Prescription of concomitant medications in patients treated with Nifurtimox Eflornithine Combination Therapy (NECT) for T.b. gambiense second stage sleeping sickness in the Democratic Republic of the Congo.

BACKGROUND: Nifurtimox eflornithine combination therapy (NECT) to treat human African trypanosomiasis (HAT), commonly called sleeping sickness, was added to the World Health Organisation's (WHO) Essential Medicines List in 2009 and to the Paediatric List in 2012. NECT was further tested and documented in a phase IIIb clinical trial in the Democratic Republic of Congo (DRC) assessing the safety, effectiveness, and feasibility of implementation under field conditions (NECT-FIELD study). This trial brought a unique possibility to examine concomitant drug management. METHODOLOGY/PRINCIPAL
FINDINGS: This is a secondary analysis of the NECT-FIELD study where 629 second stage gambiense HAT patients were treated with NECT, including children and pregnant and breastfeeding women in six general reference hospitals located in two provinces. Concomitant drugs were prescribed by the local investigators as needed. Patients underwent daily evaluations, including vital signs, physical examination, and adverse event monitoring. Concomitant medication was documented from admission to discharge. Patients' clinical profiles on admission and safety profile during specific HAT treatment were similar to previously published reports. Prescribed concomitant medications administered during the hospitalization period, before, during, and immediately after NECT treatment, were mainly analgesics/antipyretics, anthelmintics, antimalarials, antiemetics, and sedatives. Use of antibiotics was reasonable and antibiotics were often prescribed to treat cellulitis and respiratory tract infections. Prevention and treatment of neurological conditions such as convulsions, loss of consciousness, and coma was used in approximately 5% of patients.
CONCLUSIONS/SIGNIFICANCE: The prescription of concomitant treatments was coherent with the clinical and safety profile of the patients. However, some prescription habits would need to be adapted in the future to the evolving available pharmacopoeia. A list of minimal essential medication that should be available at no cost to patients in treatment wards is proposed to help the different actors to plan, manage, and adequately fund drug supplies for advanced HAT infected patients. TRIAL REGISTRATION NUMBER: The initial study was registered at ClinicalTrials.gov, number NCT00906880.

Introduction

Human African trypanosomiasis (HAT), also called sleeping sickness, affects people in sub-Saharan Africa who often live in remote or insecure areas with limited access to healthcare. The disease is caused by a trypanosome infection after a bite from a tse-tse fly and evolves from a haemo-lymphatic invasion (first stage) into a neuro-encephalitic infection (second stage) that leads to severe sleep disturbances, neurological and psychiatric disorders, coma, and in most cases to death if untreated [1]. Until 2009, treatment for the second stage T.b. gambiense HAT was limited to melarsoprol, an arsenic derivative with high toxicity [2] and in some areas, reduced efficacy [3-5], or eflornithine monotherapy, a burdensome treatment consisting in 56 slow infusions over 2 weeks [6].

Nifurtimox Eflornithine Combination Therapy (NECT) was added to the World Health Organization’s Essential Medicines List (WHO EML) in 2009 [7] and to the Paediatric WHO EML in 2012 [8]. Since then, a new oral molecule, fexinidazole, has been further assessed and was granted a positive opinion from the European Medicine Agency (EMA) for the treatment of first and second stage HAT in 2018 [9, 10]. Following the introduction of fexinidazole, NECT will still remain the first choice treatment in patients presenting a clinical picture consistent with severe second stage HAT with ≥ 100 white blood cell (WBC)/μL in the cerebrospinal fluid (CSF), or those unable to eat. It also remains the first choice for pediatric patients younger than 6 years old or weighting less than 20 kg presenting with > 5 WBC/μL or trypanosomes in the CSF [11, 12].

From 2009 to 2012, NECT was tested and documented in a phase IIIb clinical trial (NECT-FIELD study) in the Democratic Republic of Congo (DRC) [13]. In the NECT-FIELD study, the safety, effectiveness, and feasibility of implementation under field conditions were assessed. The in-hospital safety profile of NECT administered to a wide population, including vulnerable people such as children, and pregnant and breastfeeding women, was already published by Schmid et al [13], while the 24-months effectiveness analysis is under preparation and will be submitted for publication.

Before and during the HAT specific treatment the patients received an array of concomitant medication to treat co-morbidities or manage adverse events. The NECT-FIELD study brought a unique opportunity to examine in-hospital patient management, given concomitant diseases and adverse events in second stage HAT patients.

The present analysis describes the concomitant medication prescribed during hospitalization before and during treatment with NECT. In our knowledge, this has never been done so far in any clinical trial involving second stage HAT patients. The main objective of this work is to help national health systems or private actors to plan, develop, and update the essential medicine supplies adapted to their second stage HAT gambiense patients including vulnerable populations such as children as well as pregnant and breastfeeding women.

Methods

Design and study population

This is a secondary analysis of the NECT-FIELD study conducted between 2009 and 2012 in six HAT treatment centres located in reference district hospitals in the DRC and included 629 patients treated with NECT. The design, methods, and in-hospital safety results of the NECT-FIELD study are described in the published report by Schmid et al [13]. Briefly, all second stage HAT patients admitted to the treatment centres received NECT, the co-administration of nifurtimox (oral 15 mg/kg/day, three times a day) for 10 days and eflornithine (slow intravenous infusions, 400 mg/kg/day, twice a day) for 7 days. All patients were hospitalised during the entire treatment period.

Prior to NECT, the patients received standard pre-treatment according to the national guidelines, consisting of antimalarial, anthelminthic, and, if required, antipyretic/analgesic medication. Concomitant medication was prescribed according to the decision of the investigator and the local guidelines. An emergency pharmacy for eventual life-threatening issues was provided by the study coordination to the Investigators while the other drugs were routinely supplied by the national HAT program or the hospital pharmacy.

Collected data

Patients underwent daily evaluations, including vital signs, physical examination, and adverse event (AE) monitoring. The concomitant medications were documented and details such as the reason for use, dates, dosages, and route and duration of administration were recorded. AEs and their severity were reported from the first day of treatment until discharge from hospital and were assessed along with their severity and possible relation to the study treatment [14]. The AEs and concomitant medications were coded with the MedDRA dictionary (version 11) and the WHO-Drug dictionary (version Q2.06) respectively. AEs observed in ≥ 5% of the patients and concomitant medications prescribed in ≥ 2.5% have been included in the result tables for the assessment of concomitant medication prescriptions. AEs and concomitant drugs that appeared with lower frequencies but were of medical relevance were included after discussion between AK and OVM.

Statistics

The main analysis set is the intention to treat (ITT) population, which includes all subjects who received at least one dose of study drug. Statistical evaluations are descriptive. Means, standard deviations, and number of patients are provided for continuous variables, as well as frequency distributions for binary and categorical variables. Statistical analyses were performed using the SAS software version 9.1 (SAS Institute, Cary, NC) and Epi Info 7.0.

Ethical considerations

The NECT-FIELD study received approval from two Ethics Committees: the Ethics Committee of both cantons of Basel (EKBB, Basel, Switzerland; 26 February, 2009) and the local Ethics Committee in the DRC (Comite d’ethique sur la Trypanosomiase Humaine Africaine, Kinshasa, Democratic Republic of the Congo, 7 May 2009). Eligible patients provided written informed consent before enrolment into the study. In case of minors, severely ill, or mentally impaired patients unable to fully consent, written informed consent was obtained from her/his parent(s)/guardian(s). Whenever possible, depending on age and level of understanding, the children received the information and their assent was obtained.

Results

Study population and clinical profile on admission

Of the 629 patients included in this analysis, 100 were children below 12 years of age, 33 were breastfeeding women, and 14 were pregnant women (Table 1). The patient flow is published in the in-hospital safety report [13]. HAT signs and symptoms reported by the patients on admission are shown in Table 2.

Table 1

Demographic characteristics of the study population.

Characteristics	Number of patients treated n (%)*
Total number of patients (N)	629
Male/female ratio	1.3
Children 0–11 years	100 (15.9)
Adolescents/adults > 11 years	529 (84.1)
Breastfeeding women	33 (5.2)
Pregnant women	14 (2.2)
Age, mean (SD) years#	30 (16.2)
Median	28
Range (min-max)	1–77
Study sites
Kasai Oriental Province
Dipumba	146 (23.2)
Katanda	132 (21.0)
Ngandajika	94 (14.9)
Bandundu Province
Bandundu	98 (15.6)
Kwamouth	97 (15.4)
Yasa Bonga	62 (9.9)

*Unless otherwise specified

#age unknown for 2 patients

Table 2

HAT signs and symptoms reported by the patient on admission.

Percentage of patients with (%)*	Children0–11 years	Adolescents & adults>11 years	Breast-feeding women	Pregnant women	All patients
	N = 100	N = 482ǂ	N = 33	N = 14	N = 629
Sleeping disorders	80.0	80.5	72.7	64.3	79.7
Headache	50.0	78.6	84.8	92.9	74.7
Asthenia	44.0	64.5	54.5	92.9	61.4
Fever history	77.0	56.0	42.4	71.4	59.0
Pruritus	44.0	61.8	57.6	35.7	58.2
Weight loss	46.0	55.8	54.5	78.6	54.7
Tremor	35.0	45.9	30.3	57.1	43.6
Walking disorder	28.0	45.0	15.2	57.1	41.0
Behavioural disorder	42.0	32.8	24.2	21.4	33.5
Convulsions	15.0	3.5	3.0	7.1	5.4

*Unless otherwise specified

ǂall adolescents and adults except breastfeeding / pregnant women

Treatment emergent adverse events

The reporting of treatment emergent AEs showed that above all, patients developed gastrointestinal disorders including nausea and vomiting, general disorders like fever, and neurological and psychiatric disorders like asthenia, headaches, dizziness, convulsions, insomnia, and agitation that are difficult to distinguish from the disease itself (Table 3). Less frequently but of medical importance, potentially severe or life-threatening AEs if not treated such as coma, loss of consciousness, specific psychiatric disorders, infections, and cardiac disorders were also observed.

Table 3

Treatment emergent adverse events (AEs).

Percentage of patients with (%)*	Children0–11 years	Adolescents & adults>11 years	Breast-feeding women	Pregnant women	All patients
	N = 100	N = 482ǂ	N = 33	N = 14	N = 629
Treatment emergent adverse events (AEs)
Patients with at least 1 adverse event	92.0	92.1	84.8	100.0	91.9
Death	0	1.9	0	7.1	1.6
Gastrointestinal disorders	43.0	63.9	66.7	92.9	61.4
Vomiting	31.0	43.6	57.6	78.6	43.1
Nausea	13.0	22.0	6.1	21.4	19.7
Colitis or diarrhoea	13.0	13.3	6.1	7.1	12.7
Pain and discomfort of thegastrointestinal tract%	5.0	16.2	18.2	35.7	14.9
General disorders and administration site condition	57.0	41.7	60.6	85.7	46.1
Fever	44.0	25.9	42.4	28.6	29.7
Asthenia	13.0	16.8	27.3	57.1	17.6
Injection site disorders&	7.0	4.8	6.1	7.1	5.2
Nervous system disorders	21.0	37.1	24.2	57.1	34.3
Headache	8.0	15.4	12.1	35.7	14.5
Dizziness	0	13.1	6.1	14.3	10.7
Convulsions	10.0	9.1	9.1	0	9.1
Tremor	4.0	3.3	0	0	3.2
Coma or loss of consciousness	1.0	1.7	3.0	7.1	1.7
Metabolism and nutrition disorders	22.0	27.8	12.1	28.6	26.1
Anorexia	21.0	27.2	9.1	28.6	25.3
Psychiatric disorders	9.0	17.6	12.1	0	17.6
Insomnia	3.0	7.7	0	0	6.4
Agitation	5.0	5.6	12.1	0	5.7
Behavioural disorders	0	1.9	0	0	1.4
Mood disorders	1.0	1.0	3.0	0	1.1
Mental confusion	1.0	0.8	0	0	0.8
Hallucinations or delirium	0	1.5	0	0	1.1
Psychosis or acute psychosis	0	0.2	3.0	0	0.3
Depression	0	0.2	0	0	0.2
Musculoskeletal and connective tissue disorders	4.0	15.4	15.2	21.4	13.7
Lumbago	2.0	6.2	6.1	21.4	5.9
Neck pain	0	3.9	3.0	0	3.2
Skin and sub-cutaneous tissue disorders	9.0	9.8	6.1	7.1	9.4
Pruritus or cutaneous pruritus	7.0	5.8	3.0	0	5.1
Dermatitis or cutaneous eruption	2.0	1.0	0	0	1.1
Vascular disorders	3.0	8.3	6.1	14.3	7.5
Hypotension	3.0	4.8	6.1	14.3	4.8
Hypertension	0	2.9	0	0	2.2
Cardiac disorders	4.0	7.9	3.0	7.1	7.0
Palpitation or arrhythmia	3.0	5.8	3.0	0	5.1
Bradycardia	0	1.2	0	0	1.0
Tachycardia	1.0	0.8	0	7.1	1.0
Infections and infestations	8.0	4.6	3.0	14.3	5.2
Respiratory infections$	2.0	1.0	7.1	0	1.3
Cellulitis	1.0	1.0	0	7.1	1.1
Malaria	1.0	0.6	3.0	0	0.6
Septic shock	0	0.2	0	7.1	0.3
Blood and lymphatic system disorders	3.0	1.2	0	7.1	1.6
Anaemia	2.0	1.0	0	7.1	1.3

*Unless otherwise specified

ǂall adolescents and adults except breastfeeding / pregnant women

%the following AEs have been grouped under Pain and discomfort of the gastrointestinal tract: heartburn, lower abdominal pain, left hypochondrium pain, abdominal pain, dyspepsia, dysphagia, epigastralgia, upset stomach

& the following AEs have been grouped under injection site disorders: pain at the injection site, pain at the catheter site, extravasation and injection site reaction.

$including pneumonia and bronchopneumonia

Prescription of concomitant medication

Medication given before study treatment started consisted mainly in anti-parasitic pre-treatment according to HAT national guidelines, usually 1–3 days before the start of the first dose of NECT and lasting normally 3 days. This anti-parasitic pre-treatment usually comprised an antimalarial and an anthelmintic (Table 4). Depending on the treatment centre, paracetamol was either routinely administered after the lumbar puncture or when the patients complained of headaches. The majority of the patients received the antimalarial pre-treatment sulfadoxine/pyrimethamine combination, with the exception of one centre, where patients received artesunate. Severe malaria cases were managed at all sites with intravenous isotonic quinine infusion. Concomitant medication during NECT was common in all study populations and most patients received at least one concomitant medication (Table 4). Administered treatments were mainly analgesics and antipyretics, anthelmintics, antiemetics, and sedatives.

Table 4

Prescription of concomitant medication.

Percentage of patients treated with (%)	Children0–11 years	Adolescents & adults> 11 years	Breast-feeding women	Pregnant women	All patients
	N = 100	N = 482*	N = 33	N = 14	N = 629
(A) BEFORE HAT TREATMENT
Patients with at least 1 treatment	89.0	85.3	72.7	85.7	85.2
Anthelmintics
Mebendazole	33.0	32.8	27.3	28.6	32.4
Antiprotozoals
Sulfadoxine/pyrimethymine	73.0	76.1	60.6	85.7	75.0
Artesunate	7.0	6.8	12.1	0	7.0
Quinine	8.0	1.7	0	0	2.5
Analgesics, antipyretics
Paracetamol	5.0	9.1	12.1	7.1	8.6
(B) DURING NECT TREATMENT
Patients with at least 1 treatment	90.0	95.4	97.0	100.0	94.8
Antibacterials
Amoxicillin	8.0	5.8	3.0	7.1	6.0
Sulfamethoxazole/trimethoprim	5.0	5.4	3.0	0	5.1
Ciprofloxacin	2.0	2.1	3.0	0	2.1
Gentamicin	1.0	1.5	0	7.1	1.4
Ampicillin	1.0	1.5	0	0	1.3
Antiprotozoals
Sulfadoxine/pyrimethymine	10.0	14.5	24.2	14.3	14.3
Quinine	5.0	2.9	6.1	0	3.3
Metronidazole	3.0	2.5	3.0	0	2.5
Artesunate	0	1.2	0	7.1	1.1
Anthelmintics
Mebendazole	57.0	53.3	51.5	50.0	53.7
Levamisole	8.0	12.7	18.2	14.3	12.2
Scabicides
Benzyl benzoate	5.0	5.2	0	0	4.8
Analgesics, antipyretics
Paracetamol	33.0	33.4	48.5	50.0	34.5
Metamizole	30.0	23.2	39.4	35.7	25.4
Acetylsalicylic acid	12.0	6.0	3.0	0	6.7
Anti-inflammatory medicines
Diclofenac	0	2.9	3.0	0	2.4
Antihistamines
Promethazine	4.0	6.4	6.1	0	5.9
Chlorphenamine	1.0	2.5	0	0	2.1
Dexchlorpheniramine	0	2.3	0	0	1.7
Corticosteroids
Dexamethasone	6.0	5.4	0	7.1	5.2
Hydrocortisone	2.0	4.4	6.1	7.1	4.1
Cardiovascular medicines
Furosemide	1.0	2.9	0	0	2.4
Gastrointestinal medicines
Metoclopramide	6.0	10.2	12.1	7.1	9.5
Oral rehydration solution	7.0	5.4	3.0	7.1	5.6
Aluminium Hydroxide	0	3.1	3.0	0	2.5
Papaverine	1.0	2.3	3.0	21.4	2.5
Nervous system medicines
Diazepam	14.0	18.5	15.2	0	17.2
Phenobarbital	1.0	4.8	0	7.1	4.0
Chlorpromazine	2.0	3.9	9.1	0	3.8
Vitamins
Multivitamins	5.0	8.5	6.1	21.4	8.1
Vitamin B6 complex	3.0	5.8	6.1	7.1	5.4
Perfusion solutions
Hypertonic glucose	7.0	7.5	9.1	14.3	7.6
NaCl	0	4.1	0	14.3	3.5
Ringer lactate	1.0	2.9	3.0	7.1	2.7
Glucose	2.0	1.9	6.1	0	2.1

*All adolescents and adults except breastfeeding / pregnant women

The most frequently administered antibiotics during NECT were amoxicillin, ampicillin, ciprofloxacin, and gentamicin and were mainly prescribed to treat injection site infections (including cellulitis) or respiratory tract infections.

Discussion

We report an evaluation of the concomitant medication prescribed to the 629 patients included in the NECT-FIELD study conducted at six HAT treatment centres in the DRC [13]. The patients’ clinical and safety profiles were characteristic of second stage HAT patients [15-19]. It therefore appears that drugs were not only used to treat the treatment emergent AEs but also the symptoms related to the disease itself.

The known bone marrow toxicity of eflornithine [6] and the repeated eflornithine perfusions raised some concerns about the increased risk of bacterial infections in the field and the consequent use of antibiotics. The proportion of treated patients with antibiotics remained reasonable in our context which is reassuring.

Another concern in second stage patients are the neurological complications. Dexamethasone and Ringer lactate, administered intravenously in 5.2% and 2.7% of the patients, are drugs that are used in this setting to treat or prevent convulsions and coma. It seems that they have been administered at an appropriate frequency.

The concomitant drugs were prescribed in coherence with the clinical and safety profile of the study population even if some prescription habits would need to be improved. For example, one centre provided artesunate monotherapy as standard pre-treatment which is suboptimal considering the general recommendation of using it in combination. It also appeared that some classical field prescription practices such as the utilisation of metamizol and papaverine, administered in 25.4% and 2.5% of the patients respectively might be considered as suboptimal at first sight. However, after discussion with the investigators these choices were either driven by the availability of drugs at the centres or by some medical decisions. At the time of the study, between 2008 and 2010, metamizol, due to the suspicion of bone marrow toxicity, was only recommended when other antipyretics were inefficient or when the fever needed to be brought down urgently, above all in children. In this specific population, metamizol was often preferred because the intravenous route made its administration easier. Neverthelesss, metamizol has been banned in DRC since and treatment with NSAID such as ibuprofen or diclofenac would therefore be recommended today. Papaverine was administered preferably to pregnant women to treat gastrointestinal disorders such as nausea and vomiting, because metoclopramide is contra-indicated in this population.

In a low-resource setting, drug supply choices of the centers may partially be driven by the scarce financial resources but also by their availability at the hospital and surrounding or if the drug was supplied by the national HAT program. For example, the choice to prescribe levamisole and cotrimoxazole was mainly driven by the fact that these drugs were supplied by the HAT national program and their availability. However, data on concomitant drug supply and availability have not been collected at the time of the NECT-FIELD study. Therefore we cannot conclude on the relative importance of how lack of resources, supply chain, availability, and access influenced the utilization of concomitant drugs in our setting.

Another limitation of this present analysis is the replication and generalisability of the results, as we are only relying on the prescription habits of the clinicians and clinical teams of our six study sites. In our knowledge, this is the first study reporting the real-life prescription of concomitant medicine during second stage sleeping sickness treatment. In order to reassure our findings we compared the AEs reported in recent clinical trial [10, 16] and field cohorts [19] by compiling together the safety profiles in Table 5. Results suggests that the comorbidity and AE profile of patients were comparable among all these studies and that concomitant medication needs would be more or less be similar among the different HAT treatment options and treatment centers.

Table 5

Overview of adverse event profile during HAT therapy in published clinical trials.

Percentage of patients with (%)	NECT vs DFMOPhase III trial [16] *,#		NECT MSF[19] #	Fexinidazole vs NECT Phase III trial [10]
	NECTN = 143	DFMON = 143	NECTN = 684	Fexinidazole N = 264	NECT N = 130
Gastrointestinal disorders
Vomiting	48$	20$	39	28	29
Nausea	$	$	8	26	19
Diarrhoea	6	29	7	3	4
Abdominal pain	25	29	41	10	12
General disorders and administration site condition
Fever	26	43	-	9	19
Asthenia	24	20	-	23	14
Fatigue	-	-	11	-	-
Injection site disorders	10	11	-	-	-
Nervous system disorders
Headache	39	46	30	35	24
Dizziness	18	17	20	19	13
Convulsions	13	9	4	2	8
Tremor	6	1	7	22	11
Coma or loss of consciousness	1	2	-	-	-
Metabolism and nutrition disorders
Anorexia or decreased appetite	25	14	21	21	19
Psychiatric disorders
Insomnia	10	10	12	28	12
Agitation	3	8	-	4	1
Mood disorders, anxiety, or depression	1	1	8	4	-
Mental confusion	4	1	-	-	-
Hallucinations, delirium, or psychosis	1	1	3	3	3
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	30	30	25	-	-
Back pain	-	-	-	11	9
Neck pain	-	-	-	9	5
Skin and sub-cutaneous tissue disorders
Pruritus or cutaneous pruritus	9	19	4	4	3
Dermatitis or skin rash	3	14	-	-	-
Vascular disorders
Hypotension	4	3	-	-	-
Hypertension	4	13	-	5	1
Cardiac disorders
Palpitation or arrhythmia	19	22	-	5	4
Infections and infestations
All kind of infections	10	18	-	8	6
Blood and lymphatic system disorders
Anaemia	-	-	-	9	11

*Only treatment related adverse event are reported in this trial (Priotto 2009) [16]

#Adverse event recorded in NECT phase III trial [16] and in NECT MSF [19] have not been coded with MedDRA dictionary

$In NECT phase III [16], nausea and vomiting were reported together and not differentiated

“-”AE term not reported in the respective publication

In order to better manage the clinical profile of second stage HAT patients and the AEs of NECT, we propose a list of minimal essential drugs based on the results of this analysis and on the WHO EML that should be available at no cost to the patient night and day in treatment wards (Table 6) [20]. This recommendation provides new evidence to programs, health systems, donors, and other actors to plan, fund, and supply the essential medicines adapted to treat second stage sleeping sickness patients.

Table 6

Recommended minimal essential medication to be delivered at a HAT treatment centre to treat main HAT symptoms, frequent comorbidities, and adverse events.

Antibacterials	Corticosteroids
Amoxicillin, po	Dexamethasone, iv
Ampicillin, iv	Hydrocortisone, iv
Ceftriaxone, iv
Cotrimoxazole, po	Cardiovascular medicines
Ciprofloxacin, po and iv	Furosemide, po
Gentamycin, iv	Atenolol, po
Antiprotozoals	Gastrointestinal medicines
Metronidazole, po	Metoclopramide, po
Artesunate amodiaquine, po	Omeprazole, po
Artesunate lumefantrine, po	Oral rehydration salts, po
Artesunate, im or iv
	Nervous system medicines
Anthelmintics	Chlorpromazine, po
Mebendazole or levamisole, po	Haloperidol, po
	Diazepam, po
Analgesics, antipyretic	Phenobarbital, iv
Paracetamol, po
	Vitamins
Anti-inflammatory medicines	Vitamin B6 complex, po
Ibuprofen, po
	Perfusion Solutions
Antihistamines	Glucose 5%, iv
Chlorpheniramin, po	NaCl, iv
Promethazine, po	Ringer lactate, iv

In a further step and in order to improve and generalize the proposed list, analyses of the concomitant drugs used during fexinidazole [10] and acoziborole (registered under clinicaltrials.gov: NCT03087955) trials for second stage sleeping sickness patients shall be performed in a near future.

28 Oct 2019

Dear Dr. Kuemmerle:

Thank you very much for submitting your manuscript "Prescription of concomitant medications in patients treated with Nifurtimox Eflornithine Combination Therapy (NECT) for second stage sleeping sickness in the Democratic Republic of the Congo" (#PNTD-D-19-01387) for review by PLOS Neglected Tropical Diseases. Your manuscript was fully evaluated at the editorial level and by independent peer reviewers. The reviewers appreciated the attention to an important problem, but raised some substantial concerns about the manuscript as it currently stands. These issues must be addressed before we would be willing to consider a revised version of your study. We cannot, of course, promise publication at that time.

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***********************

The results in this paper are part of the NECT-FIELD study (https://clinicaltrials.gov/ct2/show/NCT00906880). The main outcome of this study (the proportion of patients discharged alive from hospital) was publised in 2012 (https://www.ncbi.nlm.nih.gov/pubmed/23209861), in that publication, submitted as additional information, the authors stated "Twenty-four months after end of treatment, patients will be assessed for the final effectiveness of treatment; these results will be reported later". Effectiveness is indeed one of the secondary outcomes of the NECT-FIELD study as indicated in the clinicaltrial.gov website: Effectiveness: The clinical cure rate (Survival without clinical and/or parasitological signs of HAT) [ Time Frame: 24 months after treatment ]. As the effectiveness results are related to the data presented in the manuscript submitted to PLoS NTDs. We would appreciate if the authors could clarify if the effectiveness results of the NECT-FIELD study have been or will be published.

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: Methods are very simple, just a data summary, all from one clinical trial. But in order to support some of their conclusions, they could add some data from routine practice outside clinical trials, some data on cost, etc, to allow comparisons that they insinuate in a superficial way.

Reviewer #2: The objectives of the study are well stated. The study design is appropriate for the stated objectives. Study population has been well described in the methodology and the sample size is sufficient to power this study. Descriptive statistics were used and this suffices for the kind of study objectives that the authors set out to determine. Being review of secondary data from a clinical trial, ethical concerns were adequately addressed.

Reviewer #3: The objective of the study are clear : indication of the use of concomitant medication during HAT treatment. The study design is appropriate and the population clearly described. The sample size is adequate and correct statistical analysis provided. Ethical comitees in both countries have been consulted.

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: Results are clearly presented, although in a minimalist way.

From that clinical trial, the results of most relevance for public health (the effectiveness of NECT), are not presented.

Reviewer #2: The results presented match the analysis plan. Results were presented in an exhaustive and logical manner, from baseline characteristics to the main findings in line with the objectives.The tables are clear and well structured (columns and rows are relevant).

Reviewer #3: The analysis is correct and the results clear. The tables are complexe but complete.

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: Several conclusions are not supported by the data presented.

Reviewer #2: The authors have described the most common types of concomitant medications prescribed in patients with late stage sleeping sickness. These include analgesics/antipyretics, antimalarial and anti-helminthic drugs. They further go ahead to suggest a list of medicines that should be availed alongside NECT.

The resource-limited setting of occurrence and treatment of sleeping sickness implies that preparations for adverse event management is defective. Various treatment centres are likely to have varying stock levels for the concomitant medicines that they may need at a certain point. The suggestions from authors contributes to the standardization of the medicines list.

These claims are novel and demonstrates the authors’ deep understanding of the gaps and therefore the needs at hand.

The context of the findings is also in line with the rest of the other sections of the manuscript.

The paper is outstanding in the field of treatment for sleeping sickness. The disease presentation in itself often warrants concomitant medicines because of the severity of some presenting symptoms. Similarly, some adverse events experienced during the course of treatment can be life threatening. The authors were able to differentiate these two time points. This gives insight into the requirements before and during treatment.

Reviewer #3: The conclusions are clear and the limitations shortly described. The results should help to implement concomitant medication for the treatment of HAT.

--------------------

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: (No Response)

Reviewer #2: 1. Lines 101 and 102 reads: ‘Prior to NECT, the patients received standard pre-treatment according to the national guidelines, consisting of antimalarial, anthelminthic, and, if required, antipyretic/analgesic medication.’ This gives an impression that all patients receive antimalarial as a pre-requisite. Please confirm this.

This contradicts line 37/38 where anti-malarial medicine is classified as ‘additional’.

2. Line 40 and 41 reads ‘Treatment of encephalopathic syndrome or similar neurological disorders was used in a relevant proportion of patients (approximately 5%)’. The word ‘relevant’ seems out of place. Did you mean ‘significant’?

3. Line 44 reads ‘…even if some prescription habits would need to be adapted in the future’. it is not well aligned to the statement preceding it. Gives a different meaning.

4. The title should specify that participants had T.b gambiense.

Reviewer #3: Line 96 : should be "the NECT-FIELD study" instead of NECT-FIELD.

Line 112 : not really clear the sentence " AES in more than 5% of the patients and concomitant medications in more than 2.5%" ? Could it be clarified ?

Line 136 and table 2 : "such as neurological, sleeping and..." the sentence neurological does not mean anything here : has to be removed also I do not understand why there are no other neurological signs described at least abnormal movements and walking disorders which are characteristic of advanced stage.

Table 3 : not clear what SOC and LLT means and makes in the first line of the table ?

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Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: General comments:

This paper provides a description of the concomitant medication given to patients included in a trial, known as NECT-FIELD, evaluating the NECT treatment for second stage sleeping sickness.

The first and principal comment is that the most important results of that trial, the efficacy of NECT in the real-life setting, in children, in pregnant and lactating women, were not published, and are not available anywhere. These data are much more awaited by the scientific and public health community, than these data on concomitant medication.

The trial was successfully completed several years ago, including the post-treatment follow-up, and the effectiveness data should be published, taking priority to the data presented in this paper.

Now regarding this article, the results presented are simply an enumeration of medicines given and their frequency. Only in the discussion the authors make some critique and suggest possible improvements, but without explaining their critique nor providing any data supporting the changes proposed.

Specific comments:

Line 77: The EMA’s opinion did not recommend fexinidazole for all second stage patients. They excluded “stage 2 patients with >100 WBC per μL of CSF”. The authors should use the appropriate references for this, such as the EMA report available in their website, or the article published by EMA authors in PLOS NTD: Pelfrene et al. The European Medicines Agency's scientific opinion on oral fexinidazole for human African trypanosomiasis. PLoS Negl Trop Dis. 2019 Jun 27;13(6):e0007381

Lines 80-83: For a complete presentation of the NECT-FIELD study, the authors should not forget to mention that efficacy was also documented, but never published.

Line 96: Instead of “design, methods, and results”, it should be “design, methods, and safety results” (because efficacy results were not included in the Schmid paper).

Line 103: As these patients were all enrolled in a clinical trial, is it true that “Concomitant medication was prescribed according to the decision of the investigator and the local guidelines.”? Didn’t the study protocol impose any concomitant medication? This is important in the interpretation of results. How much these results represent the practice in DRC (or elsewhere) outside clinical trials?

Lines 181-188: It’s not clear why the authors focus on the encephalopathic syndrome linked to melarsoprol, and they seem to judge the appropriateness of use of certain drugs related to this syndrome, which does not even appear among the AEs in the study (and none of the patients received melarsoprol). It would be logical that they assess the use of drugs in relation to the AEs observed.

Lines 193-195: The authors say that using metamizol and papaverine is inadequate. They don’t explain why, except that they are “banned in many countries with stringent drug regulation”. This argumentation is way too superficial to be acceptable. Just by searching a little I can see that metamizole is banned only in a few countries (UK, Sweden, USA, Canada) because of agranulocytosis observed in people from northern Europe, or having population from that origin. Other countries use it widely and don’t have the same problem. India banned it at some point but they lifted the ban. The only argument offered by the authors would then be that metamizole should not be used in Africa because it provokes problems in northern Europeans (!). But perhaps the authors have other data that they can share, to support their recommendations. There are at least 2 recent review papers on metamizole published, which have much different conclusions: one says “For short-term use in the hospital setting, metamizole seems to be a safe choice when compared to other widely used analgesics.” I didn’t spend time searching on papaverine, but the authors should.

Line 195: Perhaps the statement “inadequate choices in the drug supply of the centres were mainly driven by the scarce financial resources available”, could be supported with some concrete examples giving the cost of choices made, versus the cost of the alternatives.

Reviewer #2: In summary, there are no copyright issues to be concerned about. The manuscript has been submitted for consideration in line with earlier work done by the same authors.

Additionally, ethical principles have been followed as by virtue of the details in the section with the same title and the methodology.

Clarifications based on the comments in the above.

Reviewer #3: The paper provides an opportunity to clarify what kind of concomitant medication should be available in HAT treating centers. As the number of HAT cases is low ,all additional data from well conducted trials are of great interest for the general use and are thus interesting to show to the scientific community and policy makers.

--------------------

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Reviewer #1: No

Reviewer #2: Yes: Andrew Edielu

Reviewer #3: Yes: BISSER SYLVIE

12 Dec 2019

Submitted filename: NECT-FIELD comed_PLoS NTD_Response reviewers_20191211.docx

Click here for additional data file.

3 Jan 2020

Dear Dr. Kuemmerle,

We are pleased to inform you that your manuscript, "Prescription of concomitant medications in patients treated with Nifurtimox Eflornithine Combination Therapy (NECT) for T.b. gambiense second stage sleeping sickness in the Democratic Republic of the Congo", has been editorially accepted for publication at PLOS Neglected Tropical Diseases.

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Thank you again for supporting open-access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Albert Picado

Associate Editor

PLOS Neglected Tropical Diseases

Alvaro Acosta-Serrano

Deputy Editor

PLOS Neglected Tropical Diseases

***********************************************************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: Methods are appropriately described and there are no particular concerns.

**********

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: Results are well presented.

**********

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: Conclusions are supported by the data, limitations described, public health relevance addressed.

**********

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: No particular comments.

**********

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: The authors have addressed the issues raised by the review and the paper has improved considerably.

**********

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Reviewer #1: No

22 Jan 2020

Dear Dr. Kuemmerle,

We are delighted to inform you that your manuscript, "Prescription of concomitant medications in patients treated with Nifurtimox Eflornithine Combination Therapy (NECT) for T.b. gambiense second stage sleeping sickness in the Democratic Republic of the Congo," has been formally accepted for publication in PLOS Neglected Tropical Diseases.

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Thank you again for supporting open-access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Serap Aksoy

Editor-in-Chief

PLOS Neglected Tropical Diseases

Shaden Kamhawi

Editor-in-Chief

PLOS Neglected Tropical Diseases