The rates and measurement of adherence to acamprosate in randomised controlled clinical trials: A systematic review.

AIM: The current research aims to systematically review the rates of adherence reported in randomised controlled clinical trials of acamprosate. It also sought to determine the reliability of the adherence monitoring and measurement methods used in these trials.
METHODS: The protocol for this review was pre-registered (PROSPERO: CRD42021230011). A search of the literature was conducted using OVID MEDLINE, Embase and PsycINFO from database inception to January 2021. Randomised controlled trials with a minimum sample size of 10 per treatment arm that compared the efficacy of acamprosate with placebo or other active medication in adults with a diagnosis of alcohol dependence were included. Data on rates of adherence, methods of measurement and monitoring of adherence was extracted from eligible studies independently in duplicate by two reviewers. A weighted mean adherence rate was calculated. The reliability of adherence monitoring methods was determined by calculating an adherence-assurance score based on the adherence monitoring method used. Risk of bias was assessed using the Cochrane Risk of Bias Tool.
RESULTS: Fifteen studies met the eligibility criteria involving 4,450 participants (2,480 participants in the placebo arms). A mean adherence rate of 88% (54.2-95.0%) was reported across studies that reported the percentage of medication taken. A mean adherence rate of 84.9% (56.4-91.3%) was reported for trials that reported the percentage of participants taking more than 80% of medication prescribed. There is low confidence in the methods used to monitor adherence with all clinical trials having a low adherence-assurance rating. Risk of bias was judged to be high for all included studies.
CONCLUSIONS: Adherence to acamprosate in clinical trials can be poor with low confidence in the methods used to measure it. Adherence rates therefore might not be accurate, which has implications for determining the efficacy of acamprosate.

Introduction

Alcohol consumption is a leading factor for disease burden worldwide, associated with 60 acute and chronic health conditions and the leading cause of premature death in those aged 15–49 years. In 2016, alcohol consumption was attributable to 2.8 million deaths worldwide [1]. Those requiring treatment for their alcohol use often undergo frequent episodes of withdrawal and resumption of drinking with up to 70% of people returning to drinking in the year following treatment [2].

Acamprosate is a safe, effective and cost-effective medication to help support relapse prevention [3]. Guidelines produced by the National Institute for Health and Care Excellence (NICE) recommend acamprosate as a first-line treatment, in conjunction with psychosocial therapy, to help support those who have completed alcohol withdrawal to remain alcohol free [4]. Acamprosate modulates the glutamatergic system and stabilises the imbalance between inhibitory (GABA) and excitatory (glutamate) neurotransmitters in the brain during alcohol withdrawal, whereby reducing the conditioned effect of alcohol and the negative reinforcement of the addiction [5-7].

Despite the therapeutic potential of acamprosate, poor adherence to the medication poses a problem for effectiveness in clinical practice. Adherence to a medication can be considered the extent to which a patient’s actions match the recommendations agreed with the prescriber [8]. Suboptimal outcomes may result from underdosing, overdosing or taking medication at incorrect intervals. Improved treatment outcomes for alcohol dependence are associated with better adherence to medications for alcohol relapse prevention [9, 10]. Medication adherence is a common problem across clinical care but is particularly an issue in chronic conditions and greater risk of poor adherence has been associated with those who misuse substances [11]. Since clinical trials offer a controlled environment where adherence can be monitored by research staff and payment may even be received for participation, medication non-adherence in clinical practice is likely to be substantially greater than in clinical trials.

The precise measurement of adherence in clinical trials is essential to accurately assess the efficacy of the medication under investigation. Methods for monitoring adherence in clinical trials include direct supervision, pill count, patient or clinician self-report, biochemical markers and electronic adherence monitoring. Pill count and patient self-report are often used to measure adherence in clinical trials, they can be inexpensive and place minimal burden on the participant. However, self-report may lead to an over-estimate of rates of adherence [12]. Electronic adherence monitoring that involves a medication bottle cap (e.g. Medication Events Monitoring System) that records when the bottle is opened is considered the gold-standard for clinical trials but is not feasible for routine clinical care [13].

The current research aims to systematically review the rates of adherence reported in randomised controlled clinical trials of acamprosate. It also sought to determine the reliability of the adherence monitoring and measurement methods used in these trials.

Materials and method

The protocol for this systematic review was preregistered with the International Prospective Register of Systematic Reviews (PROSPERO: CRD42021230011). This paper complies with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses).

Eligibility criteria

Studies were included if they were randomised controlled trials with a minimum sample size of 10 per treatment arm comparing the efficacy of acamprosate with placebo or other active medication for alcohol relapse prevention. Included studies were of adults (aged 18 or older) with a diagnosis of alcohol dependence (ICD or DSM). Studies were excluded if they used a cross-over or open label design or included pregnant women. The eligibility of trials was confirmed in line with the inclusion/exclusion criteria.

Information source and search strategy

The electronic databases EMBASE, MEDLINE and PsycINFO (using the Ovid interface) were searched from database inception to the 3rd January 2021, combing terms for alcohol dependence, acamprosate and randomised controlled trials (see S1 File for the full search strategy). Searches were limited to studies published in English.

Study selection and data collection process

Search results were managed using Endnote and Microsoft Excel. Two reviewers (K.D. and L.H.) independently screened the titles and abstracts of all identified references. The full texts of potentially relevant articles were then screened independently in duplicate by the two reviewers. Any disagreement when screening titles, abstracts or full text documents was resolved by discussion between the two reviewers. Data from each relevant article was extracted independently in duplicate by the two reviewers using Microsoft Excel spreadsheets that had been pre-piloted. Discrepancies were discussed between the two reviewers and agreement reached. The Data extracted included; participant characteristics (number of participants in each study arm, age, gender, ethnicity), study characteristics (number of trial arms, length of treatment with acamprosate and comparator/placebo, country of the study, psychosocial intervention), medication adherence monitoring method (e.g. pill count), the frequency that adherence was measured (days), adherence rate (acamprosate and comparator/placebo), the measure of medication adherence used (e.g. % of prescribed medication taken), overall adherence rate (acamprosate and comparator/placebo).

Outcome measures

The following outcomes were assessed; 1. Medication adherence rate, 2. Medication adherence monitoring method, 3. Frequency of adherence measurement (percentage of days that the monitoring was used), 4. Measure of medication adherence, 5. Length of treatment with medication (days).

Data synthesis

Adherence rates for each trial was combined and weighted by sample size according to the adherence reporting method used. Where separate percentages were reported for active medication and placebo groups, the percentage of medication for the active medication group was taken. If separate percentages are reported for different sub-groups, for example type of psychological therapy received, all were included in the adherence rate calculations that were completed in Microsoft Excel. There was variation in the treatment length for the clinical trials included. Pearson’s correlation using IBM SPSS version 26 [14] was used to conduct a post hoc exploration of the impact of length of treatment on rate of adherence.

The method described by Swift et al. [15] was used to calculate an adherence-assurance score for the trials included in this review. All data was entered into Microsoft Word and calculated manually. To calculate the adherence-assurance score, adherence monitoring methods were assigned a monitoring confidence level which takes into consideration ability for circumvention; high/3 = supervision, medium/2 = Medication Events Monitoring System (MEMS), riboflavin or acamprosate levels, Low/1 = self-report, pill count, blister packs. The percentage of dosing days on which the monitoring method was used was calculated. Biological testing methods such as the presence of riboflavin were considered to provide confirmation of dosing on a single day. An adherence-assurance score was then calculated using the following formula; Adherence-assurance score = (monitoring confidence level) X (monitoring frequency).

Where multiple methods of adherence monitoring had been used concurrently a combined score was calculated by adding together the two adherence-assurance scores for the two methods. For trials that used two methods with the same confidence level (e.g. two low confidence methods such as pill count and self-report), no additional adherence assurance was allocated. Raw adherence-assurance scores were normalised to 100% and assigned an adherence-assurance rating of low (0–49%), medium (50–79%) or high (80–100%).

Risk of bias

Eligible studies were assessed for risk of bias using the Cochrane Risk of Bias Tool [16], which included risk of bias arising from the randomisation process, deviations from the intended interventions, missing outcome data, measurement of the outcome and selection of the reported results Two reviewers assessed each relevant article independently with discrepancies resolved by discussion.

Results

Fig 1 shows the results of the systematic search of the literature. A total of 15 studies were included involving 4,450 participants (2,480 participants in the placebo arms), the characteristics of these studies are presented in Table 1. The length of treatment with acamprosate ranged from 84 days to 365 days.

Fig 1

PRISMA flow diagram.

Table 1

Study characteristics.

Study	Country	Total N Acamprosate	Total N placebo	Participant age, mean (SD)	Participant gender, % male	Measure of adherence	Adherence rate Acamprosate	Adherence rate Placebo		Treatment length (days)	Risk of bias
Anton (2006)	USA	302 (MM = 152 and CBI = 150)	308 (MM = 153 and CBI = 156)	MMAcamprosate: 44.0 (SD 10.97Placebo: 44.2 (SD 9.15)CBIAcamprosate: 45.4 (SD 10.32)Placebo: 43.2 (SD 9.74)	MMAcamprosate: 69.1%Placebo: 67.3%CBIAcamprosate: 70.9%Placebo: 70.5%	% prescribed meds taken	84.2%	NR		112	High
Berger (2013)	USA	51	49	Acamprosate: 46.6 (7.7)Placebo: 47.7 (8.5)	Acamprosate: 58.8%Placebo: 65.3%	% of prescribed meds taken	93.3%	91.6%		84	Some concerns
Besson (1998)	Switzerland	55	55	Acamprosate: 42.7 (NR)Placebo: 42.2 (NR)	Acamprosate: 83.6%Placebo: 76.4%	Not reported	Not reported but non-significant difference between groups noted except on the last study visit–those on placebo took significantly fewer tablets			360	High
Geerlings (1997)	Benelux i.e. The Netherlands, Belgium and Luxembourg	128	134	Acamprosate: 40.3 (9.2)Placebo: 41.7 (8.1)	Acamprosate: 76%Placebo: 76%	% medication taken	86%	88%		180	High
Gual (2001)	Spain	141	147	Acamprosate: 41.4 (9.01)Placebo: 40.7 (9.47)	Acamprosate: 80%Placebo: 79%	Average % medication taken per day	91.5%	97.8%		180	High
Higuchi (2015)	Japan	163	164	Acamprosate: 51.7 (12.4)Placebo: 53.1 (12.2)	Acamprosate: 86.5%Placebo: 88.4%	Not reported	Both groups included 7 pts whose adherence rate was below 70%, no intergroup differences			168	High
Kiefer (2003)	Germany	40	40	Acamprosate: 46.3 (7.7)Placebo: 45.6 (11.1)	Acamprosate: 75%Placebo: 68%	% prescribed medication taken	81.1% overall group specific not reported (Non-significant difference between groups noted			84	High
Mann (2013)	Germany	172	86	Acamprosate: 45.1 (8.5)Placebo: 46.6 (9.3)	Acamprosate: 80%Placebo: 78%	% prescribed medication	76.7%	73.5%		84	High
Mason (2006)	USA	2g/day = 2583g/day = 83	260	Acamprosate: 2g/day = 44.9 (10.5),Acamprosate: 3g/day = 43.6 (8.9).Placebo = 44.5 (10.0)	Aamprosate 2g/day = 70%Acamprosate 3g/day = 71%Placebo = 64%	% prescribed medication	2g/day = 89.0%.3g/day = 88.5%	92.6%		168	High
Morley (2006)	Australia	55	61	Acamprosate: 45.2 (9.2)Placebo: 42.4 (9.3)	Acamprosate: 76.4%Placebo: 71.7%	% taking 80% medication	56.4%	50.8%		84	High
Paille (1995)	France	361 (Dose 1.3g/day = 188 and Dose 2g/day = 173)	177	Acamprosate 1.3g/day: 43.7 (8.6)Acamprosate 2g/day: 43.3 (9.3)Placebo: 42.5 (8.9)	Acamprosate 1.3g/day: 77.7%Acamprosate 2g/day: 79.2%Placebo: 83.1%	% pills taken	90 days: Acp 1.3g/day = 80.3%,Acp 2g/day = 76.8%.180 days: ACP 1.3g/day = 70.5%,ACP 2g/day = 54.2%.360 days: ACP 1.3g/day = 54.9%,ACP 2g/day = 35.8%		90 days = 81.9%.180 days: 64.4%.360 days = 47.3%	365	High
Pelc (1997)	Belgium and France	126 (1332mg/day = 63 and 1998mg/day = 63)	62	NR	NR	% pills taken	95% of tablets not returned—overall, no group specific values reported			90	High
Sass (1996)	Germany	136	136	Acamprosate: 41.9 (8.4)Placebo: 40.5 (8.6)	Acamprosate: 75%Placebo: 80%	Not reported	Not reported but no difference between groups noted.			336	High
Tempesta (2000)	Italy	164	166	Acamprosate: 45.9 (11.33)Placebo: 45.9 (11.19)	Acamprosate: 84.8%Placebo: 80.7	Regular intake of study medication	76.9% - 84.5% ‘regular intake’, no group specific values reported, non-significant difference between groups noted			180	High
Wolwer (2011)	Germany	IBT: 124TAU: 122	125	Acamprosate IBT: 45.1 (7.8)Acamprosate TAU: 45.7 (7.5)Placebo: 46.4 (7.7)	Acamprosate IBT: 75.8%Acamprosate TAU: 71.3%Placebo: 62.2%	% participants taking 80% or more of medication	91.3% overall			182	High

Nine studies reported the percentage of prescribed acamprosate taken with a weighted mean of 81.5% (range; 54.2% to 95%) [17-25]. Pearson’s correlation found no statistically significant correlation between the length of treatment with acamprosate and the percentage of prescribed medication taken (r = -0.308, p = 0.357). Two studies reported the proportion of participants taking at least 80% of prescribed acamprosate with a weighted mean of 84.9% of participants (range; 56.4% to 91.3%) [26, 27]. Three studies did not report adherence rates but stated that there were no differences between the acamprosate and placebo groups [28-30]. The final trial reported 76.9–84.5% of participants had regular intake of acamprosate during the trial with no differences between groups but no definition of regular intake was given [31]. The adherence assurance scores are reported in Table 2, all of which had a low adherence-assurance rating. All but one trial [29] used pill count to assess adherence to acamprosate, with ten of the trials relying solely on pill count. In addition to pill count, two trials utilised biological methods, Mason et al., [25] used plasma to monitor acamprosate adherence and Sass et al., [30] used urine analysis of acamprosate. Investigator assessment was used in addition to pill count by one trial [31] and a daily monitoring card was used by another trial [26]. A daily dosing card completed by participants was used as the only method of adherence assessment in in one trial [29]. All eligible studies were judged to have a high risk of bias, which was largely due to risk of bias arising from missing data (S1 Table).

Table 2

Adherence-assurance rating for acamprosate.

	Monitoring method A				Monitoring method B
Study	Method	Adherence assurance score	Frequency (%)	Subscore	Method/confidence	Adherence assurance score	Frequency (%)	Subscore	Raw score (%)	Normal score (%)	Adherence assurance rating
Acamprosate
Anton 2006	Pill count	1	100	100					100	33	Low
Berger 2013	Pill count	1	100	100					100	33	Low
Besson 1998	Pill count	1	100	100					100	33	Low
Geerlings 1997	Pill count	1	100	100					100	33	Low
Gual 2001	Not reported
Higuchi 2015	Self-complete daily dosing diary	1	100	100					100	33	Low
Kiefer 2003	Pill count	1	100	100					100	33	Low
Mann 2013	Pill count	1	100	100					100	33	Low
Mason 2006	Pill count	1	100	100	Plasma acamprosate	2	2	4	104	35	Low
Morley 2006	PIll count and self report	1	100	100	Daily monitoring card	1	100	100	100	33	Low
Paille 1995	Pill count	1	100	100					100	33	Low
Pelc 1997	Pill count	1	100	100					100	33	Low
Sass 1996	Pill count	1	100	100	Urine-analysis of acamprosate levels	2	Not reported	Unknown	100	33	Low
Tempesta 2000	Pill count	1	100	100	Investigator assessment	1	100	100	100	33	Low
Wölwer 2011	Pill count	1	100	100					100	33	Low

Discussion

Percentage of acamprosate taken during the clinical trials varied from 54.2% of prescribed medication taken to as high as 95%. However, the reliability of the methods used to measure adherence is low with the majority of trials relying on pill count. The risk of bias for the included trials was high, this was largely due to risk of bias arising from missing data. Dropout rates for the included trials was often high and it was unclear if this was taken into consideration when calculating adherence. Adherence rates may therefore have been inflated by only including those who completed the trial, which would be biased towards those who were adherent to acamprosate.

Since clinical trials offer a controlled environment where adherence can be monitored by research staff, medication non-adherence in usual clinical practice is likely to be greater. NICE [4] recommends that pharmacotherapies for alcohol relapse prevention are taken for at least 6 months, however, the length of time that these medications are taken often falls short of this. [32]. Therefore, service users may not be gaining the maximum benefit from acamprosate through poor medication adherence and not taking the medication for a sufficient period of time.

The impact of medication adherence on treatment effectiveness has been explored in research investigating the effect of adherence to acamprosate on alcohol outcomes. There is some evidence to suggest that non-adherence to acamprosate early in treatment is associated with poorer drinking outcomes [9, 33]. Effective methods of improving adherence to medications for alcohol relapse prevention are needed in both clinical trials and clinical practice. Simple interventions such as using text messages, dosette boxes and alarms to remind patients to take their medication are of value [34-36]. More complex psychosocial interventions such as Compliance Enhancement Therapy (CET) and Medical Management (MM) have been successfully used in clinical trials to support improved adherence to medication for those with alcohol dependence by promoting positive beliefs about medication and patient addressing concerns [17, 37]. Despite the successful inclusion of psychosocial interventions to enhance adherence in clinical trials, there has been little research into its application in a more typical clinical setting. Psychosocial interventions supporting adherence to medications for alcohol relapse prevention may not be directly transferable to clinical practice due to the burden on staff and costs of delivery [38]. Further research into how we can best support people completing treatment for alcohol dependence to take acamprosate as prescribed is needed.

This systematic review has identified a low confidence in the measures used to report adherence. A hierarchy from low to high confidence in the method used to monitor adherence to naltrexone has been proposed by Swift et al. [15]. The hierarchy, based on a patient’s ability to evade measurement of adherence, considered patient self-report and counting returned pills to have a “low” confidence. A “medium” confidence was assigned to Medication Events Monitoring System (MEMS) caps to electronically monitor pill bottle opening, or biomarkers such as the addition of riboflavin. Methods considered to have a “High” confidence included supervision of dosing, long-acting injectable preparations, or monitoring of the level of prescribed medication in the blood. Poor measurement and reporting of adherence to medications in clinical trials may lead to incorrect assertions about efficacy being made. Robust measurement is essential to ensure an accurate picture of medication adherence, which may be achieved using a combination of methods that are high/medium as well as low confidence. The implementation of standardised reporting of adherence rates and accurate, high confidence adherence measurement methods in clinical trials would assist with comparison of efficacy results across trials.

Limitations

The results of this systematic review should be interpreted considering some limitations to the research. Studies were heterogeneous in their method, measurement and reporting of adherence to acamprosate making comparison between studies difficult and further subgroup analysis not possible. Adherence measures and methods were often poorly described in the trial papers making it difficult to determine the impact of missing data bias. The review only included papers published in English due to the language limitations of the authors. We were unable to assess publication bias in this systematic review. It is possible that publication bias could have led to an overestimation of the rates of adherence to acamprosate in clinical trials. There is an association between adherence to acamprosate and its efficacy and therefore unpublished trials with negative results may have had greater rates of non-adherence to acamprosate.

Conclusions

The efficacy of acamprosate for alcohol relapse prevention is well documented. However, poor adherence to acamprosate may impact on its effectiveness in clinical practice. Pill count was the most common method of monitoring adherence, which has a low confidence. The method for measuring adherence was often poorly described and varied across studies identified in this review; harmonisation of these methods across studies would make comparison easier and results more transparent.

PRISMA 2020 for abstracts checklist.

(DOCX)

Click here for additional data file.

PRISMA 2020 checklist.

(DOCX)

Click here for additional data file.

Search strategy.

(PDF)

Click here for additional data file.

Risk of bias.

(DOCX)

Click here for additional data file.

14 Nov 2021

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Tariq Jamal Siddiqi

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Thank you for submitting the above manuscript to PLOS ONE. During our internal evaluation of the manuscript, we found significant text overlap between your submission and the following previously published works, some of which you are an author.

- http://docplayer.net/13017100-Protocol-number-page-1-of-30.html

The text that needs to be addressed involves the final paragraph of the Discussion.

We would like to make you aware that copying extracts from previous publications, especially outside the methods section, word-for-word is unacceptable. In addition, the reproduction of text from published reports has implications for the copyright that may apply to the publications.

Please revise the manuscript to rephrase the duplicated text. Please note that further consideration is dependent on the submission of a manuscript that addresses these concerns about the overlap in text with published work.

Additional Editor Comments:

Donoghue et al. has performed a systematic review on, “The rates and measurement of adherence to acamprosate in randomised controlled clinical trials” in which they show that adherence to acamprosate is poor. In my opinion, this study can be improved by incorporating the following points:

1. The exclusion criteria needs to be clearly mentioned in the methods section of the study.

2. Mentioning which particular factors were assessed in the risk of bias of RCTs can improve the quality of methods.

3. The company for the software used in data analysis is not mentioned.

4. Any sensitivity analysis that was performed is not clearly mentioned in the study.

5. The results can be improved by including the mentioning the results of trial quality assessment as well.

6. There is no evidence for how the heterogeneity of the results was improved.

7. It is not stated whether any tests for assessing the publication bias were used or not.

8. Future implications regarding the trials required or the gap in literature which can be covered is not clearly mentioned.

9. Subgroups analysis was not performed on the results which would have improved the quality of results further.

10. The discussion can be improved by discussing more about the gaps in the literature and how this study has identified new aspects in this field which can be significant in improving the medical literature.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

15 Dec 2021

Journal requirements

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming

Thank you for raising this, we have consulted PLOS ONE’s style requirements and amended as applicable.

2. Thank you for submitting the above manuscript to PLOS ONE. During our internal evaluation of the manuscript, we found significant text overlap between your submission and the following previously published works, some of which you are an author.

Apologies for this oversight. The work in question is our unpublished trial protocol that is freely available through the funder’s website. The text has been amended as below;

Original text

Swift et al. [15] suggest a hierarchy from low to high confidence in the method of adherence monitoring for naltrexone based on a patient’s ability to evade measurement of adherence. Patient self-report, counting of returned medication or inspection of blister packs were assigned “low” confidence, electronic monitoring of pill bottle opening (Medication Events Monitoring System (MEMS) caps) or biomarkers such as the addition of riboflavin were assigned a “medium” confidence. “High” confidence was assigned to supervised dosing, long-acting injectable preparations, or monitoring of blood levels of the prescribed medication.

Updated text

A hierarchy from low to high confidence in the method used to monitor adherence to naltrexone has been proposed by Swift et al. [15]. The hierarchy, based on a patient’s ability to evade measurement of adherence, considered patient self-report and counting returned pills to have a “low” confidence. A “medium” confidence was assigned to Medication Events Monitoring System (MEMS) caps to electronically monitor pill bottle opening, or biomarkers such as the addition of riboflavin. Methods considered to have a “High” confidence included supervision of dosing, long-acting injectable preparations, or monitoring of the level of prescribed medication in the blood.

Additional Editor Comments

1. The exclusion criteria needs to be clearly mentioned in the methods section of the study.

The exclusion criteria have been stated more clearly in the methods as follows (line 100-101);

Studies were excluded if they used a cross-over or open label design or included pregnant women.

2. Mentioning which particular factors were assessed in the risk of bias of RCTs can improve the quality of methods.

The following text has been added (line 155-157);

Eligible studies were assessed for risk of bias using the Cochrane Risk of Bias Tool [16], which included risk of bias arising from the randomisation process, deviations from the intended interventions, missing outcome data, measurement of the outcome and selection of the reported results.

3. The company for the software used in data analysis is not mentioned.

The following has been added (line 133);

If separate percentages are reported for different sub-groups, for example type of psychological therapy received, all were included in the adherence rate calculations that were completed in Microsoft Excel.

And also (line 138-139)

The method described by Swift et al. [15] was used to calculate an adherence-assurance score for the trials included in this review. All data was entered into Microsoft Word and calculated manually.

4. Any sensitivity analysis that was performed is not clearly mentioned in the study.

We explored the relationship between study length and adherence and found no relationship (line 169 to 171);

Pearson’s correlation found no statistically significant correlation between the length of treatment with acamprosate and the percentage of prescribed medication taken (r=-0.308, p=0.357).

5. The results can be improved by including the mentioning the results of trial quality assessment as well.

Risk of bias is already mentioned on (line 183-184);

All eligible studies were judged to have a high risk of bias, which was largely due to risk of bias arising from missing data (S2 table).

6. There is no evidence for how the heterogeneity of the results was improved.

This paper sought to determine the rates of adherence to acamprosate and the reliability of the adherence monitoring and measurement methods. Identifying heterogeneity was therefore part of the aims of the paper. We therefore do not think it is appropriate to look at improving heterogeneity for this paper.

7. It is not stated whether any tests for assessing the publication bias were used or not.

Thank you for highlighting this, we have added the following to the limitations (line 242-246);

We were unable to assess publication bias in this systematic review. It is possible that publication bias could have led to an overestimation of the rates of adherence to acamprosate in clinical trials. There is an association between adherence to acamprosate and its efficacy and therefore unpublished trials with negative results may have had greater rates of non-adherence to acamprosate.

8. Future implications regarding the trials required or the gap in literature which can be covered is not clearly mentioned.

Thank you for this suggestion we have added the following text (line 215-216);

Despite the successful inclusion of psychosocial interventions to enhance adherence in clinical trials, there has been little research into its application in a more typical clinical setting. Psychosocial interventions supporting adherence to medications for alcohol relapse prevention may not be directly transferable to clinical practice due to the burden on staff and costs of delivery [17, 37]. Further research into how we can best support people completing treatment for alcohol dependence to take acamprosate as prescribed is needed.

9. Subgroups analysis was not performed on the results which would have improved the quality of results further.

Thank you for this suggestion. There was a wide variation in the reporting of adherence with some studies using percentage of participants who took 80% of medication prescribed and others reporting the mean percentage of medication taken. Consequently, there was limited data to perform further subgroup analysis. The following has been added to the limitations section (line 239-240);

Studies were heterogeneous in their method, measurement and reporting of adherence to acamprosate making comparison between studies difficult and further subgroup analysis not possible.

10. The discussion can be improved by discussing more about the gaps in the literature and how this study has identified new aspects in this field which can be significant in improving the medical literature.

Please see number 8 above and we have also amended the following to be clearer in our discussion about the gaps in current research (line 233-234);

The implementation of standardised reporting of adherence rates and accurate, high confidence adherence measurement methods in clinical trials would assist with comparison of efficacy results across trials.

Submitted filename: Response to reviewers.docx

Click here for additional data file.

18 Jan 2022

The rates and measurement of adherence to acamprosate in randomised controlled clinical trials: A systematic review

PONE-D-21-32169R1

Dear Dr. Donoghue,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Tariq Jamal Siddiqi

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

24 Jan 2022

PONE-D-21-32169R1

The rates and measurement of adherence to acamprosate in randomised controlled clinical trials: A systematic review

Dear Dr. Donoghue:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Tariq Jamal Siddiqi

Academic Editor

PLOS ONE