Diagnostic Tools for Human African Trypanosomiasis Elimination and Clinical Trials: Early Test-of-cure

Trypanosoma Brucei Gambiense; Infection Clinical Trial

— DiTECT-WP4  

Official title:

Diagnostic Tools for Human African Trypanosomiasis Elimination and Clinical Trials: WP4 Early Test-of-cure

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03112655
• Other study ID #: DiTECT-HAT-WP4
• Status: Completed
• Phase: N/A
• Start date: February 24, 2017
• Est. completion date: January 31, 2021

Study information

• Verified date: January 2021
• Source: Institut de Recherche pour le Developpement
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The study validates the diagnostic performance of cerebrospinal fluid neopterin quantification and of blood and cerebrospinal fluid trypanosomal spliced leader RNA detection for assessing outcome after treatment of human African trypanosomiasis.

Description:

In the last decade, the prevalence of Trypanosoma brucei gambiense human African trypanosomiasis (HAT) has fallen and HAT has been targeted for elimination. Development of safe and efficacious drugs for HAT, applicable in an elimination context, is considered as a high priority. The drug developmental process is however slowed down by the need to follow-up treated patients for 18 months to decide on cure. For timely diagnosis of treatment failure in clinical trials, patients should have control visits with follow-up examinations at 6, 12 and 18 months after treatment. Furthermore, due to repeated lumbar punctures, treated patients refrain to present for control visits spontaneously, and tend not to comply with follow-up. Clinical trials on new drugs for HAT would therefore be accelerated by availability of an early test of cure. Trypanosomal spliced leader (SL)-RNA, neopterin & 5-hydroxytryptophan are good candidates for accurate and shortened treatment follow-up. In particular SL-RNA detection in blood offers an opportunity for non-invasive post-treatment follow-up.

The objective of the DiTECT-HAT-WP4 study is to validate the diagnostic performance of cerebrospinal fluid neopterin & 5-hydroxytryptophan quantification and of blood and cerebrospinal fluid trypanosomal spliced leader RNA detection for assessing treatment outcome. The DiTECT-HAT-WP4 study is embedded into an ongoing therapeutic phase II/III study (DNDi-OXA-02-HAT) testing a new oral single dose drug against HAT. Within the Framework of the therapeutical trial, patients will have post-treatment examinations, including blood and cerebrospinal fluid examination at day 11, and during follow-up at month 6, month 12 and month 18. Combination of DiTECT-HAT-WP4 with this ongoing clinical trial allows evaluation of new treatment outcome assessment markers during follow-up without the need for additional lumbar or venipunctures. The volumes of venous blood and cerebrospinal fluid taken will be increased by 2.5 mls for the DiTECT-HAT-WP4 study.

Reverse transcriptase real time PCR for spliced leader RNA detection in blood and cerebrospinal fluid and neopterin detection will be carried out in the reference laboratory in Kinshasa, (index tests). The reference laboratory will be blinded to the results of the reference standard. For evaluation of diagnostic performance of the index tests, the reference standard will consist of classification of treatment outcome according to international standards applied for the clinical trial. Receiver operator curves, sensitivity and specificity of the different index tests for treatment outcome assessment will be determined at each follow-up time point. If sufficiently accurate, trypanosomal spliced leader RNA detection in blood would allow post-treatment follow-up without the need for lumbar punctures. Improved treatment outcome assessment will not only facilitate follow-up by avoiding the feared lumbar puncture but also speed up the development and implementation of new drugs. In addition, it will also improve management of patients in routine. The proposed research will impact on clinical decision and treatment outcomes, and contribute to successful HAT elimination.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 88
• Est. completion date: January 31, 2021
• Est. primary completion date: January 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 15 Years and older

Eligibility

Inclusion Criteria:

• Eligible for participation in DNDi-OXA-02-HAT clinical trial

Exclusion Criteria:

• Excluded for DNDi-OXA-02-HAT clinical trial; No informed consent for participation in the DiTECT-HAT-WP4 study

Related Conditions & MeSH terms

• African Trypanosomiasis
• African; Trypanosomiasis, West
• Sleeping Sickness; West African
• Trypanosoma Brucei Gambiense; Infection
• Trypanosomiasis
• Trypanosomiasis, African

Intervention

Diagnostic Test:
• RNA and neopterin detection
Detection of spliced leader RNA will be performed on blood and cerebrospinal fluid taken before treatment, 11 days after treatment, 6, 12 and 18 months after treatment. Neopterin and 5-hydroxytryptophan will be quantified in cerebrospinal fluid taken at the same time points.

Locations

Country	Name	City	State
Congo, The Democratic Republic of the	Programme Nationale de Lutte contre la trypanosomiase humaine Africaine	Kinshasa

Sponsors (4)

Lead Sponsor	Collaborator
Institut de Recherche pour le Developpement	Institut National de Recherche Biomédicale. Kinshasa, République Démocratique du Congo, Institute of Tropical Medicine, Belgium, Ministry of Public Health, Democratic Republic of the Congo

Country where clinical trial is conducted

Congo, The Democratic Republic of the, 

References & Publications (4)

González-Andrade P, Camara M, Ilboudo H, Bucheton B, Jamonneau V, Deborggraeve S. Diagnosis of trypanosomatid infections: targeting the spliced leader RNA. J Mol Diagn. 2014 Jul;16(4):400-4. doi: 10.1016/j.jmoldx.2014.02.006. Epub 2014 May 9. — View Citation

Ilboudo H, Camara O, Ravel S, Bucheton B, Lejon V, Camara M, Kaboré J, Jamonneau V, Deborggraeve S. Trypanosoma brucei gambiense Spliced Leader RNA Is a More Specific Marker for Cure of Human African Trypanosomiasis Than T. b. gambiense DNA. J Infect Dis. 2015 Dec 15;212(12):1996-8. doi: 10.1093/infdis/jiv337. Epub 2015 Jun 16. — View Citation

Tiberti N, Lejon V, Hainard A, Courtioux B, Robin X, Turck N, Kristensson K, Matovu E, Enyaru JC, Mumba Ngoyi D, Krishna S, Bisser S, Ndung'u JM, Büscher P, Sanchez JC. Neopterin is a cerebrospinal fluid marker for treatment outcome evaluation in patients affected by Trypanosoma brucei gambiense sleeping sickness. PLoS Negl Trop Dis. 2013;7(2):e2088. doi: 10.1371/journal.pntd.0002088. Epub 2013 Feb 28. — View Citation

Vincent IM, Daly R, Courtioux B, Cattanach AM, Biéler S, Ndung'u JM, Bisser S, Barrett MP. Metabolomics Identifies Multiple Candidate Biomarkers to Diagnose and Stage Human African Trypanosomiasis. PLoS Negl Trop Dis. 2016 Dec 12;10(12):e0005140. doi: 10.1371/journal.pntd.0005140. eCollection 2016 Dec. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Sensitivity of SL-RNA detection in blood, SL-RNA detection in cerebrospinal fluid and of neopterin & 5-hydroxytryptophan quantification in cerebrospinal fluid for relapse after human African trypanosomiasis treatment	Index tests: qualitative detection of SL-RNA in blood, qualitative detection of SL-RNA in cerebrospinal fluid, neopterin & 5-hydroxytryptophan quantification in cerebrospinal fluid.; Reference standard: classification according to the WHO 2015 criteria as relapse or probable relapse within 18 months after treatment for human African trypanosomiasis	18 months
Primary	Specificity of SL-RNA detection in blood, SL-RNA detection in cerebrospinal fluid and of neopterin & 5-hydroxytryptophan quantification in cerebrospinal fluid for cure after human African trypanosomiasis treatment	Index tests: qualitative detection of SL-RNA in blood, qualitative detection of SL-RNA in cerebrospinal fluid, neopterin & 5-hydroxytryptophan quantification in cerebrospinal fluid.; Reference standard: classification according to the WHO 2015 criteria as cure or probable cure 18 months after treatment	18 months
Secondary	Sensitivity and specificity SL-RNA detection in blood for outcome assesment after treatment for human African trypanosomiasis	Index tests: qualitative detection of SL-RNA in blood post treatment day 11, month 6, month 12 and month 18.; Reference standard: Human African trypanosomiasis treatment outcome classification according to the WHO 2015 criteria	post treatment day 11, month 6, month 12 and month 18
Secondary	Sensitivity and specificity SL-RNA detection in cerebrospinal fluid for outcome assesment after treatment for human African trypanosomiasis	Index tests: qualitative detection of SL-RNA in cerebrospinal fluid at post treatment day 11, month 6, month 12 and month 18.; Reference standard: Human African trypanosomiasis treatment outcome classification according to the WHO 2015 criteria	post treatment day 11, month 6, month 12 and month 18
Secondary	Sensitivity and specificity by ROC analysis of neopterin & 5-hydroxytryptophan quantification in cerebrospinal fluid for outcome assesment after treatment for human African trypanosomiasis	Index tests: quantitative detection of neopterin & 5-hydroxytryptophan in cerebrospinal fluid at post treatment day 11, month 6, month 12 and month 18.; Reference standard: Human African trypanosomiasis treatment outcome classification according to the WHO 2015 criteria	post treatment day 11, month 6, month 12 and month 18

External Links

•   Human African trypanosomiasis: update of the methodological framework for clinical trials
•   phase 1 study of drug now in phase 2/3