40 kg/m2.

Assessments and endpoints

Patients used the ePRO system each day to record headache information, migraine-associated symptoms, and the use of headache medication. The Migraine-Specific Quality of Life Questionnaire (MSQ) version 2.1, which consists of 14 items across three domains of patient functioning scored from 0 to 100, with scores of < 40 indicating extreme impairment and scores of 85–100 indicating no or minimal impairment [22], was administered at randomization (baseline) and month 1, 2 and 3. The Patient Global Impression of Severity (PGI-S) scale [23], which measures severity of illness with scores ranging from 1 (normal, not at all ill) to 7 (extremely ill), and the Migraine Disability Assessment (MIDAS) score [24], which consists of five items measuring headache-related disability ranging from little or no disability (0–5) to severe disability (> 20), were administered at baseline and month 3. Safety measures included treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), death, discontinuations due to adverse events, vital signs, and weight. Immunogenicity measures included antidrug antibodies (ADA), neutralizing ADAs, and treatment-emergent ADAs.

The primary endpoint was the overall mean change from baseline in the number of monthly MHDs during the 3-month, double-blind period. Key secondary endpoints were the proportion of patients with ≥ 50%, ≥ 75%, and 100% reduction from baseline in monthly MHDs during the 3-month, double-blind period and overall mean change from baseline through months 1 to 3 in the MSQ Role Function-Restrictive domain score. Other secondary endpoints included mean changes from baseline in the number of monthly MHDs treated with acute migraine medication, MSQ total score, Role Function-Preventive and Emotional Function domain scores, PGI-S score, MIDAS total score, safety, and immunogenicity.

Statistical analysis

In total, approximately 486 patients were planned for randomization. It was estimated that 243 patients per treatment group would provide approximately 90% power to detect an effect size of 0.33 between the galcanezumab and placebo groups, at an overall 2-sided 0.05 significance level, assuming a discontinuation rate of 20% during the double-blind period.

Efficacy and safety analyses included all patients who underwent randomization and received at least one dose of study drug. The primary endpoint and continuous secondary efficacy endpoints were analyzed using a restricted maximum likelihood-based MMRM technique including the fixed categorical effects of treatment, country, month, and treatment-by-month interaction, as well as the continuous fixed covariates of baseline value and baseline-by-month interaction. Repeated binary efficacy endpoints were estimated using a categorical, pseudo-likelihood-based repeated measures analysis implemented using a generalized linear mixed model procedure including the fixed categorical effects of treatment, month, and treatment-by-month interaction, as well as the continuous, fixed covariate of baseline value. If a significant improvement in the number of monthly MHDs was observed at month 1 and maintained through to month 3, it was planned to analyze the number of weekly MHDs using an ordinal repeated measures model. The incidence of TEAEs and immunogenicity parameters were summarized by treatment group.

To provide strong control of the study-wise type I error rate, the primary and key secondary endpoints were tested using a gated approach at a 2-sided alpha level of 0.05. If the null hypothesis was rejected for the primary endpoint, the key secondary endpoints were to be sequentially tested in the following order: ≥ 50% reduction from baseline in monthly MHDs, MSQ Role Function-Restrictive domain score,  ≥ 75% and 100% reduction from baseline in monthly MHDs. The statistical evaluation was performed using SAS version 9.4 or higher.

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