Adding a treatment arm to an ongoing clinical trial: a review of methodology and practice

Incorporating an emerging therapy as a new randomisation arm in a clinical trial that is open to recruitment would be desirable to researchers, regulators and patients to ensure that the trial remains current, new treatments are evaluated as quickly as possible, and the time and cost for determining optimal therapies is minimised. It may take many years to run a clinical trial from concept to reporting within a rapidly changing drug development environment; hence, in order for trials to be most useful to inform policy and practice, it is advantageous for them to be able to adapt to emerging therapeutic developments. This paper reports a comprehensive literature review on methodologies for, and practical examples of, amending an ongoing clinical trial by adding a new treatment arm. Relevant methodological literature describing statistical considerations required when making this specific type of amendment is identified, and the key statistical concepts when planning the addition of a new treatment arm are extracted, assessed and summarised. For completeness, this includes an assessment of statistical recommendations within general adaptive design guidance documents. Examples of confirmatory ongoing trials designed within the frequentist framework that have added an arm in practice are reported; and the details of the amendment are reviewed. An assessment is made as to how well the relevant statistical considerations were addressed in practice, and the related implications. The literature review confirmed that there is currently no clear methodological guidance on this topic, but that guidance would be advantageous to help this efficient design amendment to be used more frequently and appropriately in practice. Eight confirmatory trials were identified to have added a treatment arm, suggesting that trials can benefit from this amendment and that it can be practically feasible; however, the trials were not always able to address the key statistical considerations, often leading to uninterpretable or invalid outcomes. If the statistical concepts identified within this review are considered and addressed during the design of a trial amendment, it is possible to effectively assess a new treatment arm within an ongoing trial without compromising the original trial outcomes.

Flexible selection of a single treatment incorporating short-term endpoint information in a phase II/III clinical trial

Seamless phase II/III clinical trials in which an experimental treatment is selected at an interim analysis have been the focus of much recent research interest. Many of the methods proposed are based on the group sequential approach. This paper considers designs of this type in which the treatment selection can be based on short-term endpoint information for more patients than have primary endpoint data available. We show that in such a case, the familywise type I error rate may be inflated if previously proposed group sequential methods are used and the treatment selection rule is not specified in advance. A method is proposed to avoid this inflation by considering the treatment selection that maximises the conditional error given the data available at the interim analysis. A simulation study is reported that illustrates the type I error rate inflation and compares the power of the new approach with two other methods: a combination testing approach and a group sequential method that does not use the short-term endpoint data, both of which also strongly control the type I error rate. The new method is also illustrated through application to a study in Alzheimer's disease. © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Prospective Clinical Trial Comparing Outcome Measures Between Furlow and von Langenbeck Palatoplasties for UCLP

The goal of this prospective randomized clinical trial was to compare 2 cohorts of standardized cleft patients with regard to functional speech outcome and the presence or absence of palatal fistulae. The 2 cohorts are randomized to undergo either a conventional von Langenbeck repair with intravelar velarplasty or the double-opposing Z-plasty Furlow procedure. A prospective 2 x 2 x 2 factorial clinical trial was used in which each subject was randomly assigned to 1 of 8 different groups: 1 of 2 different lip repairs (Spina vs. Millard), 1 of 2 different palatal repair (von Langenbeck vs. Furlow), and 1 of 2 different ages at time of palatal surgery (9-12 months vs. 15-18 months). All surgeries were performed by the same 4 surgeons. A cul-de-sac test of hypernasality and a mirror test of nasal air emission were selected as primary outcome measures for velopharyngeal function. Both a surgeon and speech pathologist examined patients for the presence of palatal fistulae. In this study, the Furlow double-opposing Z-palatoplasty resulted in significantly better velopharyngeal function for speech than the von Langenbeck procedure as determined by the perceptual cul-de-sac test of hypernasality. Fistula occurrence was significantly higher for the Furlow procedure than for the von Langenbeck. Fistulas were more likely to occur in patients with wider clefts and when relaxing incisions were not used.

No effect of eccentric training on jumper's knee in volleyball plays. During the competitive season : a randomized clinical trial

Background: The effect of surgery on patellar tendinopathy (jumper's knee) is questionable, and conservative treatment protocols have not been properly documented.

Purpose: The aim of this study was to investigate the effect of a newly developed eccentric training program for patellar tendinopathy in volleyball players during the competitive season.

Study Design: Randomized clinical trial.

Methods: Patients were recruited from male and female elite volleyball teams in Norway, and the diagnosis was based on clinical examination alone. Of 51 players diagnosed with patellar tendinopathy, 29 could be included in the study. The training group (n = 13) performed squats on a 25° decline board as a home exercise program (3 × 15 repetitions twice daily) for a 12-week intervention period during the final half of the competitive season. The eccentric (downward) component was done on the affected leg. The control group (n = 16) trained as usual. The primary outcome was a symptom-based questionnaire developed specifically for patellar tendinopathy (Victorian Institute of Sport Assessment score), and patients were followed up before and after the intervention period, as well as after 6 and 30 weeks. All subjects self-recorded training to document their activity level (eccentric training, volleyball training, matches, other training).

Results: There was no change in Victorian Institute of Sport Assessment score during the intervention period in the training (pre, 71.1 ± 11.3; post, 70.2 ± 15.4) or control group (pre, 76.4 ± 12.1; post, 75.4 ± 16.7), nor was there any change during the follow-up period at 6 weeks or 6 months. The training group completed 8.2 ± 4.6 weekly sessions of eccentric training during the intervention period (59% of the recommended volume), and there was no difference between groups in training or competition load.

Conclusion: There was no effect on knee function from a 12-week program with eccentric training among a group of volleyball players with patellar tendinopathy who continued to train and compete during the treatment period. Whether the training would be effective if the patients did not participate in sports activity is not known.

Single vs. two steroid injections for carpal tunnel syndrome: a randomised clinical trial

We investigated the efficacy of a single vs. double steroid injections in the treatment of carpal tunnel syndrome (CTS) in a randomised double-blind controlled trial. Patients with idiopathic CTS were randomised into (i) one group receiving a baseline methylprednisolone acetate injection plus a saline injection 8 weeks later and (ii) a second group receiving methylprednisolone acetate injection at baseline and at 8 weeks. The primary outcome was the Global Symptom Score (GSS). Forty patients were recruited. By 40 weeks, the mean GSS improved from 25.6 to 14.1 in the single-injection group whereas from 26.7 to 12.6 in the reinjection group, but there was no significant difference in GSS between the two groups (p = 0.26). There were also no significant differences in terms of electrophysiological and functional outcomes. The results suggest that an additional steroid injection confers no added benefit to a single injection in terms of symptom relief.

The validity and internal structure of the bipolar depression rating scale (BDRS): data from a clinical trial of N-acetylcysteine as adjunctive therapy in bipolar disorder

Background: The phenomenology of unipolar and bipolar disorders differ in a number of ways, such as the presence of mixed states and atypical features. Conventional depression rating instruments are designed to capture the characteristics of unipolar depression and have limitations in capturing the breadth of bipolar disorder.

Method: The Bipolar Depression Rating Scale (BDRS) was administered together with the Montgomery Asberg Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) in a double-blind randomised placebo-controlled clinical trial of N-acetyl cysteine for bipolar disorder (N = 75).

Results: A factor analysis showed a two-factor solution: depression and mixed symptom clusters. The BDRS has strong internal consistency (Cronbach's alpha = 0.917), the depression cluster showed robust correlation with the MADRS (r = 0.865) and the mixed subscale correlated with the YMRS (r = 0.750).

Conclusion: The BDRS has good internal validity and inter-rater reliability and is sensitive to change in the context of a clinical trial.

Effects of N-acetylcysteine on substance use in bipolar disorder : a randomized placebo controlled clinical trial

Objective: To evaluate the effect of N-acetylcysteine (NAC) on substance use in a double-blind, placebo-controlled trial of NAC in bipolar disorder. It is hypothesised that NAC will be superior to placebo for reducing scores on the Clinical Global Impressions scale for Substance Use (CGI-SU).

Methods: Participants were randomised to 6-months of treatment with 2 g/day NAC (n = 38) or placebo (n = 37). Substance use was assessed at baseline using the Habits instrument. Change in substance use was assessed at regular study visits using the CGI-SU.

Results: Amongst the 75 participants 78.7% drank alcohol (any frequency), 45.3% smoked tobacco and 92% consumer caffeine. Other substances were used by fewer than six participants. Caffeine use was significantly lower for NAC-treated participants compared with placebo at week 2 of treatment but not at other study visits.

Conclusion: NAC appeared to have little effect on substance use in this population. A larger study on a substance using population will be necessary to determine if NAC may be a useful treatment for substance use.

Maximising clinical trial participation - how important is the social context?

Individuals participate in clinical research for a variety of reasons, dependant not only on the trial phase and their own clinical status but also their sense of optimism, altruism, clinician influence, or financial gain. Practical factors influencing participation may include geographical access, motivation, availability, and language spoken. Widely-used health psychology models (e.g the Theory of Reasoned Action, the Health Belief Model) demonstrate that, in addition to these factors, the primary reason for non-participation in clinical research is social perception of risk. These models detail how beliefs and attitudes toward clinical research develop within, and are influenced by, an individual's social context. Perceived social benefits and barriers toward participation are considered alongside perceived susceptibility and severity of side-effects from participation, or symptoms of disease. A major factor in such models is the subjective norm i.e. individuals' beliefs that important others expect or wish him/her to perform this behaviour, and the motivation to act in accordance with their expectations or wishes. This includes, but is not limited to, the role of the media, peers and family members, clarification of risk associated with trial participation and discussion of comparative risk, and risk equivalence between trials and same treatment outside trials.
The workshop will involve a 30 minute presentation from the discussion leaders and a 30 minute group-work session to explore how an understanding of the social context of participation in clinical research can maximise appropriate clinical trial participation.