• Evidence of other cause of significant liver disease – serum ferritin > 1000, biochemical evidence of Wilson’s disease, autoantibody titres in excess of 1:160.
• Poorly controlled diabetes that, in the investigators opinion, precludes therapy. • Severe retinopathy that, in the opinion of the investigator, precludes therapy.
• Evidence of ascites seen on previous liver ultrasound.
• Haemoglobin concentration <11 g/dL in females or <12 g/dL in males or any patient with an increased risk for anaemia (e.g., thalassemia, sickle cell anaemia, spherocytosis, history of gastrointestinal bleeding) or for whom anaemia would be medically problematic.
• Albumin levels <35 G/L.
• Females who are pregnant or breast-feeding.
• History of severe psychiatric disease, including psychosis and/or depression, characterized by a suicide attempt, hospitalization for psychiatric disease, or a period of disability as a result of psychiatric disease within the last 2 years.
• History of immunologically mediated disease (e.g., inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune haemolytic anaemia, scleroderma, severe psoriasis (defined as affecting >10% of the body, where the palm of one hand equals 1%, or if the hands and feet are affected), rheumatoid arthritis requiring more than intermittent nonsteroidal anti-inflammatory medications for management.
• Other on-going serious medical condition in the opinion of the investigator that would prohibit treatment.
• Poorly controlled thyroid dysfunction that, in the investigators opinion, precludes therapy. • History of major organ transplantation with an existing functional graft.
• History of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease in the previous 6 months.
• History or laboratory testing showing evidence of a haemoglobinopathy.
• Concomitant administration with active substances that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life- threatening events. These active substances include alfuzosin, amiodarone, bepridil, quinidine, astemizole, terfenadine, cisapride, pimozide, ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine), lovastatin, simvastatin, atorvastatin, sildenafil or tadalafil (only
when used for treatment of pulmonary arterial hypertension) and orally administered midazolam or triazolam.
• Concomitant administration with Class Ia or III antiarrhythmics, except for intravenous lidocaine. • Concomitant administration of INCIVO with active substances that strongly induce CYP3A e.g. rifampicin, St John's wort (Hypericum perforatum), carbamazepine, phenytoin and phenobarbital and thus may lead to lower exposure and loss of efficacy of INCIVO (telaprevir).
For patients that were enrolled onto the trial stringent ‘stopping rules’ were applied to minimise exposure to trial medication in patients who were unlikely to benefit from treatment. These stopping rules were based on data from clinical trials evaluating telaprevir in genotype 1 HCV. Virological response at week 4 was predictive of treatment outcome in these trials so similar criteria were applied to this trial. The virological stopping criteria were as follows (figure 4.1):
• If the viral load after 4 weeks of therapy with PegIFN, Ribavirin and telaprevir was
>1000 IU/ml, therapy would be abandoned and the patient would be deemed a non-responder to therapy.
• If the viral load at week 8 was greater than 1000 IU/ml OR the viral load had not declined by more than 3 logs from the pre-treatment viral load, therapy would be abandoned and the patient deemed a non-responder to therapy.
In addition to virological criteria determining whether treatment should be discontinued, patient safety criteria were also included which would result in treatment discontinuation. These criteria were:
1. Patients would be withdrawn from the study if there was evidence of systemic drug toxicity which, in the opinion of the investigator, modified the risk: benefit ratio in favour of harm.
3. Inability or participant’s failure to comply with the protocol requirements. 4. Pregnancy in a trial participant or their partner.
The trial protocol received approval from North East London Research Ethics Committee in
November 2013, with Medicines and Healthcare Products Regulatory Agency approval in June 2014. The first trial participant was screened on the 7thof July 2014. Fourteen patients were recruited at
the four participating sites (The Royal London Hospital; Queen’s Medical Centre, Nottingham; St George’s Hospital, London; and the Bradford Royal Infirmary), with the final trial participant enrolled on the 6thof November 2014. Trial recruitment was terminated early as sofosbuvir based all oral
regimens became available on the early access programme in England and it was expected that patients with compensated cirrhosis would eligible for those treatments in the subsequent 12 months.
4.8 Results
Trial Participant demographic data
Fourteen patients were recruited onto the trial. There were ten male patients and four female patients. The median age of trial participants was 49 years (range 32-63 years). Seven patients were Asian, six were Caucasian and one patient described their ethnicity as other (table 4.1). All patients had advanced liver fibrosis or cirrhosis secondary to Hepatitis C, and all had relapsed following previous treatment with interferon and ribavirin. Thirteen out of the fourteen patients had additional co-morbidities; diabetes was the commonest co-morbidity (n=7), followed by
hypertension (n=4), dyspepsia (n=4), skin conditions (n=3), depression (n=3), hypothyroidism (n=2), previous hysterectomy (n=2), insomnia (n=1), hay fever (n=1). The co-morbidities for each individual trial participant are listed in table 4.2, with medications they were taking shown in table 4.3. The medications taken by trial participants at screening correlated with their medical history.
Demographic data (at screening) n=14 Age (years) 47 (32-63) Gender Male 10 (71%) Female 4 (29%) Ethnicity Caucasian 6 (43%) Asian 7 (50%) Other 1 (7%) Comorbidities Diabetes 7 (50%) Hypertension 3 (21%) Skin Conditions 3 (21%) Hypothyroidism 2 (14%) Depression 2 (14%) Dyspepsia 2 (14%) Previous hysterectomy 2 (14%) Insomnia 1 (7%) Hay fever 1 (7%)
Table 4.1. Demographic characteristics of Study participants at screening
Table 4.3 Medications taken by trial participants at their baseline visit
Five diabetic patients were on medication (metformin), of these five two were also on a second diabetic medication (glimepiride (n=1) and gliclazide (n=1)). Four patients with hypertension were on antihypertensive medications (ramipril n=3 and losartan n=1). The mean blood pressure for trial participants at their baseline visit was 131/79 mmHg (range 110-165/59-107), along with a pulse rate of 83 beats per minute (range 67-98). The four patients with dyspepsia were on medication for this (lansoprazole n=3, omeprazole n=1, and gaviscon n=1). One patient was on both lansoprazole and gaviscon. Mean results (and range) at baseline (as demonstrated in figure 4.2) were: HCV viral load 2.5x106IU/L (1x105-1x107); alanine transaminase levels of 104.5 IU/L (33-366), bilirubin 10
µmol/L (6-20), sodium 138 mmol/L (133-142), creatinine 62 µmol/L (35-78), haemoglobin 145.6 g/L (104-167) and platelet count 139 x109/L (53-243).
Figure 4.2. Baseline results: a) HCV viral load b) ALT c) Bilirubin d) Sodium e) Creatinine f) Haemoglobin g) Platelets