ABSTRACT
OBJECTIVES: To investigate the efficacy and safety of repurposed antiprotozoal and antiretroviral drugs, nitazoxanide and atazanavir/ritonavir, in shortening the time to clinical improvement and achievement of SARS-CoV-2 polymerase chain reaction (PCR) negativity in patients diagnosed with moderate to severe COVID-19. TRIAL DESIGN: This is a pilot phase 2, multicentre 2-arm (1:1 ratio) open-label randomised controlled trial. PARTICIPANTS: Patients with confirmed COVID-19 diagnosis (defined as SARS-CoV-2 PCR positive nasopharyngeal swab) will be recruited from four participating isolation and treatment centres in Nigeria: two secondary care facilities (Infectious Diseases Hospital, Olodo, Ibadan, Oyo State and Specialist State Hospital, Asubiaro, Osogbo, Osun State) and two tertiary care facilities (Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Osun State and Olabisi Onabanjo University Teaching Hospital, Sagamu, Ogun State). These facilities have a combined capacity of 146-bed COVID-19 isolation and treatment ward. INCLUSION CRITERIA: Confirmation of SARS-CoV-2 infection by PCR test within two days before randomisation and initiation of treatment, age bracket of 18 and 75 years, symptomatic, able to understand study information and willingness to participate. Exclusion criteria include the inability to take orally administered medication or food, known hypersensitivity to any of the study drugs, pregnant or lactating, current or recent (within 24 hours of enrolment) treatment with agents with actual or likely antiviral activity against SARS-CoV-2, concurrent use of agents with known or suspected interaction with study drugs, and requiring mechanical ventilation at screening. INTERVENTION AND COMPARATOR: Participants in the intervention group will receive 1000 mg of nitazoxanide twice daily orally and 300/100 mg of atazanvir/ritonavir once daily orally in addition to standard of care while participants in the control group will receive only standard of care. Standard of care will be determined by the physician at the treatment centre in line with the current guidelines for clinical management of COVID-19 in Nigeria. MAIN OUTCOME MEASURES: Main outcome measures are: (1) Time to clinical improvement (defined as time from randomisation to either an improvement of two points on a 10-category ordinal scale (developed by the WHO Working Group on the Clinical Characterisation and Management of COVID-19 infection) or discharge from the hospital, whichever came first); (2) Proportion of participants with SARS-CoV-2 polymerase chain reaction (PCR) negative result at days 2, 4, 6, 7, 14 and 28; (3) Temporal patterns of SARS-CoV-2 viral load on days 2, 4, 6, 7, 14 and 28 quantified by RT-PCR from saliva of patients receiving standard of care alone versus standard of care plus study drugs. RANDOMISATION: Allocation of participants to study arm is randomised within each site with a ratio 1:1 based on randomisation sequences generated centrally at Obafemi Awolowo University. The model was implemented in REDCap and includes stratification by age, gender, viral load at diagnosis and presence of relevant comorbidities. BLINDING: None, this is an open-label trial. NUMBER TO BE RANDOMISED (SAMPLE SIZE): 98 patients (49 per arm). TRIAL STATUS: Regulatory approval was issued by the National Agency for Food and Drug Administration and Control on 06 October 2020 (protocol version number is 2.1 dated 06 August 2020). Recruitment started on 9 October 2020 and is anticipated to end before April 2021. TRIAL REGISTRATION: The trial has been registered on ClinicalTrials.gov (July 7, 2020), with identifier number NCT04459286 and on Pan African Clinical Trials Registry (August 13, 2020), with identifier number PACTR202008855701534 . FULL PROTOCOL: The full protocol is attached as an additional file which will be made available on the trial website. In the interest of expediting dissemination of this material, the traditional formatting has been eliminated, and this letter serves as a summary of the key elements in the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
Subject(s)
Antiviral Agents/administration & dosage , Atazanavir Sulfate/administration & dosage , COVID-19 Drug Treatment , Ritonavir/administration & dosage , Thiazoles/administration & dosage , Administration, Oral , Adolescent , Adult , Aged , Antiviral Agents/adverse effects , Atazanavir Sulfate/adverse effects , COVID-19/diagnosis , COVID-19/virology , COVID-19 Nucleic Acid Testing , Clinical Trials, Phase II as Topic , Drug Administration Schedule , Drug Combinations , Drug Repositioning , Drug Therapy, Combination/adverse effects , Drug Therapy, Combination/methods , Female , Humans , Male , Middle Aged , Multicenter Studies as Topic , Nigeria , Nitro Compounds , Pilot Projects , RNA, Viral/isolation & purification , Randomized Controlled Trials as Topic , Ritonavir/adverse effects , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification , Severity of Illness Index , Standard of Care , Thiazoles/adverse effects , Treatment Outcome , Viral Load/drug effects , Young AdultABSTRACT
OBJECTIVE:: To use baseline audiogram parameters in order to ascertain whether drug-resistant tuberculosis (DR-TB) has effects on hearing, as well as to describe the configurations of the audiograms and to determine whether there are parameters that can be associated with those configurations. METHODS:: This was a prospective study involving patients diagnosed with DR-TB at a tuberculosis treatment center in the state of Ogun, in Nigeria. The patients included in the study were submitted to pure tone audiometry at baseline (within two weeks after treatment initiation). For comparative analyses, data regarding demographic and clinical characteristics were collected from the medical records of the patients. RESULTS:: The final sample comprised 132 patients. The mean age of the patients was 34.5 ± 12.6 years (range, 8-82 years), and the male:female ratio was 2:1. Of the 132 patients, 103 (78.0%) resided in neighboring states, 125 (94.7%) had previously experienced antituberculosis treatment failure, and 18 (13.6%) were retroviral-positive. Normal audiograms were found in 12 patients (9.1%), whereas sensorineural hearing loss was identified in 104 (78.8%), the two most common configurations being ascending, in 54 (40.9%), and sloping, in 26 (19.7%). Pure-tone averages at low frequencies (0.25-1.0 kHz) and high frequencies (2.0-8.0 kHz) were 33.0 dB and 40.0 dB, respectively. Regarding the degree of hearing loss in the better ear, 36 patients (27.3%) were classified as having normal hearing and 67 (50.8%) were classified as having mild hearing loss (26-40 dB), whereas 29 (21.9%) showed moderate or severe hearing loss. Among the variables studied (age, gender, retroviral status, previous treatment outcome, and weight at admission), only male gender was associated with audiometric configurations. CONCLUSIONS:: In this sample of patients with DR-TB, most presented with bilateral, mild, suboptimal sensorineural hearing loss, and ascending/sloping audiometric configurations were associated with male gender. OBJETIVO:: Utilizar parâmetros do audiograma basal para verificar se a tuberculose resistente (TB-R) tem efeitos na audição, descrever as configurações dos audiogramas e determinar se há parâmetros que possam ser associados a essas configurações. MÉTODOS:: Estudo prospectivo com pacientes diagnosticados com TB-R em um centro de tratamento de tuberculose no estado de Ogun, Nigéria. Os pacientes incluídos no estudo foram submetidos à audiometria de tons puros em até duas semanas após o início do tratamento (audiometria basal). Características demográficas e clínicas foram coletadas dos prontuários médicos dos pacientes para análises comparativas. RESULTADOS:: A amostra final envolveu 132 pacientes. A média de idade dos pacientes foi de 34,5 ± 12,6 anos (variação, 8-82 anos), e a razão homem:mulher foi de 2:1. A maioria dos pacientes (n = 103; 78,0%) residia nos estados vizinhos e tinha história de falha de tratamento antituberculose (n = 125; 94.7%); 18 (13.6%) apresentavam status retroviral positivo. Doze pacientes (9,1%) apresentaram audiogramas normais, e 104 (78,8%) apresentaram perda auditiva neurossensorial, sendo as configurações mais comuns do tipo ascendente, em 54 (40,9%), e descendente, em 26 (19,7%). As médias de tons puros em frequências baixas (0,25-1,0 kHz) e altas (2,0-8,0 kHz) foram de 33,0 dB e 40,0 dB, respectivamente. Quanto ao grau de perda auditiva no melhor ouvido, 36 pacientes (27,3%) apresentaram audição normal, e 67 (50,8%) apresentaram perda auditiva leve (26-40 dB), enquanto 29 (21,9%) mostraram perda auditiva moderada ou grave. Entre as variáveis estudadas (idade, gênero, status retroviral, desfecho de tratamento anterior e peso na admissão), somente o gênero masculino foi associado às configurações audiométricas. CONCLUSÕES:: Nesta amostra de pacientes com TB-R, a maioria apresentou perda auditiva neurossensorial leve e subótima bilateralmente, com configurações audiométricas ascendentes/descendentes associadas ao gênero masculino.
Subject(s)
Antibiotics, Antitubercular/adverse effects , Auditory Threshold/drug effects , Auditory Threshold/physiology , Hearing Loss/chemically induced , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Multidrug-Resistant/physiopathology , Adolescent , Adult , Aged , Aged, 80 and over , Audiometry, Pure-Tone/methods , Child , Female , Hearing Loss/physiopathology , Humans , Male , Middle Aged , Prospective Studies , Reference Values , Severity of Illness Index , Sex Factors , Time Factors , Treatment Failure , Tuberculosis, Multidrug-Resistant/complications , Young AdultABSTRACT
ABSTRACT Objective: To use baseline audiogram parameters in order to ascertain whether drug-resistant tuberculosis (DR-TB) has effects on hearing, as well as to describe the configurations of the audiograms and to determine whether there are parameters that can be associated with those configurations. Methods: This was a prospective study involving patients diagnosed with DR-TB at a tuberculosis treatment center in the state of Ogun, in Nigeria. The patients included in the study were submitted to pure tone audiometry at baseline (within two weeks after treatment initiation). For comparative analyses, data regarding demographic and clinical characteristics were collected from the medical records of the patients. Results: The final sample comprised 132 patients. The mean age of the patients was 34.5 ± 12.6 years (range, 8-82 years), and the male:female ratio was 2:1. Of the 132 patients, 103 (78.0%) resided in neighboring states, 125 (94.7%) had previously experienced antituberculosis treatment failure, and 18 (13.6%) were retroviral-positive. Normal audiograms were found in 12 patients (9.1%), whereas sensorineural hearing loss was identified in 104 (78.8%), the two most common configurations being ascending, in 54 (40.9%), and sloping, in 26 (19.7%). Pure-tone averages at low frequencies (0.25-1.0 kHz) and high frequencies (2.0-8.0 kHz) were 33.0 dB and 40.0 dB, respectively. Regarding the degree of hearing loss in the better ear, 36 patients (27.3%) were classified as having normal hearing and 67 (50.8%) were classified as having mild hearing loss (26-40 dB), whereas 29 (21.9%) showed moderate or severe hearing loss. Among the variables studied (age, gender, retroviral status, previous treatment outcome, and weight at admission), only male gender was associated with audiometric configurations. Conclusions: In this sample of patients with DR-TB, most presented with bilateral, mild, suboptimal sensorineural hearing loss, and ascending/sloping audiometric configurations were associated with male gender.
RESUMO Objetivo: Utilizar parâmetros do audiograma basal para verificar se a tuberculose resistente (TB-R) tem efeitos na audição, descrever as configurações dos audiogramas e determinar se há parâmetros que possam ser associados a essas configurações. Métodos: Estudo prospectivo com pacientes diagnosticados com TB-R em um centro de tratamento de tuberculose no estado de Ogun, Nigéria. Os pacientes incluídos no estudo foram submetidos à audiometria de tons puros em até duas semanas após o início do tratamento (audiometria basal). Características demográficas e clínicas foram coletadas dos prontuários médicos dos pacientes para análises comparativas. Resultados: A amostra final envolveu 132 pacientes. A média de idade dos pacientes foi de 34,5 ± 12,6 anos (variação, 8-82 anos), e a razão homem:mulher foi de 2:1. A maioria dos pacientes (n = 103; 78,0%) residia nos estados vizinhos e tinha história de falha de tratamento antituberculose (n = 125; 94.7%); 18 (13.6%) apresentavam status retroviral positivo. Doze pacientes (9,1%) apresentaram audiogramas normais, e 104 (78,8%) apresentaram perda auditiva neurossensorial, sendo as configurações mais comuns do tipo ascendente, em 54 (40,9%), e descendente, em 26 (19,7%). As médias de tons puros em frequências baixas (0,25-1,0 kHz) e altas (2,0-8,0 kHz) foram de 33,0 dB e 40,0 dB, respectivamente. Quanto ao grau de perda auditiva no melhor ouvido, 36 pacientes (27,3%) apresentaram audição normal, e 67 (50,8%) apresentaram perda auditiva leve (26-40 dB), enquanto 29 (21,9%) mostraram perda auditiva moderada ou grave. Entre as variáveis estudadas (idade, gênero, status retroviral, desfecho de tratamento anterior e peso na admissão), somente o gênero masculino foi associado às configurações audiométricas. Conclusões: Nesta amostra de pacientes com TB-R, a maioria apresentou perda auditiva neurossensorial leve e subótima bilateralmente, com configurações audiométricas ascendentes/descendentes associadas ao gênero masculino.
Subject(s)
Humans , Male , Female , Child , Adolescent , Adult , Middle Aged , Aged , Aged, 80 and over , Young Adult , Antibiotics, Antitubercular/adverse effects , Auditory Threshold/drug effects , Auditory Threshold/physiology , Hearing Loss/chemically induced , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Multidrug-Resistant/physiopathology , Audiometry, Pure-Tone/methods , Hearing Loss/physiopathology , Prospective Studies , Reference Values , Severity of Illness Index , Sex Factors , Time Factors , Treatment Failure , Tuberculosis, Multidrug-Resistant/complicationsABSTRACT
OBJECTIVE: The study objectives were to determine the incidence of aminoglycoside-induced ototoxicity in institutionalized patients on intensive phase of therapy for drug-resistant Tuberculosis (DR Tb) and also to assess clinical factors which could predict the ototoxicity. METHODS: The study was a prospective analytical study among consecutive DR Tb patients who were admitted for intensive phase of therapy (of 4 months) at the DR-Tb center over a 12-month period. Patients were diagnosed as DR Tb using the Gene Xpert machine to confirm Rifampicin resistance. All eligible 70 out of 87 consenting patients were consecutively recruited into the study. Patients had baseline (admission) and serial pure tone audiometries (PTAs) performed at 4 weekly intervals until discharge after 4 months of admission. Audiometric confirmation of aminoglycoside-induced ototoxicity was done by comparing serial with baseline PTA. RESULTS: Among the 70 patients the male:female ratio was 1.7:1. Nine patients (12.9%) were retroviral-positive, and 16 patients (22.9%) were confirmed to have ototoxicity by audiometric criteria. The duration of treatment when ototoxicity was detected in the patients ranged 4-17 (Mean±SD; 9.4±3.4) weeks. Ototoxicity was detected in the audiometric low frequency ranges in 7 (43.8%) and at the high frequencies in 4 (25.0%) of the patients. Univariate analyses of clinical parameters found that age, underlying diabetes mellitus, deranged baseline PTAv >25dB HL, BMI on admission and retroviral status were significantly associated, while sex and previous drug regimen failure were not associated with ototoxicity. Multivariate adjusted logistic regression analyses, controlling for sex, revealed age (OR=1.068, p=0.018), BMI on admission (OR=0.673, p=0.012) and retroviral positivity (OR=8.822, p=0.014) of patients could significantly predict aminoglycoside-induced ototoxicity. CONCLUSION: Incidence of aminoglycoside-induced ototoxicity in DR Tb patients was 22.9%. The clinical predictors for ototoxicity were age, BMI on admission, and co-existing retroviral infection in the patients. Clinicians should consider these factors in making choices of aminoglycosides to be used during intensive phase of treatment with second line anti-Tuberculous therapy.
