Reviewer No. 1 checklist for application of: inclusion of Nifurtimox + eflornithine in the WHO Essential Medicines List

Transcription

1 Reviewer No. 1 checklist for application of: inclusion of Nifurtimox + eflornithine in the WHO Essential Medicines List (1) Have all important studies that you are aware of been included? No additional clinical studies were identified. However, at the time of submission of this review, the systematic reviews referred to in the application (the Harhay et al. systematic review on stage 2 chemotherapy and the proposed Cochrane review by Seixas & Lutje) had not been made available. A protocol for the latter review could be identified on the Cochrane Collaboration web site. In terms of the NECT Phase III study, only the data presented in the application and that published previously (Ref 68 in the application) were available, not the finalised clinical study report or the planned peerreviewed publication). (2) Is there adequate evidence of efficacy for the proposed use? Yes No The evidence for the efficacy of the proposed combination therapy with nifurtimox 5 mg/kg po every 8 hours for 10 days plus eflornithine 200 mg/kg by slow iv infusion every 12 hours for 7 days (NECT) is based primarily on the recently completed multi-site, randomised, open-label, non-inferiority study, which enrolled 286 patients. An initial set of data from 103 participants enrolled at one of the sites was published separately (Ref 68 in the application). Based on the CONSORT standards, the following assessment of the quality of reporting (in the paper and the application) can be made: 1 CONSORT ELEMENT Title - How participants were allocated to interventions (eg, random allocation, randomized, or randomly assigned ), specifying that the trial is a noninferiority or equivalence trial Introduction - Background - Scientific background and explanation of rationale, including the rationale for using a noninferiority or equivalence design. Methods - Participants - Eligibility criteria for participants (detailing whether participants in the noninferiority or equivalence trial are similar to those in any trial[s] that established efficacy of the reference treatment) and the settings and locations where the data were collected. Interventions - Precise details of the interventions intended for each group, detailing whether the reference treatment in the noninferiority or equivalence trial is identical (or very similar) to that in any trial(s) that established efficacy, and how and when they were actually administered. ASSESSMENT Paper does not make design clear No detailed justification Mentioned Dose change for eflornithine described, but not justified in detail Importantly, the change from a 24-month to an 18-month follow-up period is not justified in any way, except by reference to an Informal Consultation on the Conduct of Clinical Trials in HAT, held at the WHO in The report is available on the web. a It noted the difficulties with prolonged follow-up requirements, but also that the available data suggest that between 70% and 90% of relapses occur within 18 months after treatment, and between 40% and 90% of relapses occur already within a mber%2007.pdf - 1 -

2 CONSORT ELEMENT Objectives - Specific objectives and hypotheses, including the hypothesis concerning noninferiority or equivalence. Outcomes - Clearly defined primary and secondary outcome measures, detailing whether the outcomes in the noninferiority or equivalence trial are identical (or very similar) to or equivalence trial are identical (or very similar) to those in any trial(s) that established efficacy of the reference treatment and, when applicable, any methods used to enhance the quality of measurements (eg, multiple observations, training of assessors). Sample size - How sample size was determined, detailing whether it was calculated using a noninferiority or equivalence criterion and specifying the margin of equivalence with the rationale for its choice. When applicable, explanation of any interim analyses and stopping rules (and whether related to a noninferiority or equivalence hypothesis). Randomization - Sequence generation - Method used to generate the random allocation sequence, including details of any restriction (eg, blocking, stratification). Allocation concealment - Method used to implement the random allocation sequence (eg, numbered containers or central telephone), clarifying whether the sequence was concealed until interventions were assigned. Implementation - Who generated the allocation sequence, who enrolled participants, and who assigned participants to their groups. Blinding (masking) - Whether or not participants, those administering the interventions, and those assessing the outcomes were blinded to group assignment. When relevant, how the success of the outcomes were blinded to group assignment. When relevant, how the success of blinding was evaluated. Statistical methods - Statistical methods used to compare groups for primary outcome(s), specifying whether a 1- or 2- sided confidence interval approach was used. Methods for additional analyses, such as subgroup analyses and adjusted analyses. Results Participant flow - Flow of participants through each stage (a diagram is strongly recommended). Specifically, for each group report the numbers of ASSESSMENT 12 months after treatment. It is thus possible that 10-20% of relapses were lost due to the shorter duration of the RCT. In the paper, it was noted that 3 of the 4 relapses were detected at the month 18 visit. Degree of adherence to GCP guidelines is claimed in the application but not detailed No justification for the margin specified, but stated as 10%. Described Described (opaque envelopes) Described Not blinded, and justified Not described in detail (paper), not sufficient (application)

3 CONSORT ELEMENT participants randomly assigned, receiving intended treatment, completing the trial protocol, and analyzed for the primary outcome. Describe protocol deviations from trial as planned, together with reasons. Recruitment - Dates defining the periods of recruitment and follow-up. Baseline data - Baseline demographic and clinical characteristics of each group. Numbers analyzed - Number of participants (denominator) in each group included in each analysis and whether intention-to-treat and/or alternative analyses were conducted. State the results in absolute numbers when feasible (eg, 10/20, not 50%). Outcomes and estimation - For each primary and secondary outcome, a summary of results for each group and the estimated effect size and its precision (eg, 95% confidence interval). For the outcome(s) for which noninferiority or equivalence is hypothesized, a figure showing confidence intervals and margins of equivalence may be useful. Ancillary analyses - Address multiplicity by reporting any other analyses performed, including subgroup analyses and adjusted analyses, indicating those prespecified and those exploratory. Adverse events - All important adverse events or side effects in each intervention group. Comment - Interpretation - Interpretation of the results, taking into account the noninferiority or equivalence hypothesis and any other trial hypotheses, sources of potential bias or imprecision and the dangers associated with multiplicity of analyses and outcomes. Generalizability (external validity) of the trial findings. Overall evidence - General interpretation of the results in the context of current evidence. ASSESSMENT Not specified Not reported, as not done Not provided yet Additional evidence has been claimed to come from a prematurely stopped randomised, open-label equivalence study and a prospective case series. The results obtained in the RCT were published, based on a 24 month follow-up of patients enrolled (Ref 67 in the application). Of the 17 patients treated with a combination of nifurtimox (same dose as in NECT) plus eflornithine (same total dose, but divided in 4 daily infusions not 2, over 7 days), 16 were followed to 24 months and 1 for only 6 months. All 16 of those followed up for 24 months were deemed to be cured (i.e. did not meet the criteria for therapeutic failure, which were (1) deaths in temporal relation to treatment (within 30 days of treatment start) and (2) relapses of HAT or death compatible with HAT within the 24 months of follow-up). The case series (Ref 69 in the application) was conducted in northwest Uganda following the termination of the RCT in a nearby site, and was based on the same methods. The publication combined data from 31 new cases with the 17 originally recruited for the RCT. Of the 31 cases, 28 could be followed up to the 24-month mark (2 died before 6 months, 1 of these after an assault, the other of infectious complications from tissue damage caused by being chained by her family; 1 was lost to follow-up). All 28 were considered to be cured. In this case series, eflornithine was also administered as 400mg/kg/day in 4 divided slow infusions (every 6 hours) for 7 days

4 Although based on dosing with an oral eflornithine product, a 2004 publication reported the terminal plasma half-life of this agent as 3.0 to 16.3 hours. 2 This plasma half-life was considered by the authors to be similar to the figure of 199 +/- 6 min (+/- SD) reported previously. 3 Although this plasma half-life might be taken as support for the 12-hourly dosing, no data to support the change in dosing regimen between the initial (aborted) RCT/case series and the completed RCT is provided. The potential gains in ease of administration are, however, acknowledged. In a commentary on the Priotto et al. publication in 2007 (Ref 68 in the application), Chappuis stated that If the promising results presented by Priotto et al. are confirmed at the other study sites (the definitive results of this multiple-center study will not be available before mid-2008), the eflornithinenifurtimox combination therapy should become the firstline treatment of choice for second-stage T. brucei gambiense HAT. In the meantime, standard eflornithine therapy should bemore widely used. Nifurtimox, used as part of combination treatment, should already be available for compassionate use in patients who experience relapse who, otherwise, have nothing other than death to face. 4 The current EML lists melarsoprol and eflornithine for second stage African trypanosomiasis, with nifurtimox only for American trypanosomiasis. Whether the data now available are sufficient to list the combination (and alter the WHO guidelines accordingly), rather than leave the existing options open, can be debated. (3) Is there evidence of efficacy in diverse settings and/or populations? Yes No However, the data that do exist have been developed in the affected area and are relevant to the management of this condition. (4) Are there adverse effects of concern? A commentary on a cohort study of eflornithine (Ref 49 in the application) raised concerns about bone marrow toxicity with this agent. 5 In the preliminary report of the NECT RCT (Ref 68 in the application), it was stated that blood samples were drawn before and after treatment. No details of the timings of the major laboratory AEs noted in the application were provided, nor is it clear whether such adverse effects were detected at any follow-up point after treatment (within the 18 month period). (5) Are there special requirements or training needed for safe/effective use? As outlined, the slow infusion of eflornithine, even when given every 12 hours, still needs access to suitable equipment and trained staff. (6) Is this product needed to meet the majority health needs of the population? Although the numbers of cases may have declined in recent years, the fatal nature of this condition and the large number of persons at risk in affected countries means that treatment cannot be considered non-essential. (7) Is the proposed dosage form registered by a stringent regulatory authority? Yes No As noted in the application, eflornithine is only registered for the treatment of African trypanosomiasis in the USA and France, whereas nifurtimox is only registered for treatment of Chagas disease in Argentina, Chile, Colombia, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, and Uruguay. Whether a single non-inferiority study would be sufficient to justify registration of the combination treatment for 2 nd stage HAT by a stringent regulatory authority is open to debate. In addition, no such authority exists in the countries affected by this condition

5 (8) What action do you propose for the Committee to take? Given the probability of additional data becoming available, the theoretical gains in relation to delaying or preventing the emergence of resistance (in particular to eflornithine), and the potential gains in practicality of administration, the Committee could, if it were convinced of the quality of the data from the full non-inferiority study (after receipt and consideration of the draft manuscript and/or the finalised clinical study report) consider inclusion of nifurtimox as treatment for 2 nd stage African trypanosomiasis, with the caveat that this be in combination with eflornithine. However, the data presented at this point would not constitute pivotal evidence of efficacy and safety of the NECT combination and the specific dosage recommendations made. On the basis of the data provided (including the economic analysis; Ref 48 in the application) and available data from treatment programmes 6, the Committee should consider requesting a proposal for the removal of melarsoprol from the EML or its designation as a clear 2 nd -line option. (9) Additional comment, if any. Although the application makes the point that HAT affects mainly working adults, the lack of data to guide the treatment of children should be noted

6 References 1. Piaggio G, Elbourne DR, Altman DG, Pocock SJ, Evans SJ; CONSORT Group. Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement. JAMA Mar 8;295(10): Na-Bangchang K, Doua F, Konsil J, Hanpitakpong W, Kamanikom B, Kuzoe F. The pharmacokinetics of eflornithine (alpha-difluoromethylornithine) in patients with late-stage T.b. gambiense sleeping sickness. Eur J Clin Pharmacol Jun;60(4): Epub 2004 May Haegele KD, Alken RG, Grove J, Schechter PJ, Koch-Weser J. Kinetics of alphadifluoromethylornithine: an irreversible inhibitor of ornithine decarboxylase.clin Pharmacol Ther Aug;30(2): Chappuis F. Melarsoprol-Free Drug Combinations for Second-Stage Gambian Sleeping Sickness: The Way to Go. Clin Infect Dis. 2007; 45: Checchi F, Barrett MP. African sleeping sickness. Br Med J. 2008; 336: Balasegaram M, et al. Effectiveness of melarsoprol and eflornithine as first-line regimens for gambiense sleeping sickness in nine Médecins Sans Frontières programmes. Trans R Soc Trop Med Hyg (2008). In press (doi: /j.trstmh )