Evaluation of the initial response in clinical trial efforts for COVID-19 in Brazil

Ribeiro, Tatiane Bomfim; Mazotti, Talita Aona; Silva, Nayara Aparecida de Oliveira; Stein, Airton Tetelbom; Diaz-Quijano, Fredi Alexander; Melo, Daniela Oliveira de

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Revista Brasileira de Epidemiologia

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SPECIAL ARTICLE • Rev. bras. epidemiol. 23 • 2020 • https://doi.org/10.1590/1980-549720200104 copy

Evaluation of the initial response in clinical trial efforts for COVID-19 in Brazil

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT:

Objective:

To describe the methodological characteristics and good research practices of COVID-19 interventional studies developed in Brazil in the first months of the pandemic.

Methods:

We reviewed the bulletin of the National Research Ethics Committee - Coronavirus Special Edition (Comissão Nacional de Ética em Pesquisa - CONEP-COVID) (May 28, 2020) and the databases of the International Clinical Trials Registry Platform (ICTRP), ClinicalTrials.gov, and Brazilian Clinical Trials Registry (Registro Brasileiro de Ensaios Clínicos - ReBEC) to identify interventional studies registered in Brazil that assessed drug type, biological therapy, or vaccines. We described their methodological characteristics and calculated their power for different effect magnitudes.

Results:

A total of 62 studies were included, 55 retrieved from the CONEP website, and 7 from registry databases. The most tested pharmacological interventions in these studies were: chloroquine/hydroxychloroquine, azithromycin, convalescent plasma, tocilizumab, sarilumab, eculizumab, vaccine, corticosteroids, anticoagulants, n-acetylcysteine, nitazoxanide, ivermectin, and lopinavir/ritonavir. Out of 22 protocols published on registry databases until May 2020, 18 (82%) were randomized clinical trials, and 13 (59%) had an appropriate control group. However, 9 (41%) of them were masked, and only 5 (24%) included patients diagnosed with a specific laboratory test (for example, reverse transcription polymerase chain reaction - RT-PCR). Most of these studies had power > 80% only to identify large effect sizes. In the prospective follow-up, 60% of the studies available at CONEP until May 2020 had not been published on any registry platform (ICTRP/ReBEC/ClinicalTrials) by July 21, 2020.

Conclusion:

The interventions evaluated during the Brazilian research response reflect those of international initiatives, but with a different distribution and a large number of studies assessing hydroxychloroquine/chloroquine. Limitations in methodological design and sample planning represent challenges that could affect the research outreach.

Keywords:
Coronavirus infections; Clinical trials as topic; Efficacy; Resource allocation Brazil; Clinical protocols

Interventions for the treatment or prophylaxis of COVID-19 (n=22)		n (%)
Study design	Randomized clinical trial	18	(82)
Study design	Non-randomized clinical trial	4	(18)
Trial phase	Phase 1	3	(14)
	Phase 2	5	(23)
	Phase 3	8	(36)
	Phase 4	2	(9)
	NM	4	(18)
Masking	Open-label	13	(59)
	Single-blind	1	(5)
	Double-blind	2	(9)
	Quadruple-blind	6	(27)
Control group	Placebo/standard treatment comparator	13	(59)
Multicenter^a	Yes	7	(32)
Recruitment site	Hospital	16	(73)
	Outpatient clinic	2	(9)
	NM	4	(18)
Power calculation^b Scenario of large effect size RR = 0.4; incidence: 10 vs. 25%)	High ≥ 90%^c	1	(5%)
	Good (< 90 and ≥ 80%)^d	1	(5%)
	Low (< 80 and > 50%)^e	2	(9%)
	Very low (< 50%)^f	17	(81%)
Power calculation^b Scenario of moderate effect size RR = 0.6; incidence: 7.2 vs. 12%)	High ≥ 90%^g	11	(52%)
	Good (< 90 and ≥ 80%)^h	1	(5%)
	Low (< 80 and > 50%)ⁱ	3	(14%)
	Very low (< 50%)^j	6	(29%)
Interventions for the treatment of COVID-19 (n=21)
Inclusion criterion - COVID-19	Confirmed diagnosis (test+)	5	(24)
	Suspected diagnosis - Clinical suspicion or test+	12	(57)
	Suspected diagnosis - Clinical suspicion only	4	(19)
Severity of the patients included	Hospitalized - moderate or severe	4	(19)
	Hospitalized - severe	5	(24)
	Hospitalized - moderate	1	(5)
	Hospitalized - nonspecific	6	(28)
	Not hospitalized	1	(5)
	NM	4	(19)
Use of important outcomes for COVID-19^k	As primary outcome	8	(38)
Use of important outcomes for COVID-19^k	Among secondary outcomes	18	(86)

Interventions for the treatment or prophylaxis of COVID-19 (n=22)		n	(%)
Study design	Randomized clinical trial	18	(82)
Study design	Non-randomized clinical trial	4	(18)
Trial phase	Phase 1	3	(14)
	Phase 2	5	(23)
	Phase 3	8	(36)
	Phase 4	2	(9)
	NM	4	(18)
Masking	Open-label	13	(59)
	Single-blind	1	(5)
	Double-blind	2	(9)
	Quadruple-blind	6	(27)
Control group	Placebo/standard treatment comparator	13	(59)
Multicenter^a	Yes	7	(32)
Recruitment site	Hospital	16	(73)
	Outpatient clinic	2	(9)
	NM	4	(18)
Power calculation^b Scenario of large effect size RR = 0.4; incidence: 10 vs. 25%)	High ≥ 90%^c	1	(5%)
	Good (< 90 and ≥ 80%)^d	1	(5%)
	Low (< 80 and > 50%)^e	2	(9%)
	Very low (< 50%)^f	17	(81%)
Power calculation^b Scenario of moderate effect size RR = 0.6; incidence: 7.2 vs. 12%)	High ≥ 90%^g	11	(52%)
	Good (< 90 and ≥ 80%)^h	1	(5%)
	Low (< 80 and > 50%)ⁱ	3	(14%)
	Very low (< 50%)^j	6	(29%)
Interventions for the treatment of COVID-19 (n=21)
Inclusion criterion - COVID-19	Confirmed diagnosis (test+)	5	(24)
	Suspected diagnosis - Clinical suspicion or test+	12	(57)
	Suspected diagnosis - Clinical suspicion only	4	(19)
Severity of the patients included	Hospitalized - moderate or severe	4	(19)
	Hospitalized - severe	5	(24)
	Hospitalized - moderate	1	(5)
	Hospitalized - nonspecific	6	(28)
	Not hospitalized	1	(5)
	NM	4	(19)
Use of important outcomes for COVID-19^k	As primary outcome	8	(38)
Use of important outcomes for COVID-19^k	Among secondary outcomes	18	(86)

Interventions for the treatment or prophylaxis of COVID-19 (n=22)		n	(%)
Study design	Randomized clinical trial	18	(82)
Study design	Non-randomized clinical trial	4	(18)
Trial phase	Phase 1	3	(14)
	Phase 2	5	(23)
	Phase 3	8	(36)
	Phase 4	2	(9)
	NM	4	(18)
Masking	Open-label	13	(59)
	Single-blind	1	(5)
	Double-blind	2	(9)
	Quadruple-blind	6	(27)
Control group	Placebo/standard treatment comparator	13	(59)
Multicenter^a	Yes	7	(32)
Recruitment site	Hospital	16	(73)
	Outpatient clinic	2	(9)
	NM	4	(18)
Power calculation^b Scenario of moderate effect size RR = 0.6; incidence: 7.2 vs. 12%)	High ≥ 90%^c	1	(5%)
	Good (< 90 and ≥ 80%)^d	1	(5%)
	Low (< 80 and > 50%)^e	2	(9%)
	Very low (< 50%)^f	17	(81%)
Power calculation^b Scenario of large effect size RR = 0.4; incidence: 10 vs. 25%)	High ≥ 90%^g	10	(48%)
	Good (< 90 and ≥ 80%)^h	2	(9.5%)
	Low (< 80 and > 50%)ⁱ	2	(9.5%)
	Very low (< 50%)^j	7	(33%)
Interventions for the treatment of COVID-19 (n=21)
Inclusion criterion - COVID-19	Confirmed diagnosis (test+)	5	(24)
	Suspected diagnosis - Clinical suspicion or test+	12	(57)
	Suspected diagnosis - Clinical suspicion only	4	(19)
Severity of the patients included	Hospitalized - moderate or severe	4	(19)
	Hospitalized - severe	5	(24)
	Hospitalized - moderate	1	(5)
	Hospitalized - nonspecific	6	(28)
	Not hospitalized	1	(5)
	NM	4	(19)
Use of important outcomes for COVID-19^k	As primary outcome	8	(38)
Use of important outcomes for COVID-19^k	Among secondary outcomes	18	(86)

Intervenções para tratamento ou profilaxia de COVID-19 (n=22)		n	(%)
Desenho do estudo	Estudo clínico randomizado	18	(82)
Desenho do estudo	Estudo clínico não randomizado	4	(18)
Fase da pesquisa	Fase 1	3	(14)
	Fase 2	5	(23)
	Fase 3	8	(36)
	Fase 4	2	(9)
	NM	4	(18)
Mascaramento	Não mascarado	13	(59)
	Unicego	1	(5)
	Duplo-cego	2	(9)
	Quadruplo-cego	6	(27)
Grupo Controle	Comparador placebo/tratamento padrão	13	(59)
Multicêntrico^a	Sim	7	(32)
Local de recrutamento	Hospital	16	(73)
	Ambulatório	2	(9)
	NM	4	(18)
Cálculo do Poder^b Cenário de grande tamanho de efeito (RR = 0,4; incidências: 10 vs. 25%)	Alto ≥ 90%^c	1	(5%)
	Bom (< 90 e ≥ 80%)^d	1	(5%)
	Baixo (< 80 e > 50%)^e	2	(9%)
	Muito baixo (< 50%)^f	17	(81%)
Cálculo do Poder ^b Cenário de moderado tamanho de efeito (RR = 0,6; incidência: 7,2 vs. 12%)	Alto ≥ 90%^g	11	(52%)
	Bom (< 90 e ≥ 80%)^h	1	(5%)
	Baixo (< 80 e > 50%)ⁱ	3	(14%)
	Muito baixo (< 50%)^j	6	(29%)
Intervenções para tratamento de COVID-19 (n = 21)
Critério inclusão - COVID-19	Diagnóstico confirmado (teste +)	5	(24)
	Diagnóstico suspeito - Suspeita clínica ou teste +	12	(57)
	Diagnóstico suspeito - Apenas suspeita clínica	4	(19)
Gravidade dos pacientes incluídos	Hospitalizado moderado ou grave	4	(19)
	Hospitalizado grave	5	(24)
	Hospitalizado moderado	1	(5)
	Hospitalizado inespecífico	6	(28)
	Não hospitalizado	1	(5)
	NM	4	(19)
Uso de desfechos importantes para COVID-19^k	Como desfecho primário	8	(38)
Uso de desfechos importantes para COVID-19^k	Entre os desfechos secundários	18	(86)

Intervenções para tratamento ou profilaxia de COVID-19 (n=22)		n	(%)
Desenho do estudo	Estudo clínico randomizado	18	(82)
Desenho do estudo	Estudo clínico não randomizado	4	(18)
Fase da pesquisa	Fase 1	3	(14)
	Fase 2	5	(23)
	Fase 3	8	(36)
	Fase 4	2	(9)
	NM	4	(18)
Mascaramento	Não mascarado	13	(59)
	Unicego	1	(5)
	Duplo-cego	2	(9)
	Quadruplo-cego	6	(27)
Grupo Controle	Comparador placebo/tratamento padrão	13	(59)
Multicêntrico^a	Sim	7	(32)
Local de recrutamento	Hospital	16	(73)
	Ambulatório	2	(9)
	NM	4	(18)
Cálculo do Poder ^b Cenário de moderado tamanho de efeito (RR = 0,6; incidência: 7,2 vs. 12%)	Alto ≥ 90%^c	1	(5%)
	Bom (< 90 e ≥ 80%)^d	1	(5%)
	Baixo (< 80 e > 50%)^e	2	(9%)
	Muito baixo (< 50%)^f	17	(81%)
Cálculo do Poder^b Cenário de grande tamanho de efeito (RR = 0,4; incidências: 10 vs. 25%)	Alto ≥ 90%^g	10	(48%)
	Bom (< 90 e ≥ 80%)^h	2	(9,5%)
	Baixo (< 80 e > 50%)ⁱ	2	(9,5%)
	Muito baixo (< 50%)^j	7	(33%)
Intervenções para tratamento de COVID-19 (n = 21)
Critério inclusão - COVID-19	Diagnóstico confirmado (teste +)	5	(24)
	Diagnóstico suspeito - Suspeita clínica ou teste +	12	(57)
	Diagnóstico suspeito - Apenas suspeita clínica	4	(19)
Gravidade dos pacientes incluídos	Hospitalizado moderado ou grave	4	(19)
	Hospitalizado grave	5	(24)
	Hospitalizado moderado	1	(5)
	Hospitalizado inespecífico	6	(28)
	Não hospitalizado	1	(5)
	NM	4	(19)
Uso de desfechos importantes para COVID-19^k	Como desfecho primário	8	(38)
Uso de desfechos importantes para COVID-19^k	Entre os desfechos secundários	18	(86)

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[1] Corresponding author: Tatiane Bomfim Ribeiro. Departamento de Epidemiologia, Faculdade de Saúde Pública, Universidade de São Paulo. Avenida Dr. Arnaldo, 715, Cerqueira César, CEP: 01246-904, São Paulo, SP, Brasil. E-mail: tatianeribeiro@usp.br