17th Expert Committee on the Selection and Use of Essential Medicines Geneva, March 2009

PROPOSAL FOR THE INCLUSION OF NIFURTIMOX-EFLORNITHINE COMBINATION

AS A TREATMENT FOR STAGE 2 TRYPANOSOMA BRUCEI GAMBIENSE HUMAN AFRICAN TRYPANOSOMIASIS (SLEEPING SICKNESS)

IN THE WHO MODEL LIST OF ESSENTIAL MEDICINES

Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland Persons to contact: Dr Els Torreele Drugs for Neglected Diseases initiative (DNDi) 15 Chemin Louis-Dunant 1202 Geneva Switzerland Tel: +41 (0)22 906 9230 Fax: +41 (0)22 906 9231 Email: etorreele@dndi.org Dr Gerardo Priotto NECT Study - Principal Investigator Epicentre 8 Rue St Sabin 75011 Paris France Tel: +33 (0)1 4021 2848 Email: gpriotto@epicentre.msf.org

October 2008 *Please note that the following drafts in preparation will be made available, in draft form, to EML Committee members either upon finalisation or at the time of the meeting. These drafts include:

• Seixas & Lutje manuscript (Cochrane review) • Harhay et al systematic review on stage 2 chemotherapy • Priotto et al primary article on Phase III NECT study • Finalised clinical study report of the Phase III NECT study

Contents WHO Model List Application October 2008 , Abbreviations 2 Synopsis 3 1. Summary statement of the proposal for inclusion 5 2. Name of the focal point in WHO for this application 5 3. Name of the organisation(s) consulted and/or supporting the application 5 4. International Nonproprietary Name (INN, generic name) of the medicine 5 5. Formulation proposed for inclusion 6 6. International availability 6 7. Whether listing is requested as an individual medicine or as an example of a therapeutic group 8 8. Information supporting the public health relevance:

8.1 Disease burden – Epidemiological information 8 8.2 Assessment of current use and target population 10

9. Treatment details: 9.1 Dosage regimen, duration 13 9.2 Reference to existing WHO and other clinical guidelines 14 9.3 Need for special diagnostic or treatment facilities and skills 15

10. Summary of comparative effectiveness (and/or efficacy): 10.1 Identification of clinical evidence (search strategy, systematic reviews identified, reasons for

selection/exclusion of particular data) 16 10.2 Summary of available data (appraisal of quality, outcome measures, summary of results) 17 10.3 Summary of available estimates of comparative effectiveness 21

11. Summary of comparative evidence on safety: 11.1 Estimate of total patient exposure to date 22 11.2 Description of adverse effects/reactions 22 11.3 Identification of variation in safety due to health systems and patient factors 25 11.4 Summary of comparative safety against comparators 25

12. Methodological concerns with studies 29 13. Summary of available data on comparative cost and cost effectiveness within the pharmacological class or therapeutic group:

13.1 Range of costs of the proposed medicine 30 13.2 Comparative cost effectiveness presented as range of cost per routine outcome (e.g. cost per case, cost per cure, cost per month of treatment, cost per case prevented, cost per clinical event prevented, or, if possible and relevant, cost per quality-adjusted life year gained) 31

14. Summary of regulatory status of medicines 31 15. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia) 32 16. Proposed text for WHO Model Formulary 32 Appendix 36 References 40

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Abbreviations AE : Adverse event BTT : Bi-therapy trial CATT : Card agglutination test for trypanosomiasis CNS : Central nervous system CSF : Cerebrospinal fluid DALYs : Disability-adjusted life years DFMO : α-difluoro-methyl-ornithine (eflornithine) DNDi : Drugs for Neglected Diseases initiative DRC : Democratic Republic of Congo EML : Essential Medicines List GCP : Good clinical practice HAT : Human African trypanosomiasis ISCTRC : International Scientific Council for Trypanosomiasis Research and Control INN : International nonproprietary name ITT : Intention to treat iv : Intravenous MSF : Médecins Sans Frontières NECS : Nifurtimox-eflornithine case series NECT : Nifurtimox-eflornithine combination therapy NGO : Non-governmental organisation PNLTHA : Programme Nationale de Lutte contre la Trypanosomiase Humaine

Africaine PP : Per protocol RCT : Randomised controlled trial RoC : Republic of Congo SAE : Serious adverse event STI : Swiss Tropical Institute T.b gambiense : Trypanosoma brucei gambiense . T.b. rhodesiense : Trypanosoma brucei rhodesiense TDR : Special Programme for Research and Training in Tropical Diseases (TDR) THA : Trypanosomose Humaine Africaine USD : US dollars WBC : White blood cells WHO : World Health Organization WHO HQ : World Health Organization headquarters WHO/HTM/NTD/IDM : World Health Organization/HTM Cluster/Control of

Neglected Tropical Diseases/Innovative and Intensified Disease Management

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Synopsis Human African trypanosomiasis (HAT), also known as sleeping sickness, threatens millions of people in sub-Saharan Africa, mainly affecting those in poverty-stricken, remote, rural areas. The late, meningo-encephalitic stage of the disease (referred to hereafter as stage 2 HAT) is characterised by serious neurological and behavioural symptoms including severe sleep disturbances that progress to coma. Without treatment, stage 2 HAT is invariably fatal. Case management (i.e. diagnosis and treatment) of infected individuals is one of the main aspects of HAT control, along with vector control and mass-screening/surveillance of the population at risk. However, few medicines are currently available to treat stage 2 HAT, the stage at which the disease is most frequently diagnosed. The main pharmaceutical treatment used, intravenous melarsoprol, is painful for patients to receive and can produce severe drug-related toxic side effects and even death. Eflornithine, a trypanostatic drug currently given as a monotherapy, is effective and safer but its use is greatly limited by its impracticality of administration, particularly in resource-poor settings. It needs to be given by repeated slow intravenous (iv) infusion, every 6 hours for 14 consecutive days, and requires careful nursing care, medical supervision, and large amounts of extra materials (e.g. infusion fluids, infusions sets, sterile gauze). Because of these constraints, only 30% of stage 2 patients are estimated to receive this treatment. A third medicine, oral nifurtimox, is a trypanocidal drug licensed for treatment of Chagas disease which has been used off-label on a compassionate need basis for treatment for stage 2 HAT, but has insufficient efficacy for use as a monotherapy. It has been well established that eflornithine is far better tolerated than melarsoprol; it is now the recommended first-line treatment for stage 2 HAT wherever it can be implemented. However, as stated above, practical constraints have precluded its widespread use. Increasingly high rates of melarsoprol treatment failure have been reported in several regions, sometimes up to 50%. Long-term and possibly inappropriate use of eflornithine monotherapy may also lead to increasing failure rates; the development of resistance to this medicine would have serious consequences. No new drugs for stage 2 HAT are in clinical development, so there is an urgent need to develop new regimens based on currently available drugs. However, undertaking research, especially clinical trials in HAT, is very difficult due to the remote location of the patients, the lack of health infrastructure and research capacity, and the frequency of civil disruption and war in these areas. Despite these considerable challenges, a major randomised controlled study into treatment of stage 2 HAT has just been completed; the results form the core evidence for this application. In this multicentre non-inferiority study comparing the simplified co–administration of nifurtimox and eflornithine (NECT) with eflornithine monotherapy, both treatments were shown to be well tolerated and efficacious in stage 2 HAT patients. Compared to eflornithine monotherapy, the combination treatment has the following advantages:

• The number of infusions of eflornithine is reduced from 56 to 14: o Less burdensome for the health care staff o Less risk of infections o More convenient for the patient

• The treatment duration is reduced from 14 to 10 days: o Less expensive for the severely cost-constrained health system

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o More capacity for the treatment centre o More convenient for the patient

• The number of infusions per day is reduced from 4 (every 6 hours) to 2 (every 12 hours): o Less burdensome for the health care staff o More convenient for the patient

• Reduced logistical challenges: o A half of the volume/weight (cheaper transportation) o A same volume treatment kit can contain 4 instead of 2 full treatments

• Resistance is less likely to develop as the two drugs have different modes of action, thus mutual protection is to be expected.

This application proposes the co-administration of nifurtimox (oral) and eflornithine (iv) (Nifurtimox-Eflornithine Combination Therapy – NECT) as an alternative treatment for stage 2 Trypanosoma brucei gambiense (T.b. gambiense) HAT. Both nifurtimox and eflornithine are already listed separately on the World Health Organization (WHO) Model List of Essential Medicines (sections 6.5.5.2 on Chagas disease and 6.5.5.1 on African Trypanosomiasis respectively). It is proposed that nifurtimox, to be used in combination with eflornithine, is added to section 6.5.5.1: African Trypanosomiasis (under ‘Medicines for the treatment of 2nd stage African trypanosomiasis’ with a specific point that NECT should be used exclusively for T.b.gambiense infections). 1. Summary statement of the proposal for inclusion Co-administration of oral nifurtimox with iv eflornithine (Nifurtimox-Eflornithine Combination Therapy – NECT) is proposed for inclusion in the World Health Organization (WHO) Model List of Essential Medicines, section 6.5.5.1, as an alternative treatment for patients with stage 2 (late stage, meningo-encephalitic stage)Trypanosoma brucei gambiense human African trypanosomiasis (T.b. gambiense HAT; also known by other names including gambiense HAT, West African trypanosomiasis, or chronic sleeping sickness). 2. Name of the focal point in WHO for this application Dr Pere P. Simarro Human African Trypanosomiasis WHO/HTM/NTD/IDM World Health Organization 1211 Geneva 27, Switzerland Tel: +41 (0) 22 791 1345 Fax: +41 (0) 22 791 4777 simarrop@who.int

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3. Name of the organisation(s) consulted and/or supporting the application Epicentre, Paris, France Médecins Sans Frontières (MSF) Swiss Tropical Institute (STI), Basel, Switzerland Programme National de Lutte contre la Trypanosomiase Humaine Africaine (PNLTHA), Democratic Republic of Congo (DRC) 4. International Nonproprietary Name (INN, generic name) of the medicine Nifurtimox (4-[(5-nitrofurfurylidene)amino]-3-methylthiomorpholine 1,1-dioxide) and eflornithine (eflornithine hydrochloride; α-difluoro-methyl-ornithine, DFMO) 5. Formulation proposed for inclusion Two individual medicines co-administered (one oral, one iv) as a combination therapy for stage 2 T.bgambiense HAT.

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The suggested NECT regimen is:

• Nifurtimox (oral tablets): 15 mg/kg/day (5 mg/kg every 8 hours) for 10 days Plus • Eflornithine (slow iv infusion): 400 mg/kg/day (200 mg/kg every 12 hours) for 7 days

Nifurtimox is available as 120 mg oral tablets. Eflornithine is available in 100 ml glass bottles containing a 200 mg/ml solution. This needs to be diluted with sterile watera prior to slow iv infusion over 2 hours. aAlternatives to sterile water are normal saline or 5% dextrose. Although sterile water is the recommended diluent, normal saline in a larger volume (250 ml instead of 100 ml) has been used extensively (over 6,000 patients treated between 2001 and 2007) as an alternative as it has been more widely available in endemic regions than sterile water (personal communication: G Priotto).

6. International availability Table 1. Availability of eflornithine and nifurtimox. Drug name (generic)

Drug name (proprietary)

Manufacturer Supplied in

Eflornithine (DFMO)

Ornidyl® sanofi-aventis Glass bottles (200 mg/ml in 100 ml bottles). Eflornithine must be diluted before use. Once diluted, eflornithine can be stored in the fridge for up to 24 hours.

Nifurtimox Lampit®

Bayer Glass bottles, each containing 100 tablets of 120 mg.

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Donated by sanofi-aventis to WHO, eflornithine is provided free-of-charge to national diagnosis and treatment programmes through MSF Logistique. The agreement between WHO and sanofi-aventis, first set up in 2001, was renewed in 2006 until 2011. Nifurtimox is provided free-of-charge to WHO by Bayer for the treatment of Chagas disease (American trypanosomiasis); it is expected that a similar arrangement would be made for HAT. Treatment kits A major barrier in the widespread use of eflornithine is the need for a range of infusion-associated materials for the proper administration of the treatment. In an effort to make the treatment more accessible for patients, a treatment kit has been developed in collaboration between WHO, sanofi-aventis, and MSF. The kit, which consists of the medicines and all of the materials needed for the proper administration of eflornithine, generally contains 2 full adult treatments (see Table 2 below). While eflornithine is available as a donation, the cost of the additional materials is ~110 euros (€) per treatment (personal communication P. Simarro). The total weight of the kit containing 2 adult treatments is 37.6 kg. Table 2. Contents of the eflornithine kit (containing 2 full adult treatments). Item Quantity

Eflornithine chlorhydrate, éq. 200 mg/ml base, 100 ml, ampoules 36 Other equipment:

Water for injection, 100 ml, plastic pouch 120 'Y' joint, Luer lock, air intake, sterile 120 IV catheter, injection, 20 G (1.0 x 32 mm), pink 50 IV catheter, Bouchon, male Luer cap, sterile 100 Needle, Luer, 19G (1.1 x 40 mm) cream, IV 200 Syringe, u.u., Luer, 20 ml 100 Syringe, u.u., Luer, 2 ml 100 Strip of gauze, 8 cm x 4 m, with edges 20 Gauze pad, 10 cm, 12 ply, sterile 140 Zinc oxide tape, roll, perforated, 10 cm x 5 cm 1 Cotton, roll, 500 g 1 Examination gloves, latex, one-time usage, large 100 Examination gloves, latex, one-time usage, small 100 Povidone iodine, 10% solution, 200 ml vial for pouring 1 Elastic tourniquet 100 cm x 1.8 cm 2

If nifurtimox is included in the WHO Model List of Essential Medicines (EML) for stage 2 HAT, it is expected that a similar NECT kit will be developed by WHO and its partners. This kit would be made available free-of-charge to national control programmes and non-governmental organisations (NGOs) treating HAT. Given the reduction in eflornithine-related materials, it is expected that, within the same volume, the NECT kit will be able to contain 4 full treatments as opposed to the current 2 full treatments/kit. International availability of HAT drugs Today, all HAT drugs are available through donations from the manufacturers – sanofi-aventis for eflornithine, eflornithine kits, melarsoprol and pentamidine; Bayer HealthCare for suramin. (Suramin and pentamindine are used to treat stage 1 HAT.)

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Currently, requests for HAT drugs arrive at WHO headquarters (WHO HQ) for approval via three routes:

1. Requests are sent by the national control programmes to WHO HQ via the regional offices WHO-AFRO or WHO-EMRO.

2. Requests are sent from the national control programmes, NGOs or other implementing partners to WHO HQ direct.

3. Requests are sent from MSF missions to WHO HQ via MSF Logistique in Bordeaux, France. WHO HQ then confirms the order and requests MSF Logistique to prepare and dispatch the orders to the national control programmes via the WHO country office or NGO headquarters in the disease-endemic country. Further distribution to the HAT treatment centres is the responsibility of the recipient (national control programme or NGO), who then also bears the costs for this in-country distribution. 7. Whether listing is requested as an individual medicine or as an example of a therapeutic group It is requested that nifurtimox (already listed in section 6.5.5.2 as an essential medicine for American trypanosomiasis [Chagas disease]) be listed for the treatment of stage 2 T.b. gambiense HAT (in section 6.5.5.1) as a combination therapy with another WHO EML-listed medicine (eflornithine, already listed in section 6.5.5.1). 8. Information supporting the public health relevance

8.1 Disease burden – epidemiological info Introduction: Human African trypanosomiasis (HAT), also known as sleeping sickness, is a life-threatening illness from which 60 million people in 36 countries, primarily in sub-Saharan Africa, are at risk1 (Harhay et al. submitted for publication). Infection does not appear to confer immunity, so re-infection remains possible after treatment. HAT mainly affects working adults, which means it has an immense social and economic impact on local communities in HAT-endemic countries, many of which already have to contend with poverty and armed conflict as well as other major diseases such as malaria. Transmitted by tsetse flies, HAT exists in two forms, Trypanosoma brucei gambiense (T.b. gambiense)o T ypanosoma brucei rhodesiense (T.b. rhodesiense) disease. T.b. gambiense HAT accounts for ~97% of reported cases and is endemic in 24 countries; the disease is more chronic than its rhodesiense counterpart. In both disease forms an initial haemolymphatic stage disease (stage 1), which may be subclinical, progresses to an advanced meningo-encephalitic stage (stage 2) that affects the central nervous system (CNS)

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2-5. This stage 2 disease causes neuropsychiatric problems, convulsions, and serious sleep disturbance6; eventually these symptoms lead to coma. Without appropriate treatment, the disease is invariably fatal. HAT places a large burden on communities and individual households. In 2002, WHO estimated that approximately 1.5 million disability-adjusted life years (DALYs) were lost due to HAT. A more recent study in the DRC showed that the cost to each household following a HAT outbreak was equivalent to 5 months’ income for that household7.

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Epidemiology: HAT is a major public health concern in parts of sub-Saharan Africa. Although it is highly focalised, with the vast majority (>90%) of cases occurring in DRC, Angola, Central African Republic, and Sudan (Harhay et al. manuscript submitted for publication), cases have been reported in 36 countries in total. The total number of new cases reported has decreased over recent years. In 2007 the total number of reported cases of T.b. gambiense HAT was 10,446 (personal communication, Pere Simarro), descending from a peak incidence of 37,000 per year in the late 1990s. However, a key issue with HAT is that it affects hard-to-access communities in regions with a poor health infrastructure; as a result there is probably considerable underreporting of the condition. Poor access to medical facilities, a lack of resources and skills, and misdiagnosis are all likely to contribute to this issue. Taking into account such underreporting, current WHO estimates are 50,000 – 70,000 infected people8, 9. Threat of epidemics: Three major HAT epidemics impacted Africa throughout the 20th century. The first, which killed an estimated 800,000 people, occurred from 1896, lasted until 1906, and mainly affected Uganda and Congo. A second epidemic, which occurred from 1926 and lasted until the early 1940s, spurred colonial powers on to invest in mobile teams, vector control, and to assess the use of arsenicals to treat this fatal disease. Despite being almost eliminated in the 1960s, poor control and surveillance activities, exacerbated by socio-political unrest, led to a third epidemic which began in the 1970s and mainly affected Angola, Congo, southern Sudan, and northwest Uganda; this epidemic lasted until the late 1990s10-16. While the current situation seems to be under control, the historical evidence indicates that endemic areas remain at risk of devastating epidemics if surveillance efforts are weakened. Control strategy: There are three main pillars to HAT control – mass-screening (active case finding) of the population, routine diagnosis and treatment at health facilities, and vector control. All of these efforts require trained/skilled healthcare staff and specific equipment. Diagnosis: A field-adapted serological screening test, the card-based agglutination test (CATT), is available to identify people with a risk of having been in contact with the parasite responsible for theT.b gambiense form of HAT

. 17, 18; this test is used for both passive and active case finding. The blood

or lymph of these seropositive individuals is examined subsequently by microscopy for a visual confirmation of the parasite. Because the number of circulating parasites is generally low, a series of increasingly complicated techniques are needed to concentrate the parasite in the sample so as to see it under the microscope. Once HAT infection is confirmed, disease staging requires a lumbar puncture to determine the presence of parasites or of elevated levels of white blood cells in the cerebrospinal fluid (CSF), which characterises stage 2 disease. Staging is of critical importance because treatments for stage 2 HAT are different from those for stage 1 disease. Most importantly, current stage 2 treatments are more likely to give serious adverse effects and are more cumbersome to administer. HAT staging requires trained clinical staff to collect CSF samples by lumbar puncture, and trained laboratory staff to analyse samples and interpret results. Laboratory criteria for stage 2 diagnosis are:

• presence of parasites in the blood, lymph node fluid or CSF or CATT positivity in diluted serum (degree of dilution varies per country and per epidemiological criteria)

and

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• an elevated white blood cell (WBC) count in the CSF. (Generally, stage 2 is confirmed with a count of more than 5 WBCs per microlitre in CSF, but this criterion varies from 5 to 20 according to country and protocol).

Speedy microscope examination is needed, as trypanosomes need to still be alive and moving if they are to be detected. Treatment: Stage 1 HAT is treated relatively easily and safely with pentamidine (used for T.bgambiense) or suramin (used for T.b. rhodesiense). However, patients in the early disease stage often go unnoticed since symptoms (such as intermittent fever, headache and weight loss) may be mild or confused with other conditions. Thus, patients mostly present to a hospital after stage 2 symptoms have occurred. This is particularly true in the remote rural settings where the disease is found, and where there is relatively poor access to healthcare facilities. Therefore, it is crucial that control programmes have access to safe, cost-effective and practical stage 2 treatments.

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Pentamidine and suramin are not effective when stage 2 has been reached as they do not cross the blood-brain barrier at therapeutic levels, so other treatments (melarsoprol and eflornithine; detailed discussion in Section 8.2) need to be given. The administration of both melarsoprol and eflornithine requires medical supervision; this can be a major burden on understaffed, isolated healthcare facilities. Melarsoprol, which is given by daily direct intravenous injections, is known as ‘fire in the blood’ because of the pain that can be induced by administration; more importantly, 1 in 10 patients will suffer from reactive encephalopathy during treatment, with fatal consequences for half of them19-

22. Eflornithine needs to be administered by slow iv infusions; these infusions are given every 6 hours for 14 days (a total of 56 infusions). Although eflornithine has been shown to be safer than melarsoprol and is recommended as first-line treatment for stage 2 HAT, practical constraints mean it is only utilised in a fraction of HAT treatment centres (shown in Table 3). HAT and HIV/AIDS: Little is currently known about the incidence of HAT in HIV-positive individuals, primarily because HIV testing is not yet commonplace in HAT-endemic areas (which are typically the remote, rural areas with poor health infrastructure). The presence of HIV/AIDS in HAT-endemic regions is an important factor to bear in mind as there is some evidence that eflornithine, one of the drugs used to treat trypanosomiasis, might not be as effective in HIV-positive individuals23.

8.2 Assessment of current use and target population Current treatment options: HAT has often progressed to stage 2 disease by the time symptoms emerge and the disease is diagnosed. While relatively safe and easy-to-administer drugs are available to treat stage 1 HAT, this is not the case for stage 2 treatments. One reason is that these drugs need to be able to cross the blood-brain barrier at therapeutic levels. Current treatment options for stage 2 T.b .gambiense disease primarily rely on two drugs, melarsoprol and eflornithine (see Table 3). From period between 2003 and 2007, a total of 46,265 stage 2 HAT patients were treated (approximately 60% of total HAT cases treated).

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Table 3. Percentage of stage 2 patients treated with melarsoprol versus eflornithine, 2003 – 2007 (P Simarro, personal communication). Stage 2 Treatment

2003 2004 2005 2006 2007

Melarsoprol, n (%)

10,179 (83.1) 9092 (85.7) 8205 (83.5) 6287 (88.3) 4393 (68.0)

Eflornithine, n (%)

2058 (16.8) 1506 (14.2) 1611 (16.4) 826 (11.6) 2061 (31.9)

Other, n (%)

12 (0.1) 11 (0.1) 10 (0.1) 7 (0.1) 7 (0.1)

The trivalent arsenical derivative melarsoprol, a trypanothione reductase inhibitor (introduced in 1949) is the most commonly used treatment. The mechanism of action is not fully understood, but it appears that the drug inhibits parasitic glycolysis24, 25. The drug has severe toxic side effects including reactive encephalopathy and is associated with ~3 – 6% fatality19, 20, 22, 26, 27; as such, the corticosteroid prednisolone is often given to reduce the risk of encephalopathy21, 28. Other potentially life-threatening adverse effects include liver toxicity, peripheral neuropathy, skin toxicity and severe enterocolitis1, 26. Injection of the drug can also be extremely painful and may be associated with phlebitis and necrosis at the injection site. Treatment of adverse effects caused by melarsoprol is an additional drain on resources, needing intensive nursing and medical care. As is often the case with treatments for neglected diseases, dose regimens for melarsoprol have been established on an empirical basis29. WHO guidelines (published in 1998) suggest administration via 3 – 4 series of daily injections for 3 – 4 days, with rest periods of 7 – 10 days1, 30. No specific dose is suggested there, but examples of treatment schedules give a total dose at the end of treatment of 27 – 32.4 mg/kg. A dose of 3.6 mg/kg in 3 – 4 series of four injections a week apart is commonly used. More recently, based on pharmacological and clinical evidence, a concise treatment schedule of 2.16 mg/kg/day for 10 days (a total dose at the end of treatment of 21.6 mg/kg) has been recommended by the International Scientific Council for Trypanosomiasis Research and Control (ISCTRC) in 200322, 26,

27, 29, 31. This reduces the period of hospital stay and the workload on staff; however, it does not improve the safety nor efficacy profile. Recently, increasingly high rates of melarsoprol treatment failure (some as high as 50%32) have been reported in countries such as Uganda, Sudan, Angola, Central African Republic, and the DRC33-43. While the reasons underlying these treatment failures are unclear, melarsoprol is becoming increasingly ineffective against HAT in many regions. The toxicity of melarsoprol, the increase in treatment failures, and its painful administration emphasise the need for alternative treatments. Initially developed as an anti-cancer drug, the drug eflornithine44, 45 (α-difluoro-methyl-ornithine, DFMO – an ornithine decarboxylase inhibitor with trypanostatic effects) was shown to be effective against HAT in the 1980s, and is an efficacious and less toxic alternative to melarsoprol for treatment of T.b. gambiense HAT46-48. Retrospective analyses of large cohorts in NGO-administered treatment programmes have found field efficacy to be around 90%49. However, drug administration is complex (slow iv infusion under hospital medical supervision; the most common treatment schedule is 400 mg/kg/day at 6 hourly intervals for 14 days – a total of 56 infusions, each lasting 2 hours)1, 49. Equipment is required for iv administration, and large volumes of sterile infusion fluids are required (56 infusion bags to dilute eflornithine prior to administration). This means that although eflornithine has recently become the treatment of choice where feasible (as confirmed by clinical research in the

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past decade and as recommended in 2005 by the ISCTRC50), its widespread use in disease-endemic settings has been hampered by practical constraints. Studies in which the regimen was changed from a 14-day to a 7-day regimen suggested that the 7-day regimen was inferior to the 14 day one for new cases, although it may be useful for patients with a relapse following treatment with melarsoprol51-53. Its use against T.b rhodesiense remains unadvised because of the innately reduced susceptibility of the parasite

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54. When correctly administered and well managed, eflornithine monotherapy is relatively well tolerated with case fatality rates from 0.7% to 1.5%, as documented in large series of cases within NGO treatment programmes46, 49. However, field experience has shown that, in absence of close medical supervision and adequate nursing care, mortality rates can be much higher, mainly as a result of infusion-related infections (F Chappuis, personal communication). Eflornithine treatment is associated with adverse effects including suppression of bone marrow activity, seizures, hyperthermia, infections and gastrointestinal disorders1. The most frequently observed major drug reactions have been fever spikes, generalised seizures, and diarrhoea. In most patients, these conditions have resolved favourably with supportive care and/or temporary treatment withdrawal1. Its safety for use during pregnancy has not been established. Field evidence indicates a failure rate of approximately 10% in response to eflornithine49. As the drug is trypanostatic, there is concern about the possibility of rapidly emerging resistance, particularly when used as monotherapy45.

Nifurtimox (a synthetic 5-nitrofuran that inhibits trypanothione reductase) is an orally administered, relatively inexpensive drug (costing ~15 € per NECT treatment if not available as donation), that is licensed for the treatment of American trypanosomiasis (Chagas disease; caused by Trypanosomacruzi). A trypanocidal drug which acts through oxidative stress, nifurtimox has been used for compassionate treatment of stage 2 HAT24, 25, 55-57, although it is not registered for this purpose. There is no consensus treatment schedule for HAT; regimens range from ~6 – 30 mg/kg/day in 3 doses for 14 – 60 days. As a monotherapy it shows poor cure rates (60% to 75%)58, 59. Nifurtimox is associated with neuropsychiatric (e.g. headaches, sleep disturbance, mood changes, paraesthesia) and gastrointestinal (e.g. anorexia, nausea) adverse-effects when used to treat Chagas disease60-62, though this is not well documented for HAT. Both eflornithine and nifurtimox are already listed on the 15th edition of the WHO Model List of Essential Medicines – eflornithine as treatment for stage 2 HAT (section 6.5.5.1), and nifurtimox for American trypanosomiasis/Chagas disease (section 6.5.5.2). The only prospect of improved case management for stage 2 patients in the next few years is combination therapy, in particular NECT, as there are few available drugs, each with serious limitations, and with no other new treatments expected to become available, with not even one new drug in clinical development. Moreover, the increasing failure rates with melarsoprol, and the risk of parasite resistance developing when eflornithine is used as monotherapy, highlights the urgent need to make NECT available to stage 2 HAT T.b gambiense patients. Target population: HAT is found in 36 African countries, and it is estimated that 60 million people are at risk from the disease8. In 2007, 56% of T.b. gambiense cases reported were in stage 2 of the disease (P Simarro, personal communication). The target patient population for the NECT combination

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therapy includes all individuals diagnosed with stage 2 HAT following either active case finding or self-reporting at medical facilities. 9. Treatment details:

9.1 Dosage regimen, duration Dosage regimen: Combination therapy: nifurtimox plus eflornithine.

• Nifurtimox (oral tablets): 15 mg/kg/day (5 mg/kg every 8 hours) for 10 days Plus • Eflornithine (slow iv infusion over at least 45 mins): 400 mg/kg/day (200 mg/kg every 12

hours) for 7 days

Both drugs are started on the same day. Thus, on the last 3 days nifurtimox is given alone. The decision on when the two drugs should be administered in relation to each other is based on the most practical schedule to be compatible with the overall routine of the medical centre. In the recently conducted clinical trial that forms the basis of this application (see NECT study, manuscript in preparation) eflornithine infusions were started at 6 am and 6 pm, and nifurtimox was given at 6 am, 2 pm, and 10 pm. Duration of treatment: Nifurtimox: 10 days Eflornithine: 7 days Reinfection/relapse: The definition of relapse is not well defined and is not standardized across all programmes, but it normally involves the detection of parasites in any body fluid (blood, lymph, or CSF) at any time point during 24 months post-treatment. Because parasitemia is generally low in HAT, and therefore difficult to detect, the steady and/or significant increase of WBCs in CSF can be used as a surrogate marker, as well as the reemergence of clinical signs and symptoms. In HAT, the distinction between relapse and re-infection cannot be made because no specific field-adapted tools exist. It is generally thought that the likelihood of re-infection is low as incidence rates are low in most endemic areas and most relapses are generally found to be in stage 2. If re-infection was common, most patients would be diagnosed in stage 1 because of the slow evolution of the disease. Diagnosis: The NECT combination should only be administered to individuals diagnosed with stage 2 HAT T.b.gambiense according to the currently used diagnostic protocols (see section 8.1).

Treatment facilities: The NECT combination can be administered to individuals in the same facilities that are currently used to treat stage 2 HAT patients (see section 9.3 below on information related facilities and skills needed).

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9.2 Reference to existing WHO and other clinical guidelines WHO guidelines: The most recent guidelines from WHO for the treatment of stage 2 HAT are contained in Control and Surveillance of African Trypanosomiasis, 19981. Recommended treatments are melarsoprol, eflornithine or nifurtimox. Melarsoprol:

• 3 – 4 series of daily injections for 3 – 4 days, with rest periods of 7 – 10 days. • No specific dose is suggested, but examples of treatment schedules give a total dose at the

end of treatment of 27 – 32.4 mg/kg. Eflornithine:

• For T.b. gambiense HAT: 400 mg/kg/day in four divided doses for 14 days (adults). • The dosage for children should ideally be based on body surface area, to take into account

the more rapid elimination of the drug. The recommended dose for children is 4 g per m2.

.

Nifurtimox: • Dosages vary: 15 – 20 mg/kg/day in three divided doses. Treatment duration: 30 – 60 days.

Additional treatment (stage 2 HAT treated with melarsoprol):

• Concurrent treatment with oral corticosteroids. Relapse:

• Relapse after melarsoprol treatment: eflornithine or nifurtimox. • Relapse after eflornithine: not mentioned within 1998 guidelines.

There has been no update to the 1998 WHO guidelines in the last 10 years. However, more recent expert consensus has emerged around the use of melarsoprol: at the 27th ISCTRC meeting in Pretoria, South Africa, in 200331, a concise treatment regimen of 10 consecutive days of melarsoprol treatment was recommended, based on new clinical evidence22, 27. In addition, MSF (which has been one of the NGOs at the frontline of treating HAT patients in the past twenty years) also developed guidelines for its field personnel. Summary of MSF guidelines (2005)63:

• Eflornithine is listed as a first line stage 2 (T.b gambiense HAT) treatment at 100 mg/kg (150 mg/kg for children below age 12 years) iv four times daily for 14 days.

• As a second line treatment, where melarsoprol was given first line: eflornithine 100 mg/kg iv four times daily for 14 days.

• As a third line treatment: eflornithine 100 mg/kg (150 mg/kg for children below age 12 years) iv four times daily for 14 days + nifurtimox 15 mg/kg (20 mg/kg for children below age 15 years) oral, divided in 3 doses for 14 days.

• In HIV-positive individuals, in areas with known resistance to melarsoprol, MSF suggest a combination of melarsoprol and nifurtimox for 10 days or eflornithine and nifurtimox. If nifurtimox is not available, then they suggest considering a combination of melarsoprol and eflornithine (melarsoprol 2.2 mg/kg for 10 days and eflornithine 100 – 150 mg/kg four times daily for 7 days).

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9.3 Need for special diagnostic or treatment facilities and skills In most HAT-endemic countries, HAT diagnosis and treatment is organised through vertical programmes that ensure the necessary specific training and equipment required. Compared with currently used practice, no additional special diagnostic or treatment facilities are needed. NECT will be administered to patients in the same facilities and with the same healthcare staff as are currently treating stage 2 patients.

• In facilities using eflornithine as first-line treatment, human and physical resources will be saved because the treatment regimen proposed is shorter and simpler than current therapy

• In facilities using melarsoprol, additional training related to treatment infusions will be needed; however, the reduction of serious complications will save resources.

10. Summary of comparative effectiveness (and/or efficacy) This application proposes the use of a combination of nifurtimox-eflornithine (NECT) as an alternative treatment for stage 2 T.b. gambiense HAT. A recently completed randomised controlled non-inferiority study, which was carried out in HAT-endemic regions (ie. rural health sites) and which was conducted according to good clinical practice (GCP) research standards, compared NECT with eflornithine monotherapy. Results show that both treatments are well tolerated in the context of stage 2 HAT, and that the efficacy of NECT is non-inferior to eflornithine monotherapy. At 18 months after treatment, overall cure rates of over 96% were observed with NECT and over 90% with eflornithine monotherapy. Significantly, both treatments show markedly less mortality than melarsoprol (case fatality rates of 1-2% for NECT and eflornithine, as compared with 5-6% historical evidence for melarsoprol). Considering its improved ease of use, the overall effectiveness of the combination is expected to be superior to both eflornithine monotherapy and melarsoprol. The NECT combination has several advantages over eflornithine monotherapy (which is currently the best available first-line treatment):

• The number of slow intravenous infusions of eflornithine is reduced from 56 to 14. • The treatment duration is reduced from 14 to 10 days. • The risk of iv catheter-related local or systemic bacterial infection is reduced. • It is more practical for procurement, transport, storage and distribution. • Drug resistance is less likely to develop (as the two drugs are co-administered and have

different modes of action). • It is cheaper than eflornithine monotherapy.

To date, the high complexity of use and the cost of transport have remained the main barriers to the introduction of eflornithine as a safer alternative to melarsoprol. NECT will be a more practical and cheaper alternative to eflornithine monotherapy in replacing the highly toxic and sometimes ineffective melarsoprol. The clinical trial data submitted in this application indicate that NECT is safe and effective in patients with stage 2 HAT. In addition, the use of eflornithine in combination with nifurtimox may help avert the development of drug resistance.

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10.1 Identification of clinical evidence (search strategy, systematic reviews identified, reasons for selection/exclusion of particular data)

A systematic review, which forms the basis for this section, was undertaken of reported clinical evidence on the efficacy and/or safety of stage 2 HAT treatment, found through Medline searching since 1990 (Harhay et al. manuscript submitted for publication). A Cochrane review on stage 2 HAT chemotherapy is ongoing (Seixas and Lutje, manuscript in preparation) and information has been shared for the purpose of this application. A number of papers have documented the use of melarsoprol22, 26, 27, 46, 47, 58, 64, 65, eflornithine monotherapy51, 53, 66 and nifurtimox56, 59 for the treatment of HAT. Three published papers have reported on the safety and efficacy of the nifurtimox-eflornithine combination67-69. The recently completed randomised controlled trial (RCT) (NECT study, manuscript in preparation) has provided the pivotal evidence on the combination’s safety and efficacy; this evidence forms the basis of this EML application and will be submitted for publication in the coming months.

10.2 Summary of available data (appraisal of quality, outcome measures, summary of results)

A summary of trial data is provided in Table 4 below. Table 4. Summary of trial data. Study site Trial type Study Total n°

of patients

N° of patients receiving N+E

Results

Omugo, Uganda (BTT)67

Randomised open label trial (terminated early)

Compared efficacy/safety of three drug combinations: • melarsoprol plus nifurtimox, M+N • melarsoprol plus eflornithine, M+E • nifurtimox plus eflornithine, N+E Follow up: 24 months post-treatment

54

17 Cure rate: ITTa

• M+N – 44.4% • M+E – 78.9% • N+E – 94.1% PPb

• M+N – 50.0% • M+E – 83.3% • N+E – 100.0%

Yumbe, Uganda (NECS)69

Prospective case series

All patients received N+E combination Follow up: 24 months post-treatment

31 31 Cure rate: ITTa

• N+E – 90.3%-93.5%

PPb

• N+E – 100.0% Multi-Centre: Nkayi, Republic of Congo (RoC)68; Isangi, Dipumba and Katanda, DRC (NECT study, manuscript in preparation)

Randomised open label active control phase III non-inferiority trial

Compared efficacy/safety of the NECT combination over that of standard eflornithine monotherapy Follow up: 18 months post-treatment

286 143 Cure rate: ITTa

• E – 91.6 % • NECT – 96.5% PPb

• E – 91.7 % • NECT – 97.7%

All trials were car ied out on patients diagnosed with s age 2 T.b. gambesiense HAT. r t.

I I tt

BTT = Bi-therapy trial; NECS = Nifurtimox-eflornithine case series; NECT = Nifurtimox-eflornithine combination therapya TT = ntention to treat population includes all patien s randomised; deaths during treatment or follow-up are regarded as treatment failures. bPP= Per pro ocol population includes only relapses and HAT-related deaths considered failures.M = Melarsoprol; N = Nifurtimox; E = Eflornithine.

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The first study (bi-therapy trial, BTT) investigating a combination of eflornithine and nifurtimox (N+E) for stage 2 HAT T.b. gambiense was carried out in Omugo, Uganda by Epicentre and MSF during 2001 – 2004 and reported by Priotto and colleagues in 200667. The study compared the three different combinations of melarsoprol, nifurtimox, and eflornithine. For the arm given the N+E combination, eflornithine was given at 100 mg/kg four times a day for 7 days, together with 10 days of oral nifurtimox given at 5 mg/kg three times a day. After enrolling a total of 54 patients in the three arms, the trial was terminated prematurely due to the high toxicity (including fatalities) observed in the melarsoprol-containing arms together with the fact that the Ugandan government had meanwhile adopted the use of eflornithine monotherapy as a first-line treatment. The favourable tolerability in the 17 patients who had received N+E combination in this trial, combined with a good clinical response, prompted Epicentre and MSF to further investigate this combination in a case series of 31 patients (NECS, nifurtimox-eflornithine case series). This reinforced the concept of the good tolerability of the N+E combination, in particular there were no treatment-related fatalities69. Furthermore, no relapses were observed during the 24 months follow-up of the 48 patients treated with the N+E combination in these 2 studies. Table 5 summarises the efficacy of the two Uganda (BTT and NECS) studies (copied with permission from Checchi et al.69) Table 5. Efficacy endpoints and estimates (for N+E combination). BTT (n= 17)

NECS (n=31) BTT+NECS (n=48)

Endpoints n % n % n % Died within 30 days of treatment start

0 0.0 0 0.0 0 0.0

Died during follow upa 1 5.9 2 6.5 3 6.3 Lost to follow-up 0 0.0 1 3.2 1 2.1 Relapsed 0 0.0 0 0.0 0 0.0 Cured at 24 months 16 94.1 28 90.3 44 91.7 Efficacy estimates n % (95% CI) n % (95% CI) n % (95% CI) ITT analysis Cured 16 94.1 29 93.5 45 93.8 Patients in analysis 17 (71.3 – 99.9) 31 (78.6 – 99.2) 48 (82.8 – 98.7) PP analysis Cured 17 100.0 31 100.0 48 100.0 Patients in analysis 17 (80.5 – 100.0)b 31 (88.7 – 100.0) b 48 (92.6 – 100.0) b

f r r

r r - t.

BTT = Bi-therapy trial; NECS = Ni urtimox-eflornithine case seriesITT = Intention to treat. PP = Pe p otocol. CI = confidence interval. aNone of the deaths were judged HAT- o t eatment rela ed.bOne-sided confidence interval

Following these first two studies indicating the potential of this combination, a confirmatory multicentre randomised control trial (RCT) was set up by Epicentre and MSF in 2003, comparing the N+E combination to standard eflornithine monotherapy. While the drug dose for the combination was the same as that used in the studies mentioned above (i.e. 400 mg/kg/day for 7 days), the administration schedule was further simplified: eflornithine in the combination was administered at 12 hourly (rather than 6 hourly) intervals, reducing the total number of infusions to 14. Nifurtimox in the combination was administered at 5 mg/kg, three times a day for 10 days. This simplified N+E treatment schedule is hereafter referred to as the nifurtimox-eflornithine combination therapy (NECT).

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The study was designed to test non-inferiority for the efficacy of the combination with 95% confidence and with a 10% margin on non-inferiority; accounting for a maximum 20% drop-out rate, a sample size of 280 was calculated to achieve statistical significance. Initially set up in Nkayi, Republic of Congo (RoC)68, the study was subsequently extended, in collaboration with Drugs for Neglected Diseases initiative (DNDi), to 3 sites (Isangi, Dipumba and Katanda) in the DRC, in 2 different disease foci (see figure 1). Patients who were 15 years and older, non-pregnant women, with parasitologically confirmed stage 2 HAT, and who had not received prior stage 2 HAT treatment were enrolled in the study. The primary outcome measure was efficacy at 18 months post-treatment. Figure 1. Map showing location of study sites in RoC (Nkayi) and in DRC (Dipumba, Isangi, and Katanda).

Baseline characteristics of the study population are given in the appendix – no significant differences were seen among the study arms. This trial was conducted in accordance with international GCP research standards (confirmed by independent audit in October 2007) and is one of the few RCTs to be conducted and completed in the field of HAT, given the lack of health infrastructure, research capacity, political stability, and remote location of patients. The independent auditors were able to confirm that the rights and safety of trial subjects had been safeguarded, and to confirm the integrity of the NECT trial data. No critical findings were found during the audit and they concluded: “There is nothing to deter from the completion of the follow-up and the generation of the envisaged reports. The trial data is reliable and any decisions made based on the conclusions of data analysis(es) should be accepted as valid.” The 18-month follow-up rate of the study was balanced between the two arms and was 93%, which is which is exceptionally high for these types of studies and further contributes to the robustness of

17

these data (NECT study, manuscript in preparation). Only 3/286 patients (1.0%) were completely lost to follow-up. Table 6 below summarises the primary efficacy endpoint of the NECT study, which was cure rate at 18-month follow-up after treatment. Table 6. Efficacy outcome of NECT study.

Arm

Total Cured

Cure rate (%)

∆ cure rate (%)

(E - NECT) One-sided 95%

CI* (%) E 143 131 91.6 -0.3 ITT

NECT 143 138 96.5 -4.9

E 142 131 92.3 -1.4 MITT

NECT 141 138 97.9 -5.6

E 133 122 91.7 -1.5 PP

NECT 132 129 97.7 -6

ITT = Intention to treat MITT = Modified ITT (excluding patients completely lost to follow-up ; PP = Per p otocol. ; ) r * According to method of Blackwelder: Upper limit of a two-sided 90% CI around the difference (∆) of cure rates.

The test of non-inferiority showed that the one-sided 95% confidence interval (or upper limit of the 90% CI) was less than the target difference (∆) of 10% in all populations analysed, clearly establishing the non-inferiority of the N+E combination (Table 6 and Figure 2). Figure 2. Overall cure rates. Non-inferiority analysis.

The x-axis shows ∆ (delta) = difference between cure rates (Eflornithine – NECT); the shaded area to the left of ∆=10% shows the non-inferiority zone; the area to the left of ∆=0% is the superiority zone.

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The probability of event-free survival, defined as survival without relapse, was also examined. In Figure 3, the Kaplan-Meier curve represents the duration of event-free survival up to the last follow-up assessment in the ITT population. The log-rank test for equality of survival functions shows a significant statistical difference for NECT (confirmed for all populations analysed: ITT, MITT, PP). Figure 3. Survival analysis showing probability of event-free survival for ITT population (log rank test, p = 0.0497).

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

Pro

babi

lity

of e

vent

free

sur

viva

l

0 6 12 18 24Months since start of treatment

E N+E

10.3 Summary of available estimates of comparative effectiveness Overall, the available evidence on use of the NECT combination therapy shows that the safety and efficacy of the combination is non-inferior to that of eflornithine monotherapy, with markedly less mortality than melarsoprol (see Table 7). Table 7. Case fatality and cure rates following different treatments. Treatment Case Fatality Rate

(died during treatment) Cure Rates at 18 or 24 months

Melarsoprol22 5.9%, 10-day concise tx; 5.3%, standard tx (IMPAMEL); 9.4%, standard tx in literature

70 – 92% (24 month)

Eflornithine (Cohort study)49 1.7% 89-90% (24 month) Eflornithine (NECT study, manuscript in preparation)

2.1% 91-92% (18 month)

NECT68 (NECT study, manuscript in preparation)

<1% 96-98% (18 month)

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11. Summary of comparative evidence on safety The safety data discussed in this section will focus on major clinical and laboratory adverse events (AEs), and deaths, comparing the NECT combination therapy with eflornithine monotherapy based on the recently conducted randomised controlled NECT trial. Comparisons with melarsoprol will rely on retrospective data as no trial has compared melarsoprol to eflornithine or the NECT combination. It is difficult to determine safety based on clinical trials alone. As such, pharmacovigilance systems are essential to monitor the long term safety of programmatic use of the NECT combination therapy; however, expectations should be limited given the state of the overall health system in most affected countries.

11.1 Estimate of total patient exposure to date

A total of 143 patients were exposed to the NECT combination therapy in the multicentre NECT trial. Another 48 patients were exposed to NECT combination in the two earlier studies (BTT and NECS)67, 69 which used a slightly different administration schedule, but the same daily and total drug doses67, 69, making a total of 191 patients exposed to NECT combination therapy on whom data have been reported. The NECT combination has also been used on a compassionate need basis in a number of HAT patients. For instance, it is known that MSF programmes (Ibba, Tambura, and Yambio in Sudan, Omugo in Uganda, and Mossaka and Nkayi in RoC) have treated at least 50 additional HAT patients with NECT* on a compassionate basis since 2000 (M Balasegaram/G Priotto, personal communications). The NECT combination therapy has also been used as rescue treatment in some treatment centres in DRC after eflornithine failure. Finally, another 55 patients have been treated in Uganda in an another study comparing the same, simplified NECT combination regimen with eflornithine monotherapy (ongoing TDR study not to be concluded until end-2009).

11.2 Description of adverse effects/reactions

Safety assessment in the NECT study was done according to GCP guidelines, with careful reporting of all adverse events (AEs). In-hospital safety was assessed by AE reporting which included severity grading per CTC criteria and relatedness to treatment. Treatment-related mortality was evaluated over an extended evaluation period of 30 days after the start of the treatment; a total of 4 deaths occurred among the 286 treated patients, 3 in the eflornithine monotherapy group and one in the NECT group. This is considerably less than would be expected with melarsoprol and similar to previous experience with eflornithine montherapy. There is no evidence for increased mortality or other serious adverse events (SAEs) with the NECT combination. The major safety endpoints assessed in the NECT study were:

• The number of patients with adverse events during hospitalisation by severity and relationship to study treatment and onset time.

*In compassionate use cases, both drugs were generally given for 14 days and children received 600 mg/kg/day of eflornithine and 20 mg/kg/day of nifurtimox.

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• The proportion of patients without grade 3 and 4 AEs (Common Toxicity Criteria guidelines, NIH/NCI) during the hospitalisation period.

• The number of treatment-emergent deaths (defined as deaths within 30 days from initiation of treatment) by likely cause of death (HAT, adverse events of the treatment, causes unrelated to HAT or treatment for HAT, unknown causes).

• The number of patients with treatment-emergent SAEs by relationship to treatment and onset time (during hospitalisation, plus deaths ≤ 30 days from initiation of treatment).

• The number of patients with permanently interrupted treatment.

• The number of patients with temporary treatment suspensions (at least 1, more than 1).

An AE was defined as any untoward medical occurrence (any unfavourable and unintended sign, symptom or disease, including an abnormal laboratory finding) in temporal association with the use of the investigational treatment that may or may not be causally related to it. An AE was defined as serious (i.e. an SAE) if it was fatal or life-threatening, required or prolonged a hospitalisation, or resulted in persistent or significant disability, a congenital anomaly/birth defect, resulted in an important medical event that may not be immediately life threatening or directly result in death or hospitalisation, but which may jeopardise the patient or may require intervention to prevent the other outcomes listed above. Major AEs were defined as AEs of intensity graded at level 3 (severe) and 4 (very severe), per the Common Toxicity Criteria v2.0 guidelines (NIH/NCI, 1999: available at http://ctep.cancer.gov/reporting/ctc_archive.html). Deaths occurring within 30 days after the start of treatment or resulting from an event that started within that period were regarded as temporally associated with treatment and therefore recorded as AE, even if they occurred after the hospitalisation period. They are, by definition, SAEs. In the following tables, only the AEs regarded as ‘related’ (1,262 in total - having been reported as ‘unlikely’, ‘possibly’, ‘probably’, ‘certainly’ related or ‘unknown’) are included; the 101 ‘not related’ events are not reported here. Clinical AEs were very frequent. However, it must be kept in mind that, for most events, it is difficult to discern the causality between the disease itself, other co-morbidities, concomitant treatments and the study treatment. In our description we take a conservative approach: all events are regarded as related to the treatment unless the investigators were certain to the contrary. Table 8 summarises the number and proportion of patients having at least one AE (including all related clinical and serious AEs). Of 286 patients, 268 (93.7%) had at least one related clinical AE. Seven patients experienced treatment-related SAEs, of which 6 received eflornithine monotherapy and 1 received NECT. A total of 61 patients experienced related major AEs – the proportion of patients suffering major adverse events (clinical and laboratory) was significantly lower (p=0.002) in the NECT arm.

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Table 8. Number of patients presenting at least one related AE.

E (n=143) NECT (n=143)

n % n % p-value

N° of patients having at least one related AE 138 96.5 136 95.1 0.555

N° of patients having at least one related clinical AE 134 93.7 134 93.7 1

N° of patients having at least one related serious AE 6 4.2 1 0.7 0.120

N° of patients whose treatment was interrupted 9 6.3 1 0.7 0.019

N° of deaths treatment-related deaths 3 2.1 1 0.7 0.622

N° of patients having at least one related major AE 41 28.7 20 14.0 0.002

The most frequently seen related clinical and laboratory AEs are shown in Table 9. Some AEs were more frequent in the eflornithine arm: diarrhoea, fever, infection, anorexia, and hypertension. Nausea and/or vomiting were more frequently seen with NECT. Table 9. Most frequently seen adverse events during hospitalisation, by study arm. Occurrence of clinical AEs E (n=143) N+E (n=143) p-value

n % n %

Neurological

Seizures 13 9.1 18 12.6 0.342

Anxiety/agitation 11 7.7 4 2.8 0.109*

Dizziness 24 16.8 26 18.2 0.756

Inner ear disturbance 7 4.9 10 7.0 0.365

Insomnia 14 9.8 14 9.8 1.000

Gastrointestinal

Anorexia 20 14.0 36 25.2 0.017

Abdominal pain 42 29.4 35 24.5 0.351

Diarrhoea 41 28.7 9 6.3 0.000

Nausea and/or Vomiting 29 20.3 69 48.3 0.000

Cardiovascular

Arrhythmia 31 21.7 27 18.9 0.556

Hypertension 19 13.3 6 4.2 0.006

Other

Fever 61 42.7 37 25.9 0.003

Infection 32 22.4 18 12.6 0.029 * Fisher’s exact test

Table 10 shows the most frequently seen grade 3 &4 AEs (by event). Some AEs, namely fever and neutropenia, were more frequent in the eflornithine arm.

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Table 10. Number of most frequent clinical and laboratory AEs (grade 3 & 4), by study arm. Major AEs E (n=143) N+E (n=143)

n % n % p-value

Seizures 6 4.2 6 4.2 1.000

Coma 3 2.1 1 0.7 0.622

Confusion 1 0.7 2 1.4 1.000

Hallucinations 1 0.7 1 0.7 1.000

Other neurological 2 1.4 3 2.1 -

Gastrointestinal 2 1.4 2 1.4 -

Fever 18 12.6 7 4.9 0.021

Infection 7 4.9 1 0.7 0.066

Hypertension 3 2.1 0 0.0 0.247

Headache 2 1.4 1 0.7 1.000

Acute Respiratory Distress 1 0.7 1 0.7 1.000

Other clinical AE 2 1.4 2 1.4 -

Total of major clinical AEs 48 33.6 27 18.9 -

Total of patients concerned 33 23.1 18 12.6 0.020

Anemia 1 0.7 2 1.4 1.000

Leukopenia 0 0.0 0 0.0 1.000

Neutropenia 10 7.2 2 1.4 0.035

Total of major laboratory AEs 11 7.7 4 2.8 -

Total of patients concerned 11 7.7 4 2.8 0.109

11.3 Identification of variation in safety due to health systems and patient factors No information available.

11.4 Summary of comparative safety against comparators Nifurtimox+eflornithine combination versus eflornithine The safety data from the multicentre NECT trial confirm that the combination is well tolerated in the context of stage 2 HAT, with no major safety concerns for either the NECT combination or eflornithine monotherapy. The data show a statistically significant difference in related major adverse events in favour of the NECT combination as compared with eflorntihine monotherapy (p=0.002). Melarsoprol It is well established that melarsoprol can result in severe adverse reactions which, in some cases, are deadly – the most worrying of these adverse reactions being reactive encephalopathy. Table 11 summarises the severe AEs documented with melarsoprol treatment in 2 recent studies that examined the concise (10 days) regimen (IMPAMEL I and II) and compared these to historical data with the earlier standard course (table copied with permission from Schmid et al, 200522).

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Table 11. Summary of severe adverse events documented with melarsoprol.

Impamel II Centre History Impamel I Literature

10-day

treatment (N = 2020)

Standard treatment (N = 2215)

10-day treatment (N = 250)

Standard treatment (N = 250)

Standard treatment

mean % (range)a

n° (%) n° (%) n° (%) n° (%) % (range)

Fatalities28, 70-72 119 (5.9) 117 (5.3) 6 (2.4) 6 (2.4) 9.4 (2.7 – 34) Encephalopathic syndromes (ES)b,28,

72, 73 152 (7.5) 184 (8.3) 14 (5.6) 14 (5.6) 4.7 (1.5 – 23.5)

Fatal ES (Grade 3 ES) 80 (4.0) 87 (3.9) 6 (2.4) 6 (2.4) 4.1 (3.3 – 34)

ES case fatality rate (% fatal ES) 52.6 47.3 42.9 42.9 43.8 (33 – 100)

Skin reactions28, 74 166 (8.2) 35 (1.6) 23 (9.2) 13 (5.2) < 3

Bullous eruptions 17 (0.8) 4 (0.2) 3 (1.2) 1 (0.4) < 1

Maculopapular eruptions 138 (6.8) 20 (0.9) 12 (4.8) 6 (2.4) ND

Pruritus 66 (3.3) 11 (0.5) 8 (3.2) 6 (2.4) 5

Polyneuropathiesc, 28, 75 54 (2.7) 24 (1.1) 2 (0.8) 1 (0.4) < 10

Febrile reaction74 233 (11.5) 72 (3.2) 15 (6.0) 12 (4.8) 12

Headache 146 (7.2) 43 (1.9) ND ND ND

Diarrhoea76, 77 45 (2.2) 19 (0.9) 6 (2.4) 4 (1.6) < 25

Hypotension1 16 (0.8) 19 (0.9) ND ND < 1

Jaundice1 5 (0.2) 3 (0.1) ND ND < 3

.

Data are number (%) unless otherwise indicated. aN highly variable, often only percentages were published bGrades 2 (convulsion, coma) and Grades 3 (fatal) cmotor or sensitivity polyneuropathies

ND = Not determined or no data available

Melarsoprol versus eflornithine While no comparative trials have been conducted with eflornithine and melarsoprol, historical data including retrospective comparative analyses have clearly shown the superior safety profile of eflornithine over melarsoprol. In a retrospective analysis in an MSF-treatment centre in Kiri, southern Sudan, patients with second-stage human African trypanosomiasis treated in 2003 with eflornithine (n=251) had an adjusted relative risk of death of 0.2 and experienced significantly fewer cutaneous and neurological adverse effects than did patients who were treated with melarsoprol in 2001 and 2002 (n=708) (Table 12).

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Table 12. Comparison of outcomes for patients with stage 2 HAT treated with eflornithine and melarsoprol in Kiri, Kajo-Keji County, southern Sudan. Data from southern Sudan (2000 – 2003). Copied with permission from Chappuis et al.46 Characteristic Eflornithine

(n = 251) Melarsoprol (n = 708)

p

Mortality during treatment 2 (0.8) 25 (3.5) .024

Adverse effects of treatment

Fever 27 (10.8) 218 (32.3) <.001

Hypotension 0 (0.0) 6 (0.9) .13

Hypertension

All 8 (3.2) 48 (7.3) .02

Severea 0 (0.0) 17 (2.4) .013

Macular rash

All 1 (0.4) 49 (7.5) <.001

Severeb 1 (0.4) 18 (2.5) .036

Bullous rash 0 (0.0) 4 (0.6) .22

Jaundice 0 (0.0) 8 (1.2) .08

Diarrhoea

All 52 (20.9) 68 (10.3) <.001

Severec 4 (1.6) 18 (2.5) .39

Headaches

All 105 (42.2) 270 (39.7) .5

Severeb 0 (0.0) 111 (15.7) <.001

Peripheral neuropathy

All 5 (2) 78 (11.8) <.001

Severed 0 (0.0) 12 (1.7) .038

Tremor

All 6 (2.4) 149 (22.7) <.001

Severee 0 (0.0) 18 (2.5) .011

Acute reactive encephalopathyf

All 1 (0.4) 80 (11.3) <.001

Grade 1 0 (0.0) 21 (3) .006

Grade 2 1 (0.4) 59 (8.3) <.001

Date shown are number (%) of patien s, unless otherwise indicated. t

it f . r f

it f t /

f

r f

aSeverity is defined as systolic blood pressure of >180 mm Hg and/or diastolic blood pressure of >100 mm Hg. bSever y is de ined as an event leading to interruption of treatmentcSeverity is defined as bloody diarrhoea and/o signs o dehydration. dSever y is de ined as an event leading to mo or weakness, walking disability and or interruption of treatment. eSeverity is defined as an event impairing simple activities. Grade 1 acute reactive encephalopathy is defined as new onset of psychosis during treatment. Grade 2 acute reactive encephalopathy is defined as prolonged or repeated convulsions (status epilepticus) o rapid deterioration of the state ofconsciousness (with a Glasgow Coma Score o ≤8).

In another retrospective analysis in an MSF treatment centre in the RoC (Table 13), eflornithine treatment was recommended as a better first-line therapy for stage 2 HAT patients, based on superior safety profile (case fatality rate of 1.7% with eflornithine as compared with 4.8% with melarsoprol ) and improved treatment outcome (8.1% relapse rate compared to 14 – 15.5% with melarsoprol after 12 months follow-up).

25

Table 13. Case fatality rate and risk factors for death within 30 days after admission among patients with stage 2 T.b. gambiense HAT (n = 661) treated with melarsoprol or eflornithine, RoC, April 2001 – April 2004. Adapted from Balasegaram et al, 200647 (p783), data from Republic of Congo (2001-2005). Baseline risk factor Case fatality rate Crude odds ratioa Adjusted odds ratiob

Drug Regimen

Eflornithine 1.7% (5/288) 1.00 1.00

Melarsoprol (standard) 4.8% (15/311) 2.87 (1.03 – 8.00) 2.87 (1.03 – 8.00)

Melarsoprol (short course) 6.5% (4/62) 3.90 (1.02 – 14.98) 3.90 (1.02 – 14.98) aValues in paren heses are 95% confidence intervals. t

t .

.

bAdjusted odds ratios based on logis ic regression model with P = 0.05 (for goodness of fit)

12. Methodological considerations related to HAT studies HAT presents a number of challenges in the design and conduct of clinical studies. According to the WHO Recommendations of the 2004 Informal Consultation on Issues for Clinical Product Development for HAT78, ‘the conduct of clinical studies in patients with HAT faces several difficulties which are rarely encountered simultaneously in clinical trials for other tropical diseases, and rarely in non-tropical diseases of the developed countries’. These include the facts that:

• Disease-endemic regions are difficult to access, have a poor healthcare infrastructure, and suffer extreme poverty.

• There is a lack of suitable sites and trained staff. • Endemicity, even in disease foci, is low. • Non-specific signs and symptoms mean that a large number of individuals need to be

screened to identify patients. • There are no ubiquitous diagnostic and treatment standards. • Successful treatment causing the patient base to be eliminated. • A long follow-up period to determine efficacy. • Poor follow up due to patient ‘loss’ – e.g. due to a lack of patient transport, or high patient

mobility. • Civil unrest and political instability. • Patients fear of lumbar puncture (particularly if they experience no signs and symptoms of the

disease). • Lack or inappropriately trained/functioning of review boards in the affected countries (ethics

committee, research committee, regulatory etc.). Given this context, it’s important to recognize the accomplishment of the NECT study, one of the few randomised controlled trials to be successfully completed in the field of HAT. The study has been compliant with international Good Clinical Practice (GCP) standards as verified through an independent audit, and has achieved 93% patient follow-up at 18 months. Additional considerations related to NECT study design This application proposes that NECT combination becomes the alternative treatment for stage 2 T.bgambiense HAT over melarsoprol which remains the drug most commonly used, in particular when eflornithine monotherapy cannot be introduced due to logistic and human resource constraints. In 2007, 68% of stage 2 patients were still being treated with melarsoprol (see Table 3).

26

Direct comparative studies versus melarsoprol are not considered to be ethical as the drug is known to be toxic and is associated with a proportion of treatment-related deaths. Therefore, the NECT combination has been assessed in comparison with eflornithine monotherapy, the current first-line stage 2 HAT treatment, in a randomised, controlled, non-inferiority trial. This design was chosen based on the rationale that, if both the safety and efficacy of the combination therapy were comparable with eflornithine monotherapy, the far greater ease of use of the combination therapy would be an advantage of practical significance, as this today is the major barrier for the wider utilisation of eflornithine. In addition, the combination is expected to provide protection against the possible rapid development of resistance that can be expected when giving a trypanostatic drug, with a narrow therapeutic window, as monotherapy. 13. Summary of available data on comparative cost and cost effectiveness within the pharmacological class or therapeutic group:

13.1 Range of costs of the proposed medicine It is difficult to assess what the exact costs might be for NECT as there are a number of variable factors, but it can be concluded that the combination treatment will offer a substantial reduction in cost as compared with 1 treatment course of eflornithine monotherapy (given a reduction in cost of transport and storage as well as a reduction in the number of iv infusions and treatment days; see Table 14). Transportation and storage costs remain critical issues for national control programmes, especially for distribution within countries. In some countries infusion fluids can be obtained locally, thereby substantially reducing the costs of transport. The drugs are provided free-of-charge through a donation programme organised by the WHO. Eflornithine and all materials needed for the iv infusions (provided as a kit), are currently supplied to HAT control programmes free-of-charge by the WHO, thanks to an agreement made with sanofi-aventis in 2001 and renewed until 2011. Bayer, the manufacturer of nifurtimox, currently provides the drug free-of-charge to WHO for the treatment of Chagas disease. It is anticipated that a similar donation will be made by Bayer for the use of nifurtimox in HAT. Bayer has also made donations for compassionate use of nifurtimox for HAT treatment and for clinical trials.

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Table 14. Comparison of treatment kits, including drugs and consumables needed for infusion (cost in Euros, €). Calculations based on data provided by WHO (Pere Simarro, personal communication).

1 eflornithine treatment

1 NECT treatment

Cost of kit content (excl. HAT drugs)a€ 86.5 € 27.5 € Eflornithine 360 € 180 € Nifurtimox - 15 € Volume (dm3) 85 dm3 25 dm3 Weight per treatment (kg) 19 kg 9 kg Number of treatments per container for shipment 520 1,760 Cost for transportb € 22 € 6 € Cost per treatment € Excl. cost HAT drugs

109 €

34 €

Cost per treatment € Incl. cost HAT drugs

469 € 228.5€

Treatment duration 14 days 10 days aD ugs are made available free-of-charge via the WHO drug donation programme. The compos ion of the eflornithine kit isgiven in Section 6, Table 2; the expected cost of the NECT-kit was calculated derived from this.

r it

bExample for kits transported to Kinshasa.

Today’s eflornithine kits include 2 adult treatments and all related materials needed for the proper administration of the treatment (see Section 6, Table 2). It is expected that, considering a comparable weight and volume per kit, the NECT combination kits will contain 4 full treatments.

13.2 Comparative cost effectiveness presented as range of cost per routine outcome (e.g. cost per case, cost per cure, cost per month of treatment, cost per case prevented, cost per clinical event prevented, or, if possible and relevant, cost per quality-adjusted life year gained)

No detailed analysis has been conducted on the cost and cost effectiveness of the NECT combination treatment compared with current treatments for stage 2 T.b. gambiense HAT (melarsoprol and eflornithine monotherapy). However, considering that the safety and efficacy is comparable to eflornithine, it can be concluded that the NECT combination will be more cost-effective as it uses less eflornithine, less iv infusion equipment and infusion fluids, less staff time in administering and monitoring the treatment, and treatment duration is shorter. The unacceptably high toxicity of melarsoprol should preclude its consideration. Despite high cost implications for eflornithine (i.e. drug infusion materials, and medical supervision), eflornithine monotherapy (14 day regimen at 400 mg/kg/day, given at 6 hourly intervals) was shown to be a cost-effective alternative (according to WHO choice criteria) to melarsoprol monotherapy in an MSF treatment setting in Angola because eflornithine saves more lives than melarsoprol48. The paper showed that:

• The cost/patient was 504.6 US dollars (USD) for melarsoprol and 552.3 USD for eflornithine • The cost/life saved was 527.5 USD for melarsoprol and 559.8 USD for eflornithine without

cost of drugs* (this increases to 600.4 USD and 844.6 USD per patient saved and 627.6 USD and 856.1 USD per life saved when cost of drugs are included)

*anti-trypanosomal drugs are currently available free-of-charge due to a WHO donation programme arranged with manufacturers.

28

The proposed NECT has considerable additional cost advantages over standard eflornithine monotherapy. Not only is the cost of the drug reduced (as less is needed per patient), but the costs of drug delivery are also substantially reduced as the number of infusions are reduced from 56 per patient to 14 (see section 13.1) 14. Summary of regulatory status of medicines Eflornithine was registered for the treatment of African trypanosomiasis in 1991. It is currently registered in the USA and France. Nifurtimox is registered for treatment of Chagas disease in Argentina, Chile, Colombia, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, and Uruguay. 15. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia) International Pharmacopoeia (4th edition, 2006): Eflornithine: No Nifurtimox: Yes, listed as Nifurtimoxum-Nifurtimox in antitrypanosomal drug category British Pharmacopoeia (2008): Eflornithine: No Nifurtimox: No United States Pharmacopeia: Eflornithine (see http://www.usp.org/standards/international/guidelines.html) Nifurtimox (see http://www.usp.org/standards/international/guidelines.html) 16. Proposed text for WHO Model Formulary The NECT co-administered combination therapy of oral nifurtimox and intravenous eflornithine in this application is proposed for the anti-infective medicines/antitrypanosomal medicines/African trypanosomiasis section/medicines for the treatment of 2nd stage African trypanosomiasis subsection (to be used exclusively for the treatment of the 2nd stage of Trypanosoma brucei gambiense infection) of the WHO Model Formulary under the heading ‘Nifurtimox + eflornithine’. Dosage form and strength: Tablet (nifurtimox): 120 mg + Injection (eflornithine): 200 mg (hydrochloride)/ml in 100ml bottle. The co-administered combination therapy, referred to here as the NECT combination, is: Nifurtimox: 10 days at 15 mg/kg/day (5 mg/kg every 8 hours) administered orally plus Eflornithine: 7 days at 400 mg/kg/day (200 mg/kg every 12 hours) administered as an iv infusion over 2 hours. ATC code: To be provided by WHO

29

Listing: To be provided by WHO Disease indication: Therapy for stage 2 (late stage, meningo-encephalitic stage) African trypanosomiasis (sleeping sickness) due to T ypanosoma brucei gambiense. r Rationale for inclusion: The combination of nifurtimox and eflornithine (NECT) is less toxic than melarsoprol, the current most commonly used treatment. NECT is as efficacious and well tolerated as eflornithine monotherapy, which is considered the current first choice where it is feasible to implement. Moreover, NECT is a more practical and less costly alternative as fewer infusions are needed during the course of therapy, for a shorter period of time, and only need to be administered at 12-hour intervals (twice per day). NECT may prevent the emergence of resistant parasites. General information: Description:

The two medicines to be used in combination are: • Oral nifurtimox (a 5-nitrofuran): a trypanothione reductase inhibitor with trypanocidal effects.

The chemical name is 3-methyl-4-5(5’nitrofurfuryliden-amino)-tetrahydro-4H-1,4-tianzine-1,1 dioxide.

• Injectable eflornithine (eflornithine hydrochloride, α-difluoro-methyl-ornithine, DFMO): an ornithine decarboxylase inhibitor with trypanostatic effects. The chemical name is 2-(difluormethyl)-DL-ornithine monohydrochloride monohydrate.

Uses: Treatment of patients diagnosed (see details below) with stage 2 human African trypanosomiasis due to Trypanosoma brucei gambiense. Contraindications: Hypersensitivity/allergy to eflornithine or nifurtimox. Precautions:

• Pregnancy: The safety of the NECT combination therapy during pregnancy has not been tested or established and therefore it should only be used during pregnancy if the potential benefit to the mother justifies the potential risk to the foetus (i.e. when there is no alternative). Animal studies have shown that eflornithine may cause birth defects or may cause death of the foetus and the manufacturer suggests that eflornithine should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. The effect of nifurtimox in pregnancy has not been evaluated.

• Breastfeeding: It is not known if eflornithine and/or nifurtimox pass into breast milk. Therefore physicians may wish to suggest alternative methods of feeding infants, if appropriate.

• Renal impairment: No data are available on NECT. The manufacturer of eflornithine suggests caution should be exercised in patients with renal impairment receiving eflornithine as approximately 80% of the intravenous dose of eflornithine is eliminated unchanged in the urine. Nifurtimox is not eliminated by the renal route.

30

• Paediatric and geriatric use: No studies on the use of the NECT combination therapy have been carried out.

• HIV/AIDS: The safety and efficacy of NECT for use in HIV/AIDS patients has not been tested or established. Data on the individual medicines is not available. The physician should make a judgment as to whether the benefits of treatment with NECT outweigh possible adverse effects, based on current knowledge.

• Chronic abuse of medications or alcohol: No data available. Due to the nature of drug administration and some of the adverse effects, the NECT combination therapy should only be administered in a medical facility. Also:

• The patient should be kept under medical supervision while eflornithine is administered and should be observed for the full period of treatment. Any decision to modify dosage or interrupt/cease treatment should be based on the severity of any adverse event(s) and access to support facilities. Such modifications should be documented in the patient’s hospital notes for future reference.

• Close observation is recommended when giving nifurtimox to patients with a history of cerebral damage, predisposition to epilepsy, psychosis and serious behavioural alterations.

• Patients are advised to avoid alcohol to prevent possible side effects. • Physicians are advised to monitor haematological profiles before, during and after treatment

due to the risk of myelosuppression whenever facilities are available for this. In case of abnormality, profiles should be obtained once a week after therapy until the abnormal parameter returns to baseline levels.

• Physicians are advised to follow up patients for at least 24 months after treatment wherever possible (in case of relapse and the need for further treatment) and to document outcomes in the patient’s hospital notes for future reference.

• It is advised to ensure that patients are properly fed during the treatment. • The patient should be observed specifically for signs of infection emerging during or shortly

after treatment, in which case prompt antibiotic therapy should be started. Dose: Nifurtimox: 5 mg/kg every 8 hours for 10 days orally plus Eflornithine: 200 mg/kg every 12 hours for 7 days by intravenous infusion over 2 hours Paediatrics: No specific data is available for the use of the NECT combination therapy in children. Nifurtimox is administered orally while eflornithine is administered by slow intravenous infusion. The eflornithine concentrate must be diluted in sterile water, sterile saline solution or 5% dextrose in distilled water immediately before use. In studies carried out to date, the first daily dose of nifurtimox has been administered at the same time point as the point at which the first eflornithine infusion was started each day, so that the daily treatment regimen can be completed without disturbing the patient during the night. Adverse effects: Major (i.e. severe and very severe – grades 3&4 per CTC) adverse effects that have been reported following NECT combination therapy include fever (4.9%), seizures (4.2%), confusion (1.4%), infection (0.7%), nausea and vomiting (0.7%), coma (0.7%), hallucinations (0.7%), hemiplegia (0.7%), ataxia (0.7%), tinnitus (0.7%), anorexia (0.7%), sepsis (0.7%), headache (0.7%), rash

31

(0.7%), acute respiratory distress (0.7%) and dehydration (0.7%). Only one death has occurred so far among 143 patients treated with NECT. Other adverse effects include:

• Nausea and/or vomiting (48.3%), fever (25.9%), anorexia (25.2%), abdominal pain (24.5%), , arrhythmia (18.9%), dizziness (18.2%), infection (12.6%), seizures (12.6%), insomnia (9.8%), inner ear disturbance (7.0%), diarrhoea (6.3%), hypertension (4.2%), and anxiety/agitation (2.8%), peripheral neuropathy (motor or sensory), tremor, hiccups, hypotension/shock, injection site reaction, pruritus, cough, chest pain, leucopenia and abnormal levels of bilirubin.

In addition, according to the manufacturer’s inserts, the individual drugs may cause adverse effects as listed below: Nifurtimox:

• Main adverse effects include nausea, vomiting, and abdominal pain. • Central nervous system effects include memory loss, sleep disturbances excitatory states,

seizures and psychotic behaviour. • Long-term treatment may affect the peripheral nervous system, causing tremors, muscle

weakness, mild paraesthesia and polyneuritis. Eflornithine:

• Eflornithine has been reported to cause thrombocytopenia, anaemia and leucopenia, in particular neutropenia; these adverse effects are usually reversible on stopping treatment.

• Eflornithine has been temporally associated with seizures (an adverse effect that can also be caused by the underlying disease).

• Other adverse effects include: vomiting, alopecia, abdominal pain, anorexia, headache, transient hearing impairment, asthenia, facial oedema, eosinophilia and dizziness.

Overdosage: No data are currently available on the effects of overdosage in humans. Drug interactions: No data are available. Storage:

• Nifurtimox: Store below 25°C and away from direct light. • Eflornithine: Store vial at room temperature, ideally below 30°C. Protect from freezing and

from light. The manufacturer’s package inserts of the individual drugs are given in the appendices.

32

Appendix (on the following pages) • Pack insert – Ornidyl (eflornithine) • Pack insert – Lampit (nifurtimox) • Baseline characteristics of the study population

Attached to the application as separate files:

• Slide presentation of NECT ICTM17, Jeju Island, October 2008 • Priotto et al., 2006 • Checchi et al., 2007 • Priotto et al., 2007

33

34

35

Baseline characteristics of the 286 subjects included in the safety analysis of the Phase III NECT study (Priotto et al. manuscript in preparation)

N E (n=143) N+E (n=143) Total p-value

Sex (M/F ratio) 286 1.6 1.4 1.5 0.545 Age in years (mean, SD) 285 34.6 (13.5) 32.8 (12.5) 33.7 (13.0) 0.277 Weight in kg (mean, SD) 286 53.9 (8.7) 53.0 (8.3) 53.4 (8.5) 0.390 Height in cm (mean, SD) 286 165.8 (9.1) 165.8 (7.9) 165.9 (8.5) 0.894 BMI Normal >=18.5 Thinness < 18.5

286 96 (67.1) 47 (32.9)

89 (62.2) 54 (37.8)

185 (64.7) 101 (35.3)

0.386

Mode of screening Active Passive

286 51 (35.7) 92 (64.3)

59 (41.3) 84 (58.7)

110 (38.5) 176 (61.5)

0.331

Lymph node aspirate Positive Negative or no nodes

286 88 (61.5) 55 (38.5)

88 (61.5) 55 (38.5)

176 (61.5) 110 (38.5)

1.000

Tryps in blood Positive Negative

286 74 (51.8) 69 (48.3)

67 (46.9) 76 (53.2)

141 (49.3) 145 (50.7)

0.408

Tryps in CSF Positive Negative

285 105 (74.4) 37 (25.9)

103 (72.0) 40 (28.0)

208 (72.7) 77 (26.9)

0.716

White cells count in CSF 6-20 cells/uL 21-99 cells/uL >=100 cells/uL

286 2 (1.4) 26 (18.2) 115 (80.4)

2 (1.4) 34 (23.8) 107 (74.8)

4 (1.4) 60 (21.0) 222 (77.6)

0.473

CSF IgM titer up to 1/128 1/256 to 1/1024

279 107 (75.9) 34 (24.1)

111 (80.4) 27 (19.6)

218 (78.1) 61 (21.9)

0.330

Hemoglobin g/dL (mean, SD) 286 11.8 (1.86) 11.9 (1.92) 11.8 (1.89) 0.917 Malaria co-infection 285 29 (20.4) 22 (15.4) 51 (17.9) 0.267 Clinical characteristics Lymphadenopathy 286 88 (61.5) 88 (61.5) 176 (61.5) 1.000 Hepatomegaly 286 6 (4.2) 9 (6.3) 15 (5.2) 0.426 Splenomegaly 285 29 (20.3) 21 (14.8) 50 (17.5) 0.223 Coma score < 15 284 6 (4.2) 13 (9.2) 19 (6.7) 0.097 Karnofsky index, median (mean, SD) 286 80 (77.1[12.8]) 80 (75.3[15.7]) 80 (76.2[14.4]) 0.486 Fever (>=37.5°C axillary) 286 29 (20.3) 22 (15.4) 51 (17.8) 0.799 Headache 285 119 (83.8) 115 (80.4) 234 (82.1) 0.456 Pruritus 284 102 (71.8) 104 (73.2) 206 (72.5) 0.790 Amenorrhea 88 19 (47.5) 23 (47.9) 42 (47.7) 0.969 Impotence 167 42 (48.8) 46 (56.8) 88 (52.7) 0.304 Unusual behaviour 281 66 (47.1) 56 (39.7) 122 (43.4) 0.209 Anorexia 284 42 (29.6) 53 (37.3) 95 (33.5) 0.167 Seizures 285 16 (11.3) 10 (7.0) 26 (9.1) 0.210 Tremors 284 51 (36.2) 51 (35.7) 102 (35.9) 0.929 Diurnal somnolence 285 109 (76.2) 96 (67.6) 205 (71.9) 0.105 Nocturnal insomnia 284 65 (45.8) 59 (41.5) 124 (43.7) 0.473 Speech disorder 285 24 (16.8) 29 (20.4) 53 (18.6) 0.430 Neurological signs 284 49 (34.3) 52 (36.9) 101 (35.6) 0.645 Duration of symptoms, months (mean, SD)

284 8.5 (9.19) 8.6 (9.39) 8.6 (9.27) 0.850

Figures in paren hesis are percentages, unless specified. Amenorrhoea evaluated on women of age 51 or younger. Chi2 tes , Student t test, or Wilcoxon-Mann Whi ney test, as appropriate.

t t- t

Baseline data show a balanced distribution of subjects per arm, suggesting that the randomisation procedure was effective and that the two groups are comparable.

36

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