Safety and tolerability of as-needed nalmefene in the treatment of alcohol dependence: results from the Phase III clinical programme.

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Original Research

1.

Introduction

2.

Patients and methods

3.

Results

4.

Discussion

5.

Conclusion

Safety and tolerability of as-needed nalmefene in the treatment of alcohol dependence: results from the Phase III clinical programme Wim van den Brink†, John Strang, Antoni Gual, Per Sørensen, Thomas Jon Jensen & Karl Mann †

University of Amsterdam, Academic Medical Center, Psychiatry, Amsterdam, Netherlands

Objective: To investigate safety and tolerability of nalmefene for reduction of alcohol consumption in alcohol-dependent patients. Methods: Pooled data from three randomized, placebo-controlled studies (two 6-month; one 12-month) of 18 mg nalmefene (as-needed use) in alcoholdependent patients looking at the total population (placebo n = 824, nalmefene n = 1123) and patients with high/very high drinking risk levels at screening and randomization (target population: placebo n = 374, nalmefene n = 450). Results: In the study, 62.7% of patients on placebo and 74.7% on nalmefene in the total population had treatment-emergent adverse events (TEAEs). Fourty-seven (5.9%) on placebo and 149 (13.0%) on nalmefene dropped out due to TEAEs. Thirty-five (4.4%) on placebo and 57 (5.0%) on nalmefene had serious adverse events. Tolerability and safety were similar in the target population and total population. Most frequent TEAEs were transient, mainly occurring at treatment initiation. There was no difference in tolerability and safety if nalmefene was taken daily or intermittently; no signal of increased risk of suicide-related behavior with nalmefene. The higher incidence of psychiatric events in the nalmefene group was mainly due to the TEAE of confusional state. Conclusions: Although there was a higher incidence of TEAEs and TEAEs leading to dropout, nalmefene was well-tolerated and no major safety issues were identified. Keywords: adverse events, alcohol dependence, nalmefene, opioid antagonist Expert Opin. Drug Saf. [Early Online]

1.

Introduction

With almost 15 million affected persons in the European Union (EU) and 8 million affected persons in the USA, alcohol dependence is a worldwide major public health problem [1,2]. However, in the EU, < 10% of the people with alcohol dependence receives any treatment [3] and the corresponding figure for the USA is ~ 25% [4]. One important reason for this treatment gap is that treatment is predominantly abstinence oriented and that many alcohol-dependent people are reluctant to engage in treatments directed at full abstinence [5] and prefer treatments directed at reduced drinking [6,7]. Nalmefene, an opioid system modulator with antagonist activity at the m and d receptors and partial agonist activity at the k receptor [8,9], is the first and still the only pharmacological compound registered for reduced drinking in patients with alcohol dependence.

10.1517/14740338.2015.1011619 © 2015 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted

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W. van den Brink et al.

The nalmefene Phase III pivotal clinical program consisted of two identically designed 6-month randomized placebocontrolled trials [10,11] and one 12-month randomized placebo-controlled trial [12], enrolling almost 2000 patients throughout Europe. Significant reductions of alcohol consumption with nalmefene versus placebo, measured as change from baseline in total alcohol consumption (g/day) and in monthly number of heavy drinking days were observed in all three studies. Furthermore, nalmefene treatment led to significantly lower liver enzymes and improved overall clinical state. A substantial proportion (18 -- 39%) of the patients who entered the studies were able to reduce their alcohol consumption already in the period between screening and randomization, that is, prior to receiving any formal treatment. Therefore, separate analyses of efficacy and safety were conducted for the total population and for the patients who continued their high level of alcohol consumption after initial assessment and were still drinking at high risk levels at the start of treatment, that is, the target population [12,13]. In 2013, nalmefene was granted a market authorization in the EU as the first pharmacological therapy approved for the reduction of alcohol consumption in adult patients with alcohol dependence who have a high drinking risk level according to the World Health Organization (WHO) ([14]; men: > 60 g/day and women: > 40 g/day) and who continue to drink at this level 2 weeks after initial assessment [15]. This paper constitutes the first analysis of the pooled safety data from the nalmefene Phase III clinical program. We present the following information: i) an analysis of treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs); ii) an evaluation of adverse events (AEs) of special interest for psychopharmacological compounds (depression, suicidality, drug abuse, selected psychiatric AEs) identified via standardized queries or clusters of preferred terms; and iii) an evaluation of liver parameters, since liver disorders are an important clinical outcome in alcohol dependent patients. Data are presented for the total population and the target population. 2.

Patients and methods

Patients This paper includes pooled safety data from the identically designed 6-month studies ESENSE1 (NCT00811720) and ESENSE2 (NCT00812461); and the 12-month study SENSE (NCT00811941). The studies are published and described in full elsewhere [10-12]. Briefly, the studies included adult patients with a primary diagnosis of alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders [16] assessed with the Mini-International Neuropsychiatric Interview [17] and at least medium drinking risk levels (men: > 40 g alcohol/day; women > 20 g alcohol/day) according to the WHO [14]. In contrast to the two 6-month studies, the 12-month study also included patients with stable comorbid psychiatric disorders as well as patients with average alcohol consumption below the WHO medium drinking risk level. 2.1

2

Patients in need of medication-supported detoxification were excluded, as were patients with history of delirium tremens/ alcohol withdrawal seizures. Patients with aspartate aminotransferase (ASAT) and/or alanine aminotransferase (ALAT) values > 3 times the upper limit of the reference range were also excluded. Design All patients were assigned double-blind to an out-patient treatment with as-needed use placebo or nalmefene 18 mg in a 1:1 ratio for ESENSE1 and ESENSE 2 and 1:3 ratio for SENSE. Patients were instructed to take one tablet on each day they perceived a risk of drinking alcohol (‘as-needed dosing’), preferably 1 -- 2 h prior to anticipated time of drinking, but otherwise as soon as possible after drinking had started. In addition, all patients took part in a low-intensity motivational and adherence-enhancing intervention (BRENDA [18]) starting at randomization and subsequently at all scheduled visits. Both abstinence and reduced-risk drinking were accepted; no information was collected on individual treatment goals. Monthly drinking variables were derived from the Timeline Follow-Back [19] that provided information on the daily number of standard drinks. The primary objective of the studies was to evaluate the effect of as-needed use of nalmefene on alcohol consumption based on the monthly number of heavy drinking days and the monthly total alcohol consumption. 2.2

Assessments Assessments of efficacy and safety were performed at screening, randomization and weeks 1, 2 and 4, followed by monthly assessments. The nature, incidence and severity of TEAEs were assessed at each study visit either via spontaneous reporting by patients, and/or observation by the study investigators during the trials. TEAEs were defined as AEs with an onset on or after the day of first study medication intake. Investigators were asked to rate TEAEs as mild, moderate or severe, based on the patient’s discomfort, health risk and interference with activities. Each patient was asked a non-leading question (such as, “how do you feel?”) at each visit, starting at baseline. TEAEs (including worsening of concurrent disorders, new disorders, and pregnancies) were recorded, and the investigator assessed the intensity of the AE and its relationship to the study medication. Results from relevant tests and examinations, such as clinical safety laboratory tests, vital signs and electrocardiograms, or their corresponding conditions were also recorded as AEs if considered by the investigator to be clinically significant. Based on previous clinical experience with nalmefene and other opioid system modulators and studies in alcohol dependence in general [20,21], certain areas were considered of special interest in the evaluation of the safety of nalmefene, including depression, suicidal behavior, suicide-related behaviors, drug abuse and psychosis-like symptoms. In order to capture these AEs of special interest, TEAEs were analyzed using Standardised Medical Dictionary for Regulatory Activities 2.3

Expert Opin. Drug Saf. (2015) 14(4)


Safety and tolerability of as-needed nalmefene in the treatment of alcohol dependence

(MedDRA) Queries (SMQs) or clusters of preferred terms. SMQs are validated, standard sets of MedDRA terms for investigating drug safety issues in pharmacovigilance and clinical development [22]. Some SMQs are a simple set of preferred terms while other SMQs are hierarchical containing subordinate SMQs. SMQs include narrow and/or broad terms. Narrow terms are those that are highly likely to represent the condition of interest. The following SMQs or clusters of preferred terms were used: i) depression (excl suicide and self-injury) -- sub-SMQ to SMQ Depression and suicide and self-injury, narrow search; ii) suicide/self-injury -- sub-SMQ to SMQ Depression and suicide and self-injury; iii) drug abuse, dependence and withdrawal -- SMQ, broad search; and iv) selected psychiatric AEs -- AE cluster defined prospectively by the study sponsor (preferred terms including confusional state, delusion, depersonalization, derealization, disorientation, dissociation, preferred terms including hallucination, illusion, mental status change, paranoia, personality disorder, psychotic disorder, thinking abnormal). In addition to criteria for identifying clinical safety laboratory tests of potential clinical significance (PCS), criteria recommended by US FDA [23] were used to assess potential signals of drug-induced liver injury (DILI). Statistical analyses The analyses of TEAEs in the total population and the target population [13] were based on: i) the all-patients-treated set and ii) the target safety population, respectively, which comprised all patients excluding those with no recorded intake of study medication and all study medication returned. The median duration and median time to first onset of frequent AEs (‡ 5% in either group in the total population) were estimated using the Kaplan--Meier method. For patients with more than one AE within a preferred term, the longest duration was used in the Kaplan--Meier estimation. The effects of treatment (nalmefene vs placebo), age (< 65 vs ‡ 65), sex (male vs female), WHO drinking risk level at baseline (medium vs high vs very high) and study (ESENSE1 vs ESENSE2 vs SENSE) as well as the interaction between treatment and each of the other factors on outcome defined as ‘Experiencing any AE’ were analyzed using both univariate and multivariate logistic regression analyses. All models included treatment and study as default. For detection/flagging of potential safety signals, the significance of the difference in TEAEs between treatment groups was established with Fisher’s exact test. There was no adjustment for multiplicity. AEs were coded using the lowest level term from the MedDRA, Version 13.0. 2.4

3.

Results

Study sample Patient baseline demographics and clinical characteristics for the total population and the target population are shown in Table 1.

The typical patient was a middle-aged man (72.5% males, mean age 47 years), with > 10 years of drinking problems and no previous treatment for alcohol dependence (65%). There were no significant differences in demographics, alcohol history or other baseline values between the nalmefene and placebo groups. The total population differed from the target population with respect to the number of heavy drinking days (HDDs), total alcohol consumption (TAC) and the liver parameter g-glutamyltransferase (GGT) with the target population reporting more HDDs, a higher mean TAC and higher GGT values. AEs profile In the total population, 500 of the patients in the placebo group (62.7%) and 855 of the patients in the nalmefene group (74.7%) had TEAEs (Table 2). Nausea, dizziness, insomnia and headache had an incidence ‡ 10% in the nalmefene group, and nausea, dizziness, insomnia and vomiting occurred at least twice as often in patients receiving nalmefene compared to patients receiving placebo. A total of 14% of the patients in the nalmefene group and 9% of the patients in the placebo group had TEAEs that were considered severe; the severe TEAEs with an incidence ‡ 1% in the nalmefene group were nausea, dizziness, insomnia, headache and vomiting. None of the severe TEAEs in the placebo group had an incidence ‡ 1%. The overall pattern with respect to incidences and most frequent TEAEs in the target population was similar to that in the total population. 3.2

Predictors of AEs For the total population, multivariate analyses revealed that treatment with nalmefene, being a woman and study (ESENSE1 vs ESENSE2 vs SENSE) were significant predictors of experiencing any AE, whereas for the target population, only treatment with nalmefene and study were significant predictors of experiencing any AE. The incidence of AEs was highest in ESENSE1 and lowest in ESENSE2. No significant treatmentby-subgroup interactions were observed; thus differences in AEs between nalmefene and placebo were not different for different subgroups. 3.2.1

Time to first onset and duration of AEs The most frequent TEAEs (‡ 5% in either group in the total population) were transient and mainly occurred early after the first use of study medication (Supplementary Table S1). Median time to first onset occurred within the first day after the first dose of nalmefene for nausea, dizziness, fatigue and somnolence and within ~ 1 week for insomnia, headache and vomiting. The duration was typically a few days with a median duration £ 7 days for all frequent TEAEs in the nalmefene group. Time to first onset and duration for these TEAEs in the target population was in general similar to that in the total population. 3.2.2

3.1

Recurrence of AEs Recurrence of any of the frequent AEs was not related to the pattern of study medication intake, and there was no 3.2.3


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Table 1. Demographics and baseline clinical characteristics. Randomized patients

Total population

Target population


Placebo (n = 824) Nalmefene (n = 1173) Placebo (n = 374) Nalmefene (n = 480) Race Caucasian (n; %) Sex Men (n; %) Age (years; s.d.) Body mass index (kg/m2; s.d.) Age at onset of drinking problem (years; s.d.) Previously treated for alcohol dependence No (n; %) Monthly heavy drinking days (days; s.d.) Total alcohol consumption (g/day; s.d.) g-glutamyltransferase (IU/l)* Alanine aminotransferase (IU/l)*

819 (99.4)

1165 (99.3)

371 (99.2)

478 (99.6)

585 (71.0) 47.2 (11.1) 25.8 (4.3) 34.3 (11.8)

863 (73.6) 46.3 (11.2) 25.9 (4.3) 34.3 (12.0)

248 (66.3) 48.4 (10.8) 26.2 (4.5) 35.1 (11.7)

336 (70.0) 47.7 (10.9) 26.3 (4.8) 35.4 (12.5)

527 (64.0) 17.9 (7.1) 82.9 (45.0) 50.2 28.1

768 (65.5) 17.2 (7.3) 80.1 (43.9) 46.7 28.8

249 (66.6) 21.9 (6.1) 103 (44.7) 57.4 29.0

343 (71.5) 21.8 (6.2) 106 (45.3) 54.9 30.2

Data are mean (s.d.) or number of patients (%). *Geometric mean. s.d.: Standard deviation.

Table 2. Treatment-emergent adverse events. Patients receiving study medication

Total population Placebo (n = 797)

Patients with TEAEs 500 (62.7) Women with TEAEs 156 (68.7) Men with TEAEs 344 (60.4) Patients in ESENSE1 with TEAEs 198 (66.9) Patients in ESENSE2 with TEAEs 199 (59.1) Patients in SENSE with TEAEs 103 (62.8) TEAEs (‡ 5% in either group in the total population) Nausea 47 (5.9) Dizziness 44 (5.5) Insomnia 43 (5.4) Headache 66 (8.3) Nasopharyngitis 73 (9.2) Vomiting 18 (2.3) Fatigue 37 (4.6) Somnolence 23 (2.9)

Target population

Nalmefene (n = 1144)

Placebo (n = 369)

Nalmefene (n = 475)

855 234 621 246 232 377

246 (66.7) 87 (70.2) 159 (64.9) 124 (73.4) 96 (60.8) 26 (61.9)

368 111 257 149 107 112

24 (6.5) 22 (6.0) 16 (4.3) 35 (9.5) 39 (10.6) 13 (3.5) 22 (6.0) 9 (2.4)

115 (24.2)* 104 (21.9)* 69 (14.5)* 60 (12.6) 38 (8.0) 40 (8.4)* 43 (9.1) 20 (4.2)

(74.7)* (77.7)* (73.7)* (81.5)* (68.0)* (75.2)*

253 (22.1)* 208 (18.2)* 153 (13.4)* 141 (12.3)* 107 (9.4) 100 (8.7)* 95 (8.3)* 59 (5.2)*

(77.5)* (78.7) (76.9)* (83.2)* (70.4) (77.8)*

Data are numbers of patients (%). *TEAEs for which the difference between the treatment groups had a Fisher’s Exact Test p-value < 0.05. TEAEs: Treatment-emergent adverse events.

difference in safety for the patients when nalmefene was taken daily or intermittently. Patients with only one AE could be exposed more or less continuously or could have several consecutive days without study medication, without recurrence of the event upon re-exposure. For patients with multiple reports of the same AE, these tended to occur early and did not recur later, regardless of the pattern of study medication intake. AEs leading to dropout TEAEs (mostly mild or moderate) led to the dropout of 47 patients in the placebo group (5.9%) and 149 patients in the nalmefene group (13.0%) in the total population (Table 3). 3.2.4

4

The TEAEs leading to dropout in ‡ 1% of the patients in the nalmefene group were nausea, dizziness, headache and fatigue, that is, all symptoms found among the most frequent TEAEs (‡ 5% in either group in the total population); none of the events in the placebo group led to dropout in ‡ 1% of the patients. The median time to first onset and duration of the TEAEs leading to dropout were longer in the placebo group (63 and 47 days, respectively) than in the nalmefene group (7 and 5 days, respectively). Again, the overall pattern with respect to incidences and most frequent TEAEs leading to dropout in the target population was similar to that in the total population.



Table 3. Treatment-emergent adverse events leading to dropout. Total population


Patients receiving study medication

Placebo (n = 797)


Patients with TEAEs leading to dropout 47 (5.9) 149 (13.0)* TEAEs leading to dropout (> 0.5% in either group in the total population) Dizziness 0 (0.0) 36 (3.1)* Nausea 0 (0.0) 30 (2.6)* Fatigue 0 (0.0) 15 (1.3)* Headache 0 (0.0) 13 (1.1)* Insomnia 2 (0.3) 10 (0.9) Vomiting 1 (0.1) 9 (0.8) Hyperhidrosis 0 (0.0) 8 (0.7)* Alcohol withdrawal syndrome 3 (0.4) 7 (0.6) Disturbance in attention 0 (0.0) 7 (0.6)*

Target population Placebo (n = 369)

Nalmefene (n = 475)

26 (7.0)

78 (16.4)*

0 0 0 0 1 1 0 1 0

25 (5.3)* 18 (3.8)* 7 (1.5)* 9 (1.9)* 7 (1.5) 4 (0.8) 6 (1.3)* 3 (0.6) 3 (0.6)

(0.0) (0.0) (0.0) (0.0) (0.3) (0.3) (0.0) (0.3) (0.0)

Data are numbers of patients (%). *TEAEs for which the difference between the treatment groups had a Fisher’s Exact Test p-value < 0.05. TEAEs: Treatment-emergent adverse events.

Serious AEs A total of 35 patients in the placebo group (4.4%) and 57 patients in the nalmefene group (5.0%) in the total population had SAEs (Table 4). Most SAEs were not related to study medication; no apparent trends with respect to overall incidence or distribution across organ systems were noted, except that fewer patients had alcohol withdrawal syndrome in the placebo group (1 patient [0.1%]) than in the nalmefene group (8 patients [0.7%]). In three patients in the nalmefene group, alcohol withdrawal was rated by the investigator as possibly associated with the study medication, but occurred at least 20 days after the most recent dose of nalmefene. In the other five patients, alcohol withdrawal was not associated with treatment initiation of nalmefene. The overall pattern of SAEs in the target population was similar to that in the total population. 3.2.5

3.3

AEs of special interest Depression

3.3.1

Incidence of depression-related TEAEs was very similar in both treatment conditions: 22 patients in the placebo group (2.8%) and 37 patients in the nalmefene group (3.2%) had TEAEs captured using the SMQ Depression (excluding suicide and self-injury) -- narrow search (Supplementary Table S2). The most common event in both groups was depression with 12 patients in the placebo group (1.5%) and 15 patients in the nalmefene group (1.3%). The overall pattern of depression-related TEAEs in the target population was similar to that in the total population (Supplementary Table S2). Suicidality Suicidality was not assessed prospectively with a specific tool; TEAEs potentially related to suicidality were captured using the sub-SMQ Suicide/self-injury (Supplementary Table S3). The incidence of suicide-related TEAEs was lower in the 3.3.2

nalmefene group (9 patients [0.8%]) than in the placebo group (12 patients [1.5%]). There were no completed suicides in the nalmefene group, but in the placebo group two patients committed suicide. The first patient was a 35-year-old man who hanged himself on day 33 after the start of study medication (placebo) after a conflict with his wife while severely alcohol intoxicated. The MINI performed at screening did not reveal an increased suicide risk. There was no relevant medical history or changes over time in the profile of mood states (POMS) single item scores. The second patient was a 46-year-old man who committed suicide on day 30 after start of study medication (placebo). On days 17 -- 23, his daily alcohol consumption was 19 -- 26 standard units; there was no information available on study medication or alcohol intake in the 5 days prior to the event. The MINI performed at screening did not reveal an increased suicide risk. There were no relevant changes over time in the POMS single-item scores. In the nalmefene group, one patient harmed herself with a knife (non-serious, rated by the investigator as possibly related to study medication) on day 188. She had taken nalmefene daily and had not used any alcohol since baseline. The patient recovered and completed the study. Another patient receiving nalmefene reported suicidal behavior for 1 h on day 93 (SAE, rated by the investigator as not related to study medication). The patient had taken nalmefene almost daily since baseline with occasional drinking. The day before and the day of the event, the patient drank heavily and did not take nalmefene. He dropped out from the study and was hospitalized to receive standard alcohol dependence treatment. The remaining TEAEs potentially related to suicidality were cases of intentional overdose. However, for 14 (6 on nalmefene, 8 on placebo) of these 17 patients, the ‘overdose’ consisted of the ingestion of two tablets of the study medication in an attempt to increase efficacy. The overall pattern of TEAEs potentially related to suicide in the target population was similar to that in the total population (Supplementary Table S3).


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Table 4. Serious adverse events. Total population


Patients receiving study medication

Placebo (n = 797)


Patients with SAEs 35 (4.4) 57 (5.0) SAEs occurring in > 1 patient in either treatment group in the total population Alcohol withdrawal syndrome 1 (0.1) 8 (0.7) Alcoholism 2 (0.3) 4 (0.3) Fall 1 (0.1) 3 (0.3) Alcohol poisoning 2 (0.3) 2 (0.2) Atrial fibrillation 0 (0.0) 2 (0.2) Depression 0 (0.0) 2 (0.2) Disorientation 0 (0.0) 2 (0.2) Non-cardiac chest pain 0 (0.0) 2 (0.2) Alcohol abuse 2 (0.3) 1 (0.1) Fibula fracture 2 (0.3) 1 (0.1) Pneumonia 2 (0.3) 1 (0.1) Completed suicide 2 (0.3) 0 (0.0) Convulsion 2 (0.3) 0 (0.0) Hypertension 2 (0.3) 0 (0.0) Intentional overdose 2 (0.3) 0 (0.0) Pneumothorax 2 (0.3) 0 (0.0) Pyothorax 2 (0.3) 0 (0.0) Rib fracture 2 (0.3) 0 (0.0) Tibia fracture 2 (0.3) 0 (0.0)

Target population Placebo (n = 369)

Nalmefene (n = 475)

13 (3.5)

26 (5.5)

0 1 1 1 0 0 0 0 0 1 0 1 0 0 0 2 1 2 1

1 2 2 1 0 0 1 2 0 1 1 0 0 0 0 0 0 0 0

(0.0) (0.3) (0.3) (0.3) (0.0) (0.0) (0.0) (0.0) (0.0) (0.3) (0.0) (0.3) (0.0) (0.0) (0.0) (0.5) (0.3) (0.5) (0.3)

(0.2) (0.4) (0.4) (0.2) (0.0) (0.0) (0.2) (0.4) (0.0) (0.2) (0.2) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0)

Data are numbers of patients (%). SAEs: Serious adverse events.

3.3.3

Drug abuse

The incidence of TEAEs potentially related to drug abuse, captured by the SMQ Drug abuse, dependence and withdrawal, was lower in the nalmefene group (2.8%) than in the placebo group (5.6%) (Supplementary Table S4). The overall pattern of TEAEs potentially related to drug abuse, dependence and withdrawal in the target population was similar to that in the total population (Supplementary Table S4). Selected psychiatric events The overall incidence of selected psychiatric AEs was higher in the nalmefene group (2.9%) than in the placebo group (1.0%) (Supplementary Table S5). This was mainly driven by the difference in patients with confusional states: 14 patients in the nalmefene group (1.2%) with a total of 24 events versus 2 patients in the placebo group (0.3%). Two of the confusional states in the nalmefene group (in two patients) were severe: i) a 53-year-old male reported severe confusion on day 43 after the start of treatment with nalmefene, which decreased in intensity within 15 min and disappeared within 20 h; co-reported non-serious events were nausea and vomiting. The latter events were severe, occurred intermittently and resolved at the same time as the confusion. Alcohol consumption in the week preceding the events was 36 -- 120 g/day. No further events of this kind were reported during the study with repeated exposure to alcohol with and without nalmefene; the patient completed the study as planned; ii) a 53-year-old female reported severe confusion on day 28 after the start of nalmefene and 9 days 3.3.4

6

after the latest dose. The event lasted 9 days and was described as light-headedness associated with lack of concentration; there was no change in the level of consciousness and she was oriented at all times. Alcohol consumption was 24 g/day on day 27. The vast majority of the selected psychiatric AEs occurred shortly after the first dose of nalmefene and was of short duration (a few hours to a few days). Approximately half of the events resolved under continued exposure and did not recur with repeated exposure. For two of the patients on nalmefene, the duration of the selected psychiatric AEs was ‡ 2 months (both intermittent); one of them had auditory hallucinations and persecutory delusions for 65 days and the other had derealization for 196 days. Seven patients, all on nalmefene, had a total of eight selected psychiatric AEs that were severe, including one SAE. The overall incidence, pattern of occurrence and severity of selected psychiatric AEs in the target population was similar to that in the total population, although the difference between the placebo and nalmefene groups in the incidence of selected psychiatric AEs was greater in the target population than in the total population (Supplementary Table S5). Liver parameters The proportion of patients in the total population with postbaseline PCS high GGT values (‡ 200 IU/l) was higher in the placebo group than in the nalmefene group (11.5 vs 7.5%), whereas the proportion of patients with post-baseline PCS high ALAT values (women: 3 37 IU/l; men: 3 48 IU/l) was slightly lower in the placebo group than in the nalmefene 3.4




group (2.4 vs 3.2%); for ASAT, the proportion of patients with post-baseline PCS high values (women: 3 36 IU/l; men: 3 45 IU/l) was similar in the two treatment groups (2.3 vs 2.6%, respectively). For the remaining liver tests and the international normalized ratio for pro-thrombin time (INR) values, the proportions of patients with post-baseline PCS values were < 1% in both treatment groups. The proportions of patients in the target population with post-baseline PCS high liver test and INR values were similar in the treatment groups at each assessment and similar to those in the total population for all liver parameters, except for GGT. For GGT, the proportion of patients with a PCS high value was higher at baseline than in the total population in both treatment groups and higher in the placebo group than in the nalmefene group post-baseline (16.0 vs 8.6%). In the nalmefene group, the proportion of patients with a PCS high GGT value was similar to that in the total population for all post-baseline assessments. Very few patients met any of the criteria for DILI at baseline. The proportions of patients who met a DILI criterion post-baseline are summarized in Supplementary Table S6. There was no signal of DILI. 4.

Discussion

The current pooled analysis of three placebo-controlled randomized trials of nalmefene as-needed for the reduction of alcohol consumption in patients with a diagnosis of alcohol dependence showed a high incidence of TEAEs in both patients treated with nalmefene (75%) and patients treated with placebo (63%). Nausea, dizziness, insomnia and vomiting occurred at least twice as often in patients receiving nalmefene compared to patients receiving placebo. Generally, TEAEs occurred early after treatment initiation, were mild and disappeared in less than a week. Recurrence of any of the frequent TEAEs was not related to the pattern of study medication intake (daily or intermittently). Treatment dropout due to TEAEs was higher in patients treated with nalmefene (13%) than in patients treated with placebo (6%) with nausea, dizziness, headache and fatigue being the most frequently mentioned reasons. SAEs occurred in a similar frequency in patients treated with nalmefene (5%) or placebo (4%). With regard to specific psychiatric TEAEs, we found that nalmefene treatment was not associated with depression-like TEAEs, that nalmefene treatment was associated with a lower frequency of suicide-related and drug-related events, and that nalmefene treatment was associated with a higher frequency of (generally) transient confusional states. There was no signal of nalmefene-induced liver injury. High rates of TEAEs in both the active and the placebo condition are common in almost all trials with alcohol dependent patients, including trials with acamprosate (e.g., [24]), naltrexone (e.g., [25,26]), topiramate (e.g., [27]), and varenicline [28]. The reason for the high frequency of TEAEs in placebo-treated patients in these studies is unknown, but it

could be related to certain expectations about the effects of the medication or to the problematic physical and mental health condition of many of these patients. The generally mild and transient nature of the TEAEs, however, makes the latter explanation less likely. The type of TEAEs that were over-represented in the nalmefene condition was compatible with the pharmacological profile of the study medication, but a similar overrepresentation of side effects has been reported by alcohol dependent patients treated with acamprosate [29]. Importantly, many of the most frequently occurring TEAEs (nausea, dizziness, headache and fatigue) were also associated with treatment dropout. Therefore, patients should be informed about the possibility that these side effects may occur and that they will generally be mild and transient lasting less than a week. The relatively high incidence of side effects could limit the use of nalmefene. This underscores the need to combine the prescription of nalmefene with a motivational and adherence-enhancing intervention from the first day of treatment. Treatment as-needed did not result in recurrent TEAEs in patients using nalmefene intermittently. This is important because the as-needed prescription modality is an important aspect of the reduced drinking strategy and because it has the potential to empower patients in their personal attempt to recover from the illness [30,31]. Fortunately, the pooled analysis presented here revealed no signal of nalmefene-induced liver injury. This is important because excessive alcohol use is associated with liver injury and because naltrexone, the first opioid antagonist approved for the treatment of alcohol dependence, carries a risk of hepatitis and liver injury [32], especially when given in high doses [33]. It should be noted, however, that a standard dose of naltrexone in the treatment of alcohol dependence (50 mg/day) is generally safe [25,26] and that some other studies have found that naltrexone might even be safe in doses up to 150 mg/day [34]. Nalmefene treatment was not associated with depressionlike symptoms such as depressed mood, anhedonia and dysphoria. This is important as nalmefene is a m-opioid receptor antagonist and may thus have a negative effect on the capacity to experience pleasure. Consistent with that concern, studies on the acute effect of opioid antagonists like naltrexone and naloxone have found reduced hedonic effects of physical exercise [35-37], gambling [38], eating [39], sex [40] and shopping [41]. However, a recent study on the effect of continuous long-term opioid blockade with an extended-release formulation of naltrexone in alcohol-dependent patients showed that naltrexone primarily inhibited the hedonic response associated with drinking alcohol, while sparing the experience of pleasure associated with other activities such as listening to music, being with friends, sex, eating good food and reading [42]. The authors mention differences in acute versus the long-term effects and possible differences in plasma concentrations between the different formulations (oral, immediate release vs intramuscular, extended release) as a potential


7



explanation for these inconsistent findings. Nalmefene was often used intermittently and therefore acute adverse effects like depression, anhedonia and dysphoria could have been expected. However, this was obviously not the case. One possible reason for the absence of depression-like side effects might be that nalmefene is not only a m-opioid receptor antagonist, but also a partial k-opioid receptor agonist. Alcohol dependence is associated with increased levels of dynorphine and increased occupation of the k-opioid receptors in the ventral striatum, extended amygdale and frontal cortex, resulting in dysphoria and depression [43,44]. In such a situation, a partial k-opioid receptor agonist like nalmefene acts as a functional k-opioid receptor antagonist blocking the dysphoria-like effects associated with withdrawal from alcohol and the compulsive use of alcohol during extended access to the drug [44]. The only finding that is not well understood is the increased incidence of confusional states during nalmefene use; this finding was already known from older studies with daily dosing of nalmefene [45] or naltrexone (e.g., [14,46-48]), and the use of disulfiram in alcohol dependent patients [48,49]. In the current studies, most confusional states occurred shortly after the first dose of nalmefene, were of a mild nature and of short duration and about half of these events resolved under continued exposure and did not recur with repeated exposure to nalmefene. Moreover, the symptoms included in this AE category were rather heterogeneous (e.g., attention problems, hallucinations) and withdrawal from alcohol and associated symptoms of delirium were not likely to play a causal role. Although the mechanism of this side effect is not yet clear we can exclude the following reasons: as-needed dosing strategy, combination of nalmefene with alcohol due to reduced drinking strategy, and the specific characteristics of nalmefene (compared to naltrexone). More studies are needed to better understand this unpleasant, but generally innocent, AE in the treatment of alcohol dependent patients. Finally, with the study sample being 99% Caucasian, mostly male, and generally > 40 years of age there are potential limitations to the generalisability of the results of this pooled analysis. However, the study sample is a result of the selection criteria applied in the studies, the demographic profiles of the European countries were the studies were conducted, and the epidemiology of alcohol dependence. Additional research in more demographically diverse samples of alcohol dependent patients may be warranted. 5.

Conclusion

Although there was a higher incidence of TEAEs and TEAEs leading to dropout, nalmefene was well-tolerated and no major safety issues were identified, including no increase in SAEs and no increase in suicide-related AEs. AEs were generally mild, transient and mainly occurred shortly after treatment initiation. As-needed dosing was not associated with more or recurring TEAEs. A combination of nalmefene with 8

motivational and adherence-enhancing interventions is needed to prevent treatment dropout due to (mostly innocent but unpleasant) AEs and to stimulate treatment continuation and good long-term outcomes.

Acknowledgments We thank all patients for their participation in the studies, and all clinical research staff for their contributions. We also thank Johan Hellsten, an employee of Lundbeck, for providing medical writing assistance in the manuscript preparation, revision, and editing. Parts of this work has previously been presented at the 22nd European Congress of Psychiatry, Munich, Germany, 1-4 March 2014, and at the 37th Annual RSA Scientific Meeting, Bellevue, Washington, USA, 21-25 June 2014

Declaration of interest Funding for this paper was received from H. Lundbeck A/S, Valby, Denmark. The sponsor had a role in the study design and data analysis, but the report was mainly written by the first author. This manuscript contains an analysis of pooled safety data from the three Lundbeck-sponsored nalmefene Phase III clinical studies with the following trial registration numbers (ClinicalTrials.gov): NCT00811720, NCT 00811941, and NCT00812461.W van den Brink has received honoraria from Lundbeck, Merck Serono, Schering-Plough, Reckitt Benckiser, Pfizer, and Eli Lilly, speaker fees from Lundbeck, investigator initiated industry grants from Alkermes, Neurotech, and Eli Lilly, is a consultant to Lundbeck, Merck Serono, Schering-Plough, and Teva, and has performed paid expert testimony for Schering-Plough. J Strang has received project grant support and/or honoraria and/or consultancy payments from Department of Health, National Treatment Agency, Public Health England, Home Office, and National Institute for Health and Clinical Excellence, and has worked with the World Health Organisation and with the United Nations Office for Drug Control. He and his institution have also received research grant support and/or payment in the form of honoraria, consultancy payments and/or travelling and/or accommodation and/or conference expenses from various pharmaceutical companies who produce, or have been considering producing, new medicines for use in the addiction treatment field, including Viropharma, Martindale, ReckittBenckiser, Schering-Plough, Lundbeck, UCB, MundiPharma, Alkermes, iGen. Antoni Gual has received honoraria and travel grants from Lundbeck, Janssen, and Servier. P Sørensen is employed by Lundbeck and Thomas Jon Jensen was employed by Lundbeck at the time of the conduct of the research for this paper. K Mann has received research grants from ScheringPlough, Alkermes, Lundbeck, McNeil, and Merck. He has been a paid consultant to Alkermes and Desitin, is a consultant to Lundbeck and Pfizer, and has received speaker fees from Lundbeck.



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Affiliation

Wim van den Brink†1, John Strang2, Antoni Gual3, Per Sørensen4, Thomas Jon Jensen4 & Karl Mann5 † Author for correspondence 1 University of Amsterdam, Academic Medical Center, Psychiatry, Meibergdreef 5, Gerrit vd Veenstraat 84-hs, Amsterdam, 1077el, Netherlands E-mail: [email protected] 2 Institute of Psychiatry and The Maudsley, National Addiction Centre, London SE5 8AF, London, UK 3 Neurosciences Institute, Hospital Clinic, Barcelona, Spain 4 Lundbeck, Valby, Denmark 5 University of Heidelberg, Central Institute of Mental Health, Mannheim, Germany

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