Therapeutic Effect of Evenamide, a Glutamate Inhibitor, in Patients With Treatment-Resistant Schizophrenia (TRS): Final, 1-Year Results From a Phase 2, Open-Label, Rater-Blinded, Randomized, International Clinical Trial

Overall Design

Study NW-3509/014/II/2019 (Study 014) was a 6-week, open-label, rater-blinded, randomized, international study conducted in India, Sri Lanka, and Italy to evaluate the safety, tolerability, and preliminary efficacy of 3 fixed oral doses of evenamide (7.5, 15, and 30 mg bid) as add-on in patients with TRS not responding adequately to their current AP medication given at a stable therapeutic dose. Patients who completed Study 014 were eligible to continue treatment with evenamide in an optional 46-week, open-label, extension study, NW-3509/015/II/2019 (Study 015), evaluating the long-term safety, tolerability (primary endpoint), and preliminary evidence of efficacy of evenamide (secondary endpoint). All patients provided written informed consent before enrollment in each trial, and both studies were approved by an Institutional Review Board/ Ethics Committee at each site and conducted in accordance with the Declaration of Helsinki (World Medical Association, 2013).

The design of Study 014 and its long-term extension, Study 015, have been extensively described in the previous publication, which also includes the key patient selection criteria and the safety and efficacy outcome measures used throughout the 1-year treatment period (Anand et al., 2023).

In Study 015, after the baseline assessment (Week 6, ie, final visit of Study 014), patients were required to return to the clinic for scheduled visits at Weeks 12, 18, 30 (designated as the 6-month timepoint), and 42, at which time selected safety and efficacy evaluations were performed. In addition, patients received telephone contacts from the investigator/site staff at Weeks 36 and 47 to inquire about any safety or tolerability issues. Patients returned for the final evaluation at Week 52 (1 year of total treatment), or at early discontinuation, at which time all final safety and efficacy evaluations were performed.

Patient Population

Studies 014 and 015 aimed to collect short and long-term data, respectively, primarily on the safety and tolerability, but also aimed at obtaining preliminary evidence of efficacy of evenamide for up to 1 year of treatment at 3 different doses. These 2 consecutive companion studies were designed using 2 different study protocols, each one with a matching informed consent form (ICF). Patients who completed Study 014 were considered eligible for Study 015 if, according to the investigators, they were not at risk for suicidality, had not experienced any moderate/severe neurological side effects (eg, extrapyramidal symptoms [EPSs]), had not shown significant worsening of their symptoms of schizophrenia, and had demonstrated adequate compliance with medications during the first 6 weeks of treatment.

The Safety population, consisting of all patients who took at least one dose of the study medication in Study 015, was used for the primary endpoints of the study, that is, incidence of treatment-emergent adverse events (TEAEs), incidence of serious adverse events (SAEs), and changes from baseline for all the other safety measures. In addition, all the demographic and baseline characteristics for patients enrolled in Study 015 will be described using the Safety population, including the differences compared with the Study 014 patients’ baseline characteristics, if any.

All the efficacy analyses performed are exploratory in nature due to the absence of a control group and the open-label design of this study. The efficacy analyses were conducted using an intention-to-treat (ITT) population, as defined below:

• - The ITT₀₁₅ population for Study 015 consists of all subjects who completed Study 014, including Week 6 evaluations, met the criteria for Study 015, and signed the ICF for Study 015, regardless of whether a dose of the study medication was taken in Study 015.

Final, short-term results of Study 014 (Week 6) were published previously using the modified ITT (mITT₀₁₄) population (Anand et al., 2023), while this paper presents results pertaining to Study 015 only, evaluating changes from the Study 014 baseline (ie, prior to initiating treatment with evenamide) up to and including 1 year of total treatment for all patients enrolled in Study 015.

Statistical Methods

In Study 015, patients randomized to 7.5 mg bid evenamide in Study 014 were switched to 15 mg bid, thus the original randomized treatment groups from Study 014 were not maintained. For this reason, data from all 3 randomized treatment groups (7.5, 15, and 30 mg bid) were pooled in a single evenamide group for the primary analysis.

The Safety assessment (primary endpoint of the study) included the evaluation of attrition, the incidence of TEAEs and SAEs, and changes from baseline in vital signs (including blood pressure, heart rate, respiratory rate, body weight, temperature, body mass index (BMI), and waist circumference), laboratory parameters, electrocardiograms (ECGs), EPSs (Extrapyramidal Symptom Rating Scale—Abbreviated version [ESRS-A]; Chouinard et al., 2023) and symptoms of depression (Calgary Depression Scale for Schizophrenia [CDSS]; Addington et al., 1993). Additional exploratory analyses were performed evaluating each randomized dose group separately.

Changes from baseline in the Positive and Negative Syndrome scale (PANSS; Kay et al., 1987) total score, Clinical Global Impression—Severity of disease (CGI-S; Guy et al., 1976), and Strauss-Carpenter Level of Functioning scale (LOF; Strauss and Carpenter 1977) at 6 weeks, 6 months (30 weeks), and 1 year (52 weeks) after initiation of treatment in Study 014 were summarized with descriptive statistics. The CGI-Change from baseline (CGI-C; Guy et al., 1976) ratings by timepoint were summarized using descriptive statistics. Patients considered “responders” (PANSS ≥20% improvement from baseline; CGI-C rated as at least “much improved”; and CGI-S improvement of at least 2 categories from baseline) were described using the number of “responders” at each timepoint and the ITT population as the denominator. All exploratory efficacy analyses evaluating change from baseline were performed using paired t-test for the ITT population using the Multiple Imputation (MI) and Observed Cases (OCs) approaches for the primary (PANSS) and key secondary (CGI-S) efficacy measures at the endpoint. Results for the 6-month and 1-year timepoints are summarized for all efficacy measures.

Patient Disposition

One-hundred-and-sixty-one (161) of the 186 patients screened were enrolled in Study 014, and 160 received at least one dose of evenamide; one patient was randomized but withdrew consent before receiving the first dose.

Of the 153 patients who completed Study 014 (Anand et al., 2023), 144 (89%) entered the additional 46-week, long-term extension study (Study 015), while 8 patients decided not to enter, and 1 patient was not eligible due to noncompliance with medication. At the 6-month timepoint, 132 (82%) patients were continuing in the study, with 121 (75%) completing the 1-year treatment period. Discontinuations in the long-term extension study (N = 23) were mainly due to withdrawal of consent (N = 16), along with a small number of patients who were lost to follow-up (N = 5), one who discontinued due to an adverse event (somnolence), and one who died (see Long-Term Safety section).

The Study 014 efficacy analysis set (mITT₀₁₄) included 156 patients (Anand et al., 2023), while the ITT₀₁₅ and the Safety Populations for Study 015 comprised 144 patients (Figure 1).

Demographic and Baseline Characteristics

The mean (SD) age of patients enrolled in Study 015 was 38.0 (9.9) years; 71% were males, and most were Asian (98.6%), with 1.4% being White or Caucasian. Patients had a mean (SD) duration of schizophrenia of 6.8 (3.0) years, and a mean (SD) duration of the current episode of 8.0 (4.9) months. In addition to the current background AP drug taken during the study, on average, 2.9 trials with other APs had been attempted beforehand. The most used background APs were risperidone (54.9%) and olanzapine (27.1%), with a mean (min-max) daily dose of 7.6 (2-12) mg and 21.7 (10-40) mg, respectively. The mean (SD) PANSS total score at baseline for the patients enrolled in Study 015 was 79.6 (5.06), with a mean CGI-S rating of 4.5 (0.58) and LOF score of 18.1 (3.76).

The demographic and baseline characteristics of the Study 015 Safety Population (N = 144) described above do not differ meaningfully from those presented for the Study 014 Safety Population (Anand et al., 2023).

Long-term Safety Results

The long-term safety data confirmed that evenamide was well tolerated at all doses, as had been observed in Study 014 (Anand et al., 2023). Considering the Study 015 Safety Population, no adverse events with an incidence exceeding 4% occurred, and no hospitalizations for exacerbation of schizophrenia were reported. In addition, no pattern of abnormalities was noted in laboratory tests, vital signs, ECGs, or physical/neurological/standard eye examinations, confirming the good tolerability of evenamide at the doses tested. This is further supported by the low rate of discontinuation due to adverse events, with only 1 (0.7%) patient discontinuing for somnolence. The number (%) of patients reporting TEAEs in the extension period was 40 (27.8%), without any evidence of an increased incidence with higher doses. The most common TEAEs were blood cholesterol increase, creatine phosphokinase (CPK) increase, insomnia, anemia, schizophrenia (worsening), and upper respiratory tract infection, each reported in 3 (2.1%) patients.

Only 2 (1.4%) patients experienced a SAE:

• - One with dilutional hyponatremia followed by an acute symptomatic seizure (26 days after the last dose of study medication);

• - One sudden death was reported for a patient treated with evenamide 30 mg bid on day 185. The patient did not report any adverse events during the study and improved by >25% on the PANSS total score. An autopsy indicated the presence of several atherosclerotic plaques in the aorta and branches of the coronary arteries (left anterior descending, and right circumflex). Bilateral congestion with mild pulmonary edema was noted in the lungs. These findings may be suggestive of a contribution of cardiovascular dysfunction in the subject’s death.

Importantly, no increase was noted in the incidence of EPS, as assessed by the ESRS-A, depressive symptoms, as assessed by the CDSS, metabolic syndrome, or sexual dysfunction.

Long-Term Efficacy Results

The improvement of symptoms of schizophrenia, already noted on the PANSS at the Week 6 timepoint (endpoint of Study 014), continued throughout the extension study, as demonstrated by the gradual reduction in the PANSS total score from baseline through 6 months (−16.0%), reaching −19.4% at 1 year.

Continuing improvements from baseline in other measures, including the CGI-S, CGI-C, and LOF, were also observed. The proportions of patients exhibiting a clinically meaningful benefit, as evident from a reduction of 20% or more on the PANSS total score (as described by Rosenheck et al., 1997; Meltzer et al., 2008), a 2-category improvement on the CGI-S, or a CGI-C rating of “much improved” increased over time, as shown in Table 1.

Effect of Dose

A total of 161 patients were randomized in Study 014 to one of the 3 evenamide fixed doses (7.5 mg bid N = 50; 15 mg bid N = 60; 30 mg bid N = 51), but 13 patients originally randomized to treatment with evenamide 7.5 mg bid had their dose increased to 15 mg bid during the long-term extension (Study 015) after the implementation of a protocol amendment that dropped the 7.5 mg bid dose from the study. Based on these changes, dose–response for efficacy or safety was difficult to discern.