The feasibility of using the EQ-5D-3L with adults with mild to moderate learning disabilities within a randomized control trial: a qualitative evaluation.

BACKGROUND: In trials incorporating a health economic evaluation component, reliable validated measures for health-related quality of life (HRQOL) are essential. The EQ-5D is the preferred measure for cost-effectiveness analysis in UK trials. This paper presents a qualitative evaluation of the use of the EQ-5D-3L in a feasibility randomised control trial with participants who had a mild- to  moderate learning disability and type 2 diabetes. METHODS: Researchers administered the EQ-5D-3L to 82 participants at baseline and 77 at follow-up. After each interview, researchers rated the ease of administering the EQ-5D-3L and made free-text entries on the administration experience. For a subset of 16 interviews, researchers audio-recorded more detailed journal entries. Ease of administration data were analysed using descriptive statistics. Free-text responses were subject to a basic content analysis. The EQ-5D-3L-related journal entries were transcribed, coded and analysed thematically. RESULTS: Over half of participants were perceived to experience difficulty answering some or all of the items in the EQ-5D-3L (60% at baseline; 54% at follow-up). Analysis of the free-text entries and audio journals identified four themes that question the use of the EQ-5D-3L in this population. The first theme is related to observations of participant intellectual ability and difficulties, for example, in understanding the wording of the measure. Theme 2 is related to the normalisation of adjustments for impairments, which rendered the measure less sensitive in this population. Theme 3 is related to researcher adaptation and non-standard administration. An overarching fourth theme was identified in that people with learning disabilities were viewed as 'unreliable witnesses' by both researchers and supporters. CONCLUSIONS: It is recommended that the EQ-5D-3L should not be used in isolation to assess health-related quality of life outcomes in trials research in adults with a learning disability. Further research is required to develop and evaluate a version of the EQ-5D appropriate for this population in trials research. It is unrealistic to expect that adjustments to the wording alone will deliver an appropriate measure: supporter or researcher involvement will almost always be required. This requirement needs to be factored into the development and administration guidelines of any new version of the EQ-5D for adults with a learning disability. TRIAL REGISTRATION: Current Controlled Trials ISRCTN41897033 [registered 21 January 2013].

Randomized controlled feasibility trial of supported self-management in adults with Type 2 diabetes mellitus and an intellectual disability: OK Diabetes.

AIMS: To undertake a feasibility randomized controlled trial of supported self-management vs treatment as usual in a population of adults with obesity, Type 2 diabetes and an intellectual disability. METHODS: We conducted an individually randomized feasibility trial. Participants were adults aged >18 years with a mild or moderate intellectual disability, living in the community with Type 2 diabetes, on any therapy other than insulin. Participants had mental capacity to consent to research and the intervention. Inclusion criteria included HbA1c > 48 mmol/mol (6.5%), BMI >25 kg/m2 , or self-reported physical activity below national guideline levels. The experimental intervention was standardized supported self-management delivered by diabetes specialist nurses plus treatment as usual, compared with treatment as usual alone. Feasibility outcomes included: recruitment and retention; intervention acceptability and feasibility; data collection and completeness for physiological state and values for candidate primary outcomes (HbA1c and BMI). RESULTS: A total of 82 participants (89% of those contacted and eligible) were randomized. All supported self-management sessions were completed by 35/41 participants (85%); only four completed no sessions. Data on the follow-up candidate primary outcomes HbA1c and BMI were obtained for 75/82 (91%) and 77/82 participants (94%), respectively. The mean baseline HbA1c was 56±16.5 mmol/mol (7.3±1.5%) and the mean BMI was 34±7.6 kg/m2 . CONCLUSIONS: Adherence to supported self-management and willingness to have blood taken for outcome measurement was good. A definitive randomized controlled trial is feasible in this population. (Trial registration: Current Controlled Trials ISRCTN41897033).

Results of the randomized phase IIB ARCTIC trial of low-dose rituximab in previously untreated CLL.

ARCTIC was a multicenter, randomized-controlled, open, phase IIB non-inferiority trial in previously untreated chronic lymphocytic leukemia (CLL). Conventional frontline therapy in fit patients is fludarabine, cyclophosphamide and rituximab (FCR). The trial hypothesized that including mitoxantrone with low-dose rituximab (FCM-miniR) would be non-inferior to FCR. A total of 200 patients were recruited to assess the primary end point of complete remission (CR) rates according to IWCLL criteria. Secondary end points were progression-free survival (PFS), overall survival (OS), overall response rate, minimal residual disease (MRD) negativity, safety and cost-effectiveness. The trial closed following a pre-planned interim analysis. At final analysis, CR rates were 76 FCR vs 55% FCM-miniR (adjusted odds ratio: 0.37; 95% confidence interval: 0.19-0.73). MRD-negativity rates were 54 FCR vs 44% FCM-miniR. More participants experienced serious adverse reactions with FCM-miniR (49%) compared to FCR (41%). There are no significant differences between the treatment groups for PFS and OS. FCM-miniR is not expected to be cost-effective over a lifetime horizon. In summary, FCM-miniR is less well tolerated than FCR with an inferior response and MRD-negativity rate and increased toxicity, and will not be taken forward into a confirmatory trial. The trial demonstrated that oral FCR yields high response rates compared to historical series with intravenous chemotherapy.

Phase I pharmacokinetic study of intraperitoneal etoposide.

The synergistic interaction of etoposide with cisplatin in certain tumors prompted an evaluation of its potential role in the i.p. treatment of ovarian cancer and other intraabdominal malignancies. We conducted a Phase I evaluation of etoposide as a single agent to determine the maximum tolerated dose i.p., to describe dose-limiting and other toxic effects, and to examine the pharmacokinetics of etoposide in this setting. Etoposide was diluted in 2 liters of normal saline, and instilled i.p. over 10 to 25 min following maximal drainage of ascites. The dwelling time was 4 h, followed by peritoneal drainage. Twenty-two patients received 56 courses at doses which ranged from 100 to 800 mg/m2. The median age was 49, the median performance status was 1, and 18 patients had received prior chemotherapy, with or without radiation. The principal acute toxicity was abdominal pain in 10 patients; this was usually accompanied by signs of peritoneal irritation and was always responsive to nonsteroidal antiinflammatory medications. The major toxicity was dose-related neutropenia; Grade 3 or 4 toxicity affected five of six patients at 800 mg/m2. Thrombocytopenia, nausea and vomiting, and alopecia were also observed. The recommended dose for further study is 700 mg/m2. The pharmacokinetics of etoposide in plasma and peritoneal fluid was measured in 19 patients. Peritoneal levels over the 4-h dwelling time declined monoexponentially with a harmonic mean half-life of 3.5 h (range, 1.9 to 7.8). Plasma levels rose to a peak at 2.9 +/- 1.7 (SD) h and then declined exponentially with a harmonic mean terminal half-life of 7.7 h (range, 4.2 to 15.6). The plasma area under the concentration-time curve increased linearly with respect to dose. The relative pharmacological advantage (ratio of peritoneal to plasma area under concentration-time curve) for i.p. administration was measured as 2.8 and was independent of dose. Based on the high plasma protein binding of etoposide (94%) and the minimal protein binding in the fluid instilled i.p., the ratio of the areas under the concentration-time curves of free drug is estimated to be 4%. These results illustrate that tumor confined to the peritoneal cavity would be exposed to substantially higher free (diffusible) drug concentrations following i.p. than following i.v. administration and support the further evaluation of etoposide by this route.

Pharmacologic study of etoposide and cisplatin by the intraperitoneal route.

Based on the previous demonstration of a high peritoneal-to-plasma ratio of drug exposure for intraperitoneal (IP) etoposide, the authors performed a clinical/pharmacokinetic trial of etoposide (600 mg/m2) in combination with cisplatin (100 mg/m2). The drugs were administered concurrently IP, and allowed to dwell for 4 hours, after which the peritoneum was drained. Six patients received 13 cycles of treatment. Grade 4 neutropenia occurred in three patients; toxicity was otherwise moderate. Plasma etoposide concentrations reached a peak at 4.2 +/- 2.5 hours and declined exponentially with a terminal half-life of 9.5 +/- 3.6 hours. Peritoneal etoposide concentrations declined monoexponentially with a half-life of 3.7 +/- 2.6 hour. The calculated peritoneal-to-plasma ratio of unbound etoposide was 35. The plasma and peritoneal half-lives of ultrafilterable cisplatin were 21.7 +/- 14.1 hours and 1.8 +/- 0.7 hours, respectively. The peritoneal/plasma area under curve AUC ratio was 18.3. These pharmacokinetic indices for both drugs are consistent with those obtained with the use of each drug as a single agent. Thus, the concomitant use of one does not alter the pharmacokinetic activity of the other. The high AUC ratios support the further clinical development of these drugs in combination in the intraperitoneal setting.