Study 329 continuation phase: Safety and efficacy of paroxetine and imipramine in extended treatment of adolescent major depression

2.1 Participants

The acute phase participants comprised 275 adolescents between the ages of 12 and 18 years, meeting DSM-IV criteria [9] for a current episode of major depression of at least eight weeks’ duration(see Le Noury et al. [3] for details of eligibility criteria, standardization across sites, randomization, blinding, recruitment, screening, consent, demographic and baseline characteristics). In the continuation phase, patients who had responded to treatment were eligible to continue on the same medication at the same dosage for an additional six months.

Some participants were not able to progress to the continuation phase because of a shortage of study medication supplies, resulting from a slower-than-expected rate of enrollment, which led to some of the medication expiring before use (CSR, p. 000027), Amendment 2 of the Study 329 protocol (approved 28 October 1996) provided two options for these patients: treatment by a third party, who was provided with the identity of the study medication, or open-label paroxetine treatment for up to six months (after a one-week down-titration and washout period) by the study physician (p. 000538).

2.2 Interventions

Study medication was provided to patients in weekly blister packs. Patients were instructed to take the medication twice daily. There were six dosing levels. Over the first four weeks of the acute phase, all patients were titrated to level 4, corresponding to paroxetine 20 mg or imipramine 200 mg, regardless of response. Non-responders (those failing to reach responder criteria) could be titrated over the following four weeks up to level 5 or 6, corresponding to a maximum dose of 60 mg paroxetine 60 mg and 300 mg imipramine.

Medication compliance was evaluated based on the number of capsules dispensed, taken, and empty blister packs returned. Non-compliance was defined as taking less than 80% or more than 120% of the number of capsules expected to be returned at two consecutive visits, and resulted in withdrawal from the study. Any patient missing two consecutive visits was also withdrawn.

Patients were provided with 45-minute weekly sessions of supportive psychotherapy, [10] primarily for the purpose of assessing the treatment effects.

2.3 Taper phase

A discontinuation taper phase was recommended for all patients, whether terminating the study early (during both the acute and continuation phase), or completing the acute phase but not continuing, or completing the six-month continuation phase. If the patient accepted a taper phase, the protocol recommended tapering medication/placebo in a linear fashion over a seven to 17 day period, with patient, family, and clinical and research personnel all remaining blind to medication assignment.

Not all patients agreed to a taper phase. For those who did taper their medication, it was difficult in some cases to be certain of the exact duration of exposure, because the date of last dose was left incomplete. We have used the exact number of days where available, and for other patients we have assumed an average taper phase of 2 weeks, unless there were indications to the contrary. The taper phase includes patients tapering during the acute phase as well as the continuation phase, so there are more patients in the taper phase than in the continuation phase.

2.4 Outcomes

Patients were evaluated every four weeks from week 12 to week 32 during the six months of the continuation phase.

2.5 Sources of safety data

Adverse event data come from the CSR of the continuation phase lodged on GSK’s website, primarily Appendix D: Patient Data Listings of Adverse Experiences. Appendix B provides details of concomitant medications. Additional information was available from the summary narratives in the body of the CSR for patients who had adverse events that were designated as serious or led to withdrawal. However, a number of other patients discontinued because of adverse events that were not regarded as serious, or discontinued because of lack of efficacy or protocol violations, did not generate patient narratives.

The tables in Appendix D of the CSR report the verbatim terms used by the blinded investigators along with preferred terms as coded by SKB using the Adverse Drug Events Coding System (ADECS) dictionary. Appendix D also includes ratings of severity and ratings of relatedness. We used the MedicalDictionary for Regulatory Activities (MedDRA^®) to code the verbatim terms provided in CSR Appendix D. MedDRA terminology is the international medical terminology developed under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) www.meddra.org). It has been endorsed by the United States Food and Drug Administration (FDA) and is now used by GSK [11].

Our analysis of the acute phase [3] had established that there are significant adverse event data missing from CSR Appendix D, so all CRFs for all patients entering the continuation phase were scrutinised for all adverse events occurring during the continuation phase. These adverse events were compared with those reported in CSR Appendix D. This review process identified additional adverse events that had not been recorded as verbatim terms in CSR Appendix D. It also led to recoding of a number of the reasons for discontinuation. The new adverse events and the reasons for changing discontinuation category are recorded in RIAT Appendix 2 accompanying this paper.

2.6 Coding of adverse events

The protocol (p. 000574) stated that adverse events were to be coded by body system and preferred terms, and compared using descriptive statistics, but did not specify a coding dictionary. The CSR (written after the study concluded) specified that adverse events were coded using the Adverse Drug Experience Coding System (ADECS), which SKB used at the time (p. 000044). ADECS was derived from a coding system developed by the FDA, Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART), but ADECS is not itself a recognized system and is no longer available.

We coded adverse events using MedDRA, which has replaced COSTART for the FDA, because it is by far the most commonly used coding system today. For coding purposes, we have taken the original terms used by the clinical investigators as transcribed into the CSR Appendix D, and applied MedDRA codes to these descriptions. Information from Appendix D was transcribed into spreadsheets (available at Restoring Study329.org). The verbatim terms and the ADECS coding terms were transcribed first into these sheets, allowing all coding to be done before the drug names were added in. The transcription was carried out by a research assistant who was a MedDRA trained coder, but took no part in the actual coding. All coding was carried out by JLN, and checked by DH, or vice versa.

All of our coding from the verbatim terms in the CSR Appendix D was done blind, as was coding from the CRFs.

In general, MedDRA coding stays closer to the original clinician description of the event than ADECS. Most coding was straightforward. The vast majority of the verbatim terms simply mapped onto coding terms in MedDRA. The main coding challenges arose in relation to suicide-related events in the acute phase; these are covered in Le Noury et al. [3].

2.7 Analysis of safety data

As in our acute study re-analysis, in analysing the safety data, we present all adverse events rather than only those happening at a particular rate. Secondly, we have grouped events into broader system-organ-class (SOC) groups–psychiatric, cardiovascular, gastrointestinal, respiratory and other. Thirdly, we break down events by severity, selecting adverse events coded as severe, and utilising the listing in the CSR (Appendix G) of patients who discontinued for any reason.

In our acute study re-analysis [3], we laid out our categorization of suicidal events in detail. These were events whose coding in our opinion should have included a suicide-related code. There were also a considerable number of events coded under headings such as nightmares or abnormal thoughts. At the time this study was conceived and executed, few investigators or patients were familiar with the phenomenon of treatment-induced behavioral change, up to and including suicidality, and no rating instruments were included to ensure that such events were recorded systematically. Investigators and patients were apparently not briefed on this possibility. It is possible that a number of treatment induced behavioral disturbances would have been communicated obliquely. We have therefore taken events that might conceal a suicide-related event and presented these together in Table 12a, along with more clearly suicide-related events. The details of all patients included in this way are laid out in Table 12b.

As the acute and continuation phases are of very different duration, and a significant number of patients dropped out in the course of the continuation phase, a simple listing of the adverse events from each phase risks misleading. We have therefore presented the total number of events but also estimated the rate at which events occurred by duration of exposure.

2.8 Data access

We have made available on Study329.org all the data we have used, with the exception of the actual CRFs, which we do not have permission to share.

2.9 Statistical methods

No formal hypothesis testing was planned for the continuation phase. We applied ANOVA testing (generalized linear model) using a model including effects of site, treatment, and site×treatment interaction as per the Study 329 protocol. Otherwise we used only descriptive statistics.

3.1 Efficacy

The overall profiles of HAM-D scores for observed cases in both acute and continuation phases for all three arms of the study are presented in Fig. 1.

Although efficacy could be assessed for the acute phase, the dropout rates between the acute and continuation phases and within the continuation phase were too high to allow a standard efficacy analysis. In the continuation phase, the dropout rates were 30/49 [61%] for paroxetine; 27/39 [69%] for imipramine; and 18/31 [58%] for placebo.

Table 3 shows response (remission) and relapse rates, which ranged from 21% for placebo to 41% for paroxetine. We have included in Table 3 a category of potential completers, to take into account 13 patients who dropped out of the study although their HAM-D scores were well within the responder range (HAM-D of 2 or 3). Some of them were discontinued because further blinded treatment was unavailable; for others, no clear explanation for discontinuation was given.

3.2 Discontinuations

During the continuation phase, 75 patients discontinued (30 from paroxetine, 27 from imipramine and 18 from placebo). The reasons for discontinuation are given in Table 4. Table 4 in RIAT Appendix 2 gives a breakdown of when these dropouts occurred.

Following a review of the codes given for reasons for withdrawal from the study that were found in the CSR (Appendix G), along with a review of patient narratives and CRFs where applicable, we proposed changes to these reasons for withdrawal in a proportion of those discontinued. These proposed changes can be found in Table 5 in RIAT Appendix 2.

3.3 Safety

Table 5 gives the number of adverse events reported by SKB in their continuation phase CSR. The report only provides data on events happening at a 5% or greater rate.

This can be contrasted with the data in Table 6, which presents all adverse events found in both CSR Appendix D and the CRFs, summarised by System Organ Class (SOC). In MedDRA, some adverse events always fall within a particular SOC; others require that the coder choose between SOCs. A full summary and full breakdown of adverse events can be found in Tables 1 and 2 in RIAT Appendix 2.

3.4 Severity ratings

Designating adverse events as serious hinged on the judgement of the clinical investigator. We are therefore not able to make comparable judgements of seriousness, but there are two other methods to approach the issue of severity of adverse events. One is to look at those rated as severe rather than moderate or mild at the time of the event (see Table 7).

A full breakdown of the severe adverse events within each SOC can be found in Table 3 of RIAT Appendix 2. A second method is to look at those that led to dropouts (Table 4).

3.5 Adverse events by exposure

As there were a large number of discontinuations in the continuation phase, a simple listing of adverse events may tell a different story from an analysis of these events in proportion to the duration of exposure.

Table 8 shows the weeks of exposure for each group in each phase. Tables 9 and 10 show the numbers of adverse events and severe adverse events in each phase, with the rates per 100 weeks exposure displayed in Figs. 2 and 3.

We have also looked at all behavioral adverse events in each phase (Table 11 and Fig. 4). These events include: agitation, aggravated depression, akathisia, abnormal dreams, depersonalisation,disinhibition, feelings of despair, hallucinations, impulsive behavior, negative thoughts, neurosis, paranoia, psychosis, suicide attempt, suicidal ideation, suicidal gesture, self-harm, and self-injury.

Table 12 gives the numbers of suicidal adverse events in each phase, with the rates per 100 weeks exposure displayed in Fig. 5. A full listing of all patients who experienced potentially suicidal events is presented in Table 13.

3.6 Adverse event profile of patients entering the continuation phase

Patients who completed acute and continuation phases may belong to different cohorts. Accordingly we analysed the acute-phase adverse event profiles of patients who entered the continuation phase, compared with those who did not, shown in Table 13. A full breakdown of all these adverse events can be found in Table 12 in RIAT Appendix 2.