Designing a series of clinical trials

This thesis presents designs for a series of clinical trials where instead of designing clinical trials individually, each of the trials is designed as part of a series of trials. The framework of the design is based on a combination of classical frequentist and Bayesian approaches which is sometimes known as the hybrid approach. The unknown parameter of the treatment efficacy is assumed to be random and follows a prior distribution in the design stage but at the end of the trial a frequentist test statistic is used on the observed data to infer the parameter. The design introduced in Chapter 5 aims to determine an optimum sample size for each trial by optimizing the average power of each trial and the overall resources while fixing the conventional type I error. The design has the exibility to either run sequentially or concurrently. The design is then extended to allow interim analyses in each trial (Chapter 6). The focus of the extended design is on a series of Bayesian decision-theoretic phase II trials and one frequentist phase III trial. At each interim stage, a decision is made based on the expected utilities of subsequent actions. There are four possible actions to choose from, namely, to continue the current trial by recruiting more patients, to initiate a new phase II trial, to abandon the development plan or to proceed to a phase III trial with this treatment against a control arm. For the last action, the phase III trial is designed with the hybrid methodology as described above. Finally, the prior distributions for each treatments are assumed to be correlated and as information is gathered from the previous and current trials, the current and following prior distributions are updated (Chapter 7)

Value of information methods to design a clinical trial in a small population to optimise a health economic utility function

Background: Most confirmatory randomised controlled clinical trials (RCTs) are designed with specified power, usually 80% or 90%, for a hypothesis test conducted at a given significance level, usually 2.5% for a one-sided test. Approval of the experimental treatment by regulatory agencies is then based on the result of such a significance test with other information to balance the risk of adverse events against the benefit of the treatment to future patients. In the setting of a rare disease, recruiting sufficient patients to achieve conventional error rates for clinically reasonable effect sizes may be infeasible, suggesting that the decision-making process should reflect the size of the target population. Methods: We considered the use of a decision-theoretic value of information (VOI) method to obtain the optimal sample size and significance level for confirmatory RCTs in a range of settings. We assume the decision maker represents society. For simplicity we assume the primary endpoint to be normally distributed with unknown mean following some normal prior distribution representing information on the anticipated effectiveness of the therapy available before the trial. The method is illustrated by an application in an RCT in haemophilia A. We explicitly specify the utility in terms of improvement in primary outcome and compare this with the costs of treating patients, both financial and in terms of potential harm, during the trial and in the future. Results: The optimal sample size for the clinical trial decreases as the size of the population decreases. For non-zero cost of treating future patients, either monetary or in terms of potential harmful effects, stronger evidence is required for approval as the population size increases, though this is not the case if the costs of treating future patients are ignored. Conclusions: Decision-theoretic VOI methods offer a flexible approach with both type I error rate and power (or equivalently trial sample size) depending on the size of the future population for whom the treatment under investigation is intended. This might be particularly suitable for small populations when there is considerable information about the patient population

Approaches to sample size calculation for clinical trials in rare diseases

We discuss 3 alternative approaches to sample size calculation: traditional sample size calculation based on power to show a statistically significant effect, sample size calculation based on assurance, and sample size based on a decision-theoretic approach. These approaches are compared head-to-head for clinical trial situations in rare diseases. Specifically, we consider 3 case studies of rare diseases (Lyell disease, adult-onset Still disease, and cystic fibrosis) with the aim to plan the sample size for an upcoming clinical trial. We outline in detail the reasonable choice of parameters for these approaches for each of the 3 case studies and calculate sample sizes. We stress that the influence of the input parameters needs to be investigated in all approaches and recommend investigating different sample size approaches before deciding finally on the trial size. Highly influencing for the sample size are choice of treatment effect parameter in all approaches and the parameter for the additional cost of the new treatment in the decision-theoretic approach. These should therefore be discussed extensively

A Standardized Transcutaneous Electric Acupoint Stimulation for Relieving Tobacco Urges in Dependent Smokers

The efficacy of acupuncture in smoking cessation, and its effect on the urge to smoke are unclear. We evaluated the effect of a standardized protocol of transcutaneous electric acupoint stimulations (TEAS) on alleviating the urge to smoke. Ninety-eight smokers were recruited in two double-blind studies. Participants abstained from smoking for 26 h, and were randomized to receive TEAS alternating between 2 and 100 Hz at four acupoints (LI4 and PC8, PC6 and TE5) at four different intensities (10, 5, Intermittent 5 or 0 mA). The urge to smoke was assessed by the Questionnaire of Smoking Urges (QSU-Brief). In Experiment 1, the 10 mA group (n = 20) was compared with the 5 mA group (n = 20); the increase in smoking urges did not differ significantly. Considering the possibility that 5 mA may be an active intervention, in Experiment 2, a true placebo (0 mA), and a proxy of placebo [Intermittent 5 mA (i5 mA)] were compared with 10 mA TEAS. In this experiment, 10 mA (n = 20) TEAS showed a tendency to alleviate smoking urges compared with 0 mA (n = 16), and i5 mA (n = 19) TEAS. Only when the data of smokers with Fagerstöm Test for Nicotine Dependence score ≥5 were analyzed that the difference between the 10 mA group and the control group (0 and i5 mA) became significant. Based on these preliminary findings, we conclude that TEAS applied on the skin may antagonize the increase in urge to smoke in abstinent-dependent smokers. It seems warranted to assess the efficacy of TEAS in smoking cessation clinical trials involving a larger population of dependent smokers

A standardized transcutaneous electric acupoint stimulation for relieving tobacco urges in dependent smokers

The efficacy of acupuncture in smoking cessation, and its effect on the urge to smoke are unclear. We evaluated the effect of a standardized protocol of transcutaneous electric acupoint stimulations (TEAS) on alleviating the urge to smoke. Ninety-eight smokers were recruited in two double-blind studies. Participants abstained from smoking for 26 h, and were randomized to receive TEAS alternating between 2 and 100 Hz at four acupoints (LI4 and PC8, PC6 and TE5) at four different intensities (10, 5, Intermittent 5 or 0 mA). The urge to smoke was assessed by the Questionnaire of Smoking Urges (QSU-Brief). In Experiment 1, the 10 mA group (n = 20) was compared with the 5 mA group (n = 20); the increase in smoking urges did not differ significantly. Considering the possibility that 5 mA may be an active intervention, in Experiment 2, a true placebo (0 mA), and a proxy of placebo [Intermittent 5 mA (i5 mA)] were compared with 10 mA TEAS. In this experiment, 10 mA (n = 20) TEAS showed a tendency to alleviate smoking urges compared with 0 mA (n = 16), and i5 mA (n = 19) TEAS. Only when the data of smokers with Fagerstöm Test for Nicotine Dependence score ≥5 were analyzed that the difference between the 10 mA group and the control group (0 and i5 mA) became significant. Based on these preliminary findings, we conclude that TEAS applied on the skin may antagonize the increase in urge to smoke in abstinent-dependent smokers. It seems warranted to assess the efficacy of TEAS in smoking cessation clinical trials involving a larger population of dependent smokers

Does the low prevalence affect the sample size of interventional clinical trials of rare diseases? An analysis of data from the aggregate analysis of clinicaltrials.gov

Background Clinical trials are typically designed using the classical frequentist framework to constrain type I and II error rates. Sample sizes required in such designs typically range from hundreds to thousands of patients which can be challenging for rare diseases. It has been shown that rare disease trials have smaller sample sizes than non-rare disease trials. Indeed some orphan drugs were approved by the European Medicines Agency based on studies with as few as 12 patients. However, some studies supporting marketing authorisation included several hundred patients. In this work, we explore the relationship between disease prevalence and other factors and the size of interventional phase 2 and 3 rare disease trials conducted in the US and/or EU. We downloaded all clinical trials from Aggregate Analysis of ClinialTrials.gov (AACT) and identified rare disease trials by cross-referencing MeSH terms in AACT with the list from Orphadata. We examined the effects of prevalence and phase of study in a multiple linear regression model adjusting for other statistically significant trial characteristics. Results Of 186941 ClinicalTrials.gov trials only 1567 (0.8%) studied a single rare condition with prevalence information from Orphadata. There were 19 (1.2%) trials studying disease with prevalence <1/1,000,000, 126 (8.0%) trials with 1–9/1,000,000, 791 (50.5%) trials with 1–9/100,000 and 631 (40.3%) trials with 1–5/10,000. Of the 1567 trials, 1160 (74%) were phase 2 trials. The fitted mean sample size for the rarest disease (prevalence <1/1,000,000) in phase 2 trials was the lowest (mean, 15.7; 95% CI, 8.7–28.1) but were similar across all the other prevalence classes; mean, 26.2 (16.1–42.6), 33.8 (22.1–51.7) and 35.6 (23.3–54.3) for prevalence 1–9/1,000,000, 1–9/100,000 and 1–5/10,000, respectively. Fitted mean size of phase 3 trials of rarer diseases, <1/1,000,000 (19.2, 6.9–53.2) and 1–9/1,000,000 (33.1, 18.6–58.9), were similar to those in phase 2 but were statistically significant lower than the slightly less rare diseases, 1–9/100,000 (75.3, 48.2–117.6) and 1-5/10,000 (77.7, 49.6–121.8), trials. Conclusions We found that prevalence was associated with the size of phase 3 trials with trials of rarer diseases noticeably smaller than the less rare diseases trials where phase 3 rarer disease (prevalence <1/100,000) trials were more similar in size to those for phase 2 but were larger than those for phase 2 in the less rare disease (prevalence ≥1/100,000) trials

Graft-vs-tumor effect in patients with advanced nasopharyngeal cancer treated with nonmyeloablative allogeneic PBSC transplantation

While nonmyeloablative peripheral blood stem cell transplantation (NST) has shown efficacy against several solid tumors, it is untested in nasopharyngeal cancer (NPC). In a phase II clinical trial, 21 patients with pretreated metastatic NPC underwent NST with sibling PBSC allografts, using CY conditioning, thymic irradiation and in vivo T-cell depletion with thymoglobulin. Stable lymphohematopoietic chimerism was achieved in most patients and prophylactic CYA was tapered at a median of day +30. Seven patients (33%) showed partial response and three (14%) achieved stable disease. Four patients were alive at 2 years and three showed prolonged disease control of 344, 525 and 550 days. With a median follow-up of 209 (4–1147) days, the median PFS was 100 days (95% confidence interval (CI), 66–128 days), and median OS was 209 days (95% CI, 128–236 days). Patients with chronic GVHD had better survival—median OS 426 days (95% CI, 194–NE days) vs 143 days (95% CI, 114–226 days) (P=0.010). Thus, NST may induce meaningful clinical responses in patients with advanced NPC

Protocol update for a randomised controlled feasibility trial of exercise rehabilitation for people with postural tachycardia syndrome: the PULSE study

BACKGROUND: The PULSE (PostUraL tachycardia Syndrome Exercise) study is a randomised controlled trial assessing the feasibility of conducting a multicentre RCT testing supervised exercise rehabilitation with behavioural and motivational support, compared to best-practice usual care, for people with Postural Tachycardia Syndrome (PoTS). The original trial protocol was published in BMC Pilot & Feasibility Studies (accessible at https://doi.org/10.1186/s40814-020-00702-1 ). The PULSE intervention consists of (1) individual assessment; (2) 12-week, twice-weekly, supervised exercise training; (3) behavioural and motivational support; and (4) guided lifestyle physical activity. The control intervention is best-practice usual care with a single 30-min, one-to-one practitioner appointment, and general advice on safe and effective physical activity. Sixty-two people (aged 18-60 years) with a confirmed diagnosis of PoTS will be invited to enrol on a feasibility RCT with an embedded qualitative study. The primary outcome will be feasibility; process-related measures will include eligibility, recruitment, randomisation and withdrawal rates, along with indicators of exercise programme adherence and acceptability. Secondary physiological, clinical and health-related outcomes will be assessed. In response to the COVID-19 pandemic, here we describe amendments to the trial protocol. METHODS: Restrictions imposed by the COVID-19 pandemic meant it was necessary to change the delivery of the PULSE and control interventions. These changes reflected the need to limit the risk of COVID-19 transmission in a clinical population, some of whom were at increased risk of contracting the virus and suffering serious illness. The major change was that the originally intended centre-based PULSE and control interventions would now be delivered remotely on-line. Subsequently, there were minor changes to the participant eligibility criteria. These decisions followed an on-line co-creation session with people affected by PoTS, and relevant public and professional stakeholders. CONCLUSIONS: We present an update of the original trial protocol in response to the COVID-19 pandemic. No participants were recruited to the original protocol; thus, results will reflect the on-line delivery of the intervention. PULSE will be the first randomised trial to assess the feasibility of conducting a definitive multi-centre RCT testing supervised on-line exercise rehabilitation with behavioural and motivational support, compared to best-practice usual care, for people with PoTS. TRIAL REGISTRATION: ISRCTN45323485 registered on 7 April 2020