Master of Science / Department of Statistics / Christopher Vahl / Non-inferiority trials have been widely used in many medical areas. The goal of a non-inferiority trial is to show that a new test therapy is either better or not too much worse than the active control rather than showing the test therapy is superior to a negative control (i.e. placebo). The appeal of a non-inferiority trial is that it is often unethical to give some patients a treatment with no therapeutic benefit. When designing a non-inferiority trial, the issues of assay sensitivity, sample size, constancy condition, and a suitable non-inferiority margin need to be considered. A poor choice of the non-inferiority margin is a major reason that many non-inferiority trials fail. A numerical example is presented to show how to estimate the non-inferiority margin without historical data.

Dysarthria describes the impaired speech intelligibility caused by weakness of muscles involved in speech following stroke. This is a common consequence of stroke and can have a detrimental impact on self-confidence leading to social isolation for many. There is limited evidence for dysarthria intervention but we know that research into speech difficulties after stroke is a priority for stroke survivors. An online speech rehabilitation programme was developed, ReaDySpeech, with the potential to offer improved quality of independent practice, increased intensity of practice and the ability to record interaction. The research presented in this thesis aimed to systematically examine the existing evidence base, to carry out some preliminary acceptability work on ReaDySpeech, and implement a feasibility trial. The initial study was a Cochrane systematic review of the effectiveness of interventions for people with non-progressive dysarthria after stroke or other adult-acquired brain injury. This found insufficient evidence to know whether dysarthria intervention is effective or not. This led to a study of early acceptability work for ReaDySpeech and whether there were any technical barriers to use. This found no significant technical barriers other than lack of Wi-Fi and it was acceptable to participants and therapists. This enabled a progression to a feasibility trial following amendments and improvements to the protocol and ReaDySpeech itself. The feasibility trial found recruitment, retention and the intervention were all feasible to carry out during a trial. Further in-depth consideration of the findings indicates more work is needed to widen recruitment and to develop the intervention, comparator and methodology of a future trial for this to be a success with valid clinical implications. This thesis reports this body of work and discusses potential future directions for dysarthria research.

Tumor biopsies may help to reliably distinguish hepatocellular carcinoma (HCC) from other tumors, mostly cholangiocarcinoma as well as to identify the patient populations who most benefit from target-driven HCC treatments, in order to improve the success rate of experimental therapies. Clarifying tumor biology may also lead to identify biomarkers with prognostic role and/or enabling to predict response or resistance to therapies. Recently, clinical trials have more efficiently included biomarker endpoints and increasingly collected tumor tissue from enrolled patients. Due to their frail status and sometimes fast-progressing disease, the performance status of patients with HCC progressing on first-line therapy can deteriorate quickly, preventing their enrollment in clinical trials. However, the challenge of identifying the proper patient at the proper time can be overcome by periodic inter-department meetings involving the key specialists taking care of HCC patients, and solid networks between research centers and referring institutions. An early planned biopsy would also facilitate timely inclusion of patients in biology-driven clinical trials. Ultimately, institution of multidisciplinary teams can optimize treatment choice, biopsy timing, and quick enrollment of patients in clinical trials, before their performance status deteriorates.

Background Hay fever is typically poorly managed, particularly in adolescents, in whom it is responsible for considerable morbidity and impairment in educational performance. Evidence-based training of professionals has the potential to improve outcomes, but it can be expensive and so warrants formal evaluation. This trial sought to evaluate the effectiveness of a training intervention for primary care-based health care professionals on adolescent disease-specific quality of life. Methods A cluster randomised controlled trial was conducted in UK general practices. Practices were centrally randomised to a short, intensive training course on the evidence-based management of hay fever (intervention arm) or distribution of guidelines (control arm). The primary outcome measure was the change in the validated Rhinoconjunctivitis Quality of Life Questionnaire with Standardized Activities (RQLQ(S)) score in adolescents with hay fever between baseline and six weeks post-intervention (minimal clinically important difference = 0.5). Secondary outcome measures included health care professionals’ knowledge and confidence in managing hay fever, number of hay fever-related consultations, relevant treatments prescribed and symptom scores. Multi-level modelling using a random effects model was used to take account of between and within cluster variation, adjusting for strata, individual covariates and year of study. Results Thirty-eight general practices were randomised (20 in the intervention arm) and 246/341 patients (50.2% male, mean age 15 years) were included in the primary outcome analysis. Health care professionals’ self-assessed knowledge and confidence improved (prescribing/recommending treatment mean score 95% CI 1.4, 2.8), and the training was perceived to be of value. This did not however result in clinically or statistically significant improvements in RQLQ(S): -0.15, 95% CI -0.52 to +0.21. There were no differences in consultation frequency (95% CI -0.02, +0.63), treatments issued for hay fever (95% CI -0.24, +0.08) or symptom scores (95% CI - 1.03, +0.54). Conclusions Although attendance on this short, intensive hay fever training course was associated with professionals’ increased self-assessed confidence and understanding of the clinical management of hay fever, this did not translate into improvements in disease-specific quality of life or reduction in rhinitis symptoms in adolescents with hay fever.

Background: People with Multiple Sclerosis experience difficulties with balance and mobility. Pilates exercises are often used to address these difficulties. Design: This was a multi-centre, double blind, block randomised, controlled trial. Eligible participants were recruited from seven UK centres. Participants were randomly allocated to either: Pilates based core stability training (Pilates), Standardised Exercise (SE) or Relaxation (placebo). All received face-to-face training sessions over a 12 week period; together with a home exercise programme. Blinded assessments were taken before training, at the end of the 12 week programme and at 16 weeks (follow-up). The primary outcome measure was the 10metre timed walk (10mtw). Secondary outcome measures were the MS walking Scale (MSWS-12), Functional Reach Test (FRT ) (forwards and lateral), a 10 point Visual Analogue Scale (VAS) to determine “Difficulty in carrying a drink when walking”, and the Activities-specific Balance Confidence (ABC) Scale. Effects on deep abdominal muscles were measured with ultrasound imaging (USI) in a subgroup of patients. Independent t-tests were performed to compare groups. Sensitivity analyses were undertaken to confirm the results. A mixed factorial ANOVA analysed the effect of intervention over time upon TrAb and IO upon USI. Results: Of the 100 participants recruited, 13 relapsed leaving 94 for intention to treat analysis. At 12 weeks there were significant differences between: (1) Pilates and Relaxation for walking velocity (p=0.04), forward (p=0.04) and lateral (p=0.04) FRT. (2) SE and Relaxation for all measures (p < 0.05) apart from the VAS. These remained at 16 weeks for 10mtw (p=0.04), LFR (p < 0.01) MSWS-12 (p=0.03) and ABC (p = 0.03). There were no significant interactions (p > 0.05) between groups or over time for TrAb and IO. Conclusions: Participants improved with both Pilates and SE in the short term; with broader and longer-lasting effects in the SE group. USI did not detect any effect of group over time.

This thesis is about the trial of President Andrew Johnson.

BACKGROUND: Multiple myeloma is a rare form of cancer that affects the proper function of plasma cells in the immune system. Patients experience symptoms ranging from bone pain to otherwise avoidable infections that can have negative effects on quality of life. Despite advances in multiple myeloma treatment leading to longer patient survival, it is still an incurable form of blood cancer. As a result, it is important for researchers to constantly investigate new avenues of treatment in order to delay disease progression. This study investigated whether the next generation proteasome inhibitor, ixazomib, could safely delay disease progression in patients who failed a combination regimen that included either the proteasome inhibitor bortezomib or carfilzomib. METHODS: This study is a phase 1/2, 3+3 design, intra-patient, multicenter, open-label, and non-randomized clinical trial that recruited patients that were previously on one of ten combination treatments containing the proteasome inhibitors bortezomib or carfilzomib. Patients must have shown progressive disease while on this treatment in order to qualify. They were given the same drugs and doses they were previously taking except that the proteasome inhibitor was replaced with ixazomib. The safety and efficacy measurements were taken periodically to assess patients’ disease burden. To assess safety, adverse events (AEs) and serious adverse events (SAEs) were recorded, codified, and quantified for analysis. In addition, the maximum tolerated dose (MTS) of ixazomib for three regimens for which it was unknown was investigated through the analysis of dose limiting toxicities (DLTs). Clinical benefit rate (CBR) and overall response rate (ORR) using response data were also determined. Lastly, Kaplan-Meir statistical analysis was used to calculate the secondary efficacy endpoints such as progression free survival (PFS) using data collected throughout the trial. RESULTS: Safety: 24.4% of patients experienced at least one ≥ Grade 3 serious adverse event, 33.3% experienced at least one ≥ Grade 3 adverse event, and two experienced dose limiting toxicities. Efficacy: ORR was 13.2% and the CRR was 18.4%. Median PFS was 2.1 months, duration of response (DOR) was 2.0 months, and overall survival (OS) was 7.9 months. However, the MTD of ixazomib for the three regimens which it was unknown for was not found due to the nature of the data distribution. CONCLUSION: The results indicated that ixazomib is not an effective replacement for bortezomib or carfilzomib in combination treatments containing these drugs, which is apparent from low primary and secondary efficacy endpoints. However, due to a low occurrence of adverse events, serious adverse events, and dose limiting toxicities safety was confirmed. In addition, physicians should determine the MTD on a case by case basis through individual dose escalations if ixazomib is to be used in this context.

Treatment of duodenal ulcer with the histamine H2-receptor antagonist, ranitidine, was assessed in a double-blind, randomized, multicenter trial in which patients were treated for two consecutive 4-week periods with ranitidine 150 mg b.i.d. or a placebo. All patients were allowed to take antacids as necessary for symptoms. Three hundred eighty-two patients were entered and 355 completed the first 4-week trial period. Ranitidine significantly improved healing at 2 weeks (37 versus 19%, p < 0.01) and at 4 weeks (73 versus 45%, p < 0.01), with better relief of pain and lower use of antacids. In the second 4-week trial period, 124 unhealed patients from the first 4 weeks were re-randomized. Ranitidine treatment resulted in a greater healing rate regardless of previous treatment (p < 0.05). In this trial, side effects were uncommon and not different between placebo and the tested drug. One case of hepatitis in the ranitidine treated group was presumed on the evidence to be non-A non-B. Ranitidine is effective and appears to be safe in the treatment of duodenal ulcer and its symptoms.

To determine if known androgenic hormone precursors for testosterone in the androgen pathway would be readily transformed to testosterone, eight male subjects [mean age 23.8 (SEM 3) years, bodymass 83.1 (SEM 8.7) kg, height 175.6 (SEM 8.5) cm] underwent a randomized, double-blind, cross-over, placebo-controlled oral treatment with 200 mg of 4-androstene-3,17-dione (Δ4), 4-androstene-3β,17β-diol (Δ4Diol), and placebo (PL). The periods of study were separated by 7 days of washout. Blood was drawn at baseline and subsequently every 30 min for 90 min after treatment. Analysis revealed mean area-under-the-curve (AUC) serum Δ4 concentrations to be higher during Δ4 treatment [2177 (SEM 100) nmol.l-1] than Δ4Diol [900 (SEM 96) nmol.l-1] or PL [484 (SEM 82) nmol.l-1; P < 0.0001]. The Δ4 treatment also revealed a significant effect on total testosterone with a mean AUC [1632.5 (SEM 121) nmol.l-1] that was greater than PL [1418.5 (SEM 131) nmol.l-1; P < 0.05] but not significantly different from those observed after Δ4Diol treatment [1602.9 (SEM 119) nmol.l-1; P = 0.77]. Free testosterone concentrations followed a similar pattern where mean AUC for the Δ4 treatment [6114.0 (SEM 600) pmol.l-1] was greater than after PL [4974.6 (SEM 565) pmol.l-1; P < 0.06] but not significantly different from those observed after Δ4Diol [5632.0 (SEM 389) pmol.l-1; P = 0.48]. The appearance and apparent conversion to total and free testosterone over 90 min was stronger for the Δ4 treatment (r = 0.91, P < 0.045) than for Δ4Diol treatment (r = 0.69, NS) and negatively correlated for PL (r = -0.90, P < 0.02). These results would suggest that Δ4, and perhaps Δ4Diol, taken by month are capable of producing in vivo increases in testosterone concentrations in apparently healthy young men as has already been observed in women after treatment with Δ4.

No description available.