Questionnaire Follow-Up study
Research type
Research Study
Full title
Questionnaire Follow-Up Study (Q Follow-Up study*)
IRAS ID
262550
Contact name
Lakshminarayan Ranganath
Contact email
Sponsor organisation
Royal Liverpool University Hospital
Clinicaltrials.gov Identifier
N/A, N/A
Duration of Study in the UK
1 years, 0 months, 1 days
Research summary
The Questionnaire Follow-Up Study will consist of patients who completed 4 years in the SONIA 2 study at the UK site. They will be sent a brief questionnaire to understand the state of their health since leaving the study.
Summary of results
Study drug nitisinone was not made available at end of SONIA 2 clinical trial. Access to nitisinone post-study was difficult and limited despite proper planning. Pain increased in those patients on nitisinone in SONIA 2 after SONIA 2 study cpmpletion and nitisinone withdrawal. In those who accessed nitisinone post-SONIA 2, pain decreased promptly without weeks. Response rate in the questionnaire follow-up study was reasonable considering that it was a postal questionnaire tarns-national study.Summary of results
There is a strong school of thought that access to study drugs after completion of participation in a drug trial should be made available 9,10. During SONIA 2 study it was possible to provide the study drug nitisinone only for the duration of the study period. This was because of the potential for adverse events in the event nitisinone was provided since it was not possible to monitor these patients’ post-participation. Specifically, there was a 14.5% prevalence of painful corneal keratopathy during SONIA 2 where diet of patients was not adjusted to minimise tyrosinaemia; however, these patients had slit-lamp examinations and 6-monthly questionnaires to monitor safety. This was not possible after SONIA 2 with no possibility of ensuring safety if just given access to the study drug and hence nitisinone was not provided upon completion of SONIA 2.
Access to nitisinone by local healthcare was limited and patchy after patient participation in SONIA 2. Most patients in Q-FU study were non-UK, including those who attended the Liverpool site. AKU patients in the UK were already attending the UK National Alkaptonuria Centre (NAC) and it was unethical to recruit these to SONIA 2 (and therefore also for the Q-FU study) given the risk of placing these patients in the no-nitisinone arm as they would have been eligible to receive nitisinone in the NAC. Despite approval by the European Medicines Agency of nitisinone for alkaptonuria in September 2020 2 as well as
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the European Commission approval 11 to make nitisinone available for alkaptonuria in October 2020, access has been difficult for most SONIA 2 participants. To address this the pharmaceutical partner Swedish Orphan Biovitrum (Sobi) undertook the MoCA process (mechanism of coordinated access to orphan medical products) to facilitate access by engaging with European stakeholders 12. Nitisinone was only provided for the nitisinone group per-protocol in SONIA 2until the end of four years of study. In the Q-FU study, which included only data from the Liverpool and Piešťany site it was found that 31.8% of controls and 46.7% of nitisinone-treated groups managed to obtain nitisinone locally after SONIA 2.
(Table 2). The proportions accessing nitisinone in the control and nitisinone groups at the Liverpool site were14.3% and 30%, while those at the Piešťany sites were 62.5% and 80%, while noting that the responder number was lower at the Piešťany site.
The Q-FU study was a postal questionnaire study. The overall response rate of 45.7% in the Q-FU study was acceptable for a postal questionnaire study. An earlier identification study caried out by the lead investigator yielded a response rate of 18.2% 13 . One postal survey reported at response rate of 29.5% 15, while another reported an increase in response to repeated mailing so that at third mailing the response rate was 55.4% 15 . Others support the use postal questionnaire studies compared to studies collecting data online 16,17. The responder rate was 53.7 and 30.6% respectively in the Liverpool and Piešťany sites. All the study activities were carried out at the Liverpool site, such as posting the questionnaires, receiving the responses, collecting and analysing the data. Recent publications suggest that on-line surveys yield higher responses rates and are also easier to re-administer.
The age at baseline in the control and nitisinone groups in the Liverpool, Piešťany, and combined sites was similar and is shown in Table 1. Overall, there were 10 males and 12 females in the control groups, and 9 and 6 respectively in the nitisinone group in the Q-FU study. Baseline pain scores recalculated for the groups excluding Paris in the Q-FU study showed that all patients had a positive pain score. Like the full data set from SONIA 2, this abbreviated Q-FU study dataset also showed that pain score at end of SONIA 2 study was lower than those at baseline 1 .
The self-declared pain experiences in the combined control group of the Q-FU study before access to nitisinone showed in equal proportion an increase or remaining the same in those where there was a response (Table 2); in the combined nitisinone group of the Q-FU study, almost equal proportions showed a decrease or no change in those gaining access to
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nitisinone, with these changes occurred within 2 months of starting nitisinone; likewise, the change in analgesic medications either remained the same or decreased in those providing a response.
In the combined nitisinone group of the Q-FU study before access to nitisinone, more showed an increase in subjective pain in patients providing a response (Table 3). This group reported mostly a decrease in pain in those regaining access to nitisinone, with these changes occurred within 2 months of starting nitisinone; the change in analgesic medications either remained the same or increased in those providing a response. It has been reported already 1 that nitisinone group was older and had more severe disease at baseline than the control group and may explained the analgesia requirements even in the Q-FU study.
There were limitations in the data. This was a study where a postal questionnaire was administered only once. The original SONIA 2 study even though is the largest ever conducted in this filed of inherited metabolic diseases was still small compared to other reported questionnaire studies 18. Like many questionnaire studies there was a problem with incomplete responders and responses. With most participants being from outside UK, care was taken to use suitably translated questionnaires to minimise barriers due to language and understanding. Even though the Q-FU study was initiated during the completion of SONIA 2, the eventual study only commenced sometime after the end of SONIA 2 and we cannot exclude difficulties in recalling information requested in the questionnaires.REC name
East Midlands - Derby Research Ethics Committee
REC reference
19/EM/0204
Date of REC Opinion
10 Jun 2019
REC opinion
Favourable Opinion