Not provided
| ID | Type | Description | Link |
|---|---|---|---|
| U01AI089342-01A1 | U.S. NIH Grant/Contract | View source |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| National Institute of Allergy and Infectious Diseases (NIAID) | NIH |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
The purpose of this study is to determine if there is a benefit to taking trimethoprim-sulfamethoxazole (TS) as prophylaxis among HIV positive adults who have viral load suppression and a good clinical response on anti-retroviral therapy (ART). If there is a benefit, then is it due to antimalarial or antibacterial properties.
The investigators hypothesize that there will be a long-term benefit on survival and disease control in the context of prophylaxis and that the benefit will largely be attributed to prevention of malaria. The main study hypothesis is that 1)TS and chloroquine (CQ) will decrease the rates of morbidity and mortality among adults after 6 or more months of ART and 2) CQ prophylaxis will be associated with more prolonged viral suppression and higher CD4 cell counts than TS prophylaxis or no prophylaxis.
This is a randomized, controlled, open-label, phase III trial of standard of care TS prophylaxis and CQ prophylaxis compared to no prophylaxis in adults receiving ART. Adults who have been receiving ART for at least six months with a good clinical response and provide informed consent and fulfill the eligibility criteria will be randomized to one of three arms: (1) to continue standard of care trimethoprim-sulfamethoxazole (TS) prophylaxis, (2) discontinue standard of care TS prophylaxis and begin weekly CQ prophylaxis or (3) discontinue standard of care TS prophylaxis. Participants will be asked to return to the research clinic every four weeks for the first 24 weeks then every 12 weeks thereafter, and any time they are ill to facilitate both active and passive follow-up of the study endpoints. Participation will last for 32 to approximately 66 months. Participants who develop a WHO clinical stage 3 or 4 illness, experience a sustained decline in their CD4 count below 200 cells/mm3, or who experience ART failure will be placed on standard of care TS prophylaxis. Those with confirmed ART failure will be evaluated for second-line therapy according to the Malawi Ministry of Health guidelines.
The study population will include up to 1500 Malawian adults aged 18 years or older living with HIV in or near Blantyre or Zomba, Malawi, Central Africa who have been receiving antiretroviral therapy for at least 6 months with good clinical response to ART, have an undetectable HIV viral load and a CD4 count >250/mm3.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Standard of Care Prophylaxis (TS) | Active Comparator | Standard of care prophylaxis with daily trimethoprim sulfamethoxazole (TS). |
|
| Chloroquine (CQ) prophylaxis | Experimental | Discontinuation of standard of care TS prophylaxis and starting weekly chloroquine prophylaxis |
|
| Discontinuation of standard of care | No Intervention | Control arm - Discontinuation of standard of care trimethoprim sulfamethoxazole. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Standard of Care prophylaxis | Drug | Daily trimethoprim sulfamethoxazole |
|
| Measure | Description | Time Frame |
|---|---|---|
| Severe Events | Incidence of severe events (composite of death and WHO stage 3 and 4 illness) | 22-66 months |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With at Least One Detectable HIV Viral Load | Number of participants who ever have a detectable viral load (>400 copies/ml). | Throughout study participation, measured every six months (2-5.5 years). |
| CD4 Cell Count |
| Measure | Description | Time Frame |
|---|---|---|
| Bacterial or Malaria Infection With CQ or TS Resistant Organism | Occurrence of bacterial or malaria infection with CQ or TS resistant organism | 32-66 months |
| Clinical and Parasitological Response to Antimalarial Therapy |
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Miriam K Laufer, MD, MPH | University of Maryland, Baltimore | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Blantyre Malaria Project Research Clinic | Blantyre | Malawi | ||||
| Tisungane Clinic |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33744963 | Background | Laurens MB, Mungwira RG, Nampota N, Nyirenda OM, Divala TH, Kanjala M, Mkandawire FA, Galileya LT, Nyangulu W, Mwinjiwa E, Downs M, Tillman A, Taylor TE, Mallewa J, Plowe CV, van Oosterhout JJ, Laufer MK. Revisiting Co-trimoxazole Prophylaxis for African Adults in the Era of Antiretroviral Therapy: A Randomized Controlled Clinical Trial. Clin Infect Dis. 2021 Sep 15;73(6):1058-1065. doi: 10.1093/cid/ciab252. | |
| 35848575 | Derived | Mungwira RG, Laurens MB, Nyangulu W, Divala TH, Nampota-Nkomba N, Buchwald AG, Nyirenda OM, Mwinjiwa E, Kanjala M, Galileya LT, Earland DE, Adams M, Plowe CV, Taylor TE, Mallewa J, van Oosterhout JJ, Laufer MK; TSCQ Study Team. High burden of malaria among Malawian adults on antiretroviral therapy after discontinuing prophylaxis. AIDS. 2022 Oct 1;36(12):1675-1682. doi: 10.1097/QAD.0000000000003317. Epub 2022 Jul 15. |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Standard of Care Trimethoprim Sulfamethoxazol (TS) Prophylaxis | Participants will continue standard of care daily TS prophylaxis (two tablets each of 80 mg trimethoprim and 400 mg sulfamethoxazole or one tablet each of 160 mg trimethoprim and 800 mg sulfamethoxazole). |
| FG001 | Chloroquine (CQ) Prophylaxis | Participants will discontinue standard of care trimethoprim sulfamethoxazol prophylaxis and start weekly CQ prophylaxis at 300 mg. |
| FG002 | Discontinuation of Standard of Care (Control Arm) | Participants will discontinue standard of care trimethoprim sulfamethoxazol prophylaxis and receive no prophylaxis. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Standard of Care Trimethoprim Sulfamethoxazol (TS) Prophylaxis | Participants will continue standard of care daily TS prophylaxis (two tablets each of 80 mg trimethoprim and 400 mg sulfamethoxazole or one tablet each of 160 mg trimethoprim and 800 mg sulfamethoxazole). |
| BG001 | Chloroquine (CQ) Prophylaxis |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Severe Events | Incidence of severe events (composite of death and WHO stage 3 and 4 illness) | Posted | Number | Events per 100 participant-years | 22-66 months |
|
2 to 5.5 years
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Standard of Care Trimethoprim Sulfamethoxazo (TS) Prophylaxis | Participants will continue standard of care daily TS prophylaxis (two tablets each of 80 mg trimethoprim and 400 mg sulfamethoxazole or one tablet each of 160 mg trimethoprim and 800 mg sulfamethoxazole). |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Infections | Infections and infestations | MedDRA | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Infections | Infections and infestations | MedDRA | Systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Miriam K. Laufer, M.D., M.P.H. | University of Maryland School of Medicine | 410-706-5333 | mlaufer@som.umaryland.edu |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Sep 2, 2016 | Jul 23, 2019 | Prot_SAP_000.pdf |
Not provided
| ID | Term |
|---|---|
| D008288 | Malaria |
| ID | Term |
|---|---|
| D011528 | Protozoan Infections |
| D010272 | Parasitic Diseases |
| D007239 | Infections |
| D000096724 | Mosquito-Borne Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D015662 | Trimethoprim, Sulfamethoxazole Drug Combination |
| D002738 | Chloroquine |
| ID | Term |
|---|---|
| D013420 | Sulfamethoxazole |
| D000096926 | Benzenesulfonamides |
| D013449 | Sulfonamides |
| D000577 | Amides |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Chloroquine (CQ) prophylaxis | Drug | Discontinue standard of care and start weekly CQ. |
|
|
Number of Participants with at Least One CD4 Count <200
| Every 6 months for 22-66 months |
| WHO HIV Stage 2, 3, 4 Illness | Incidence of any WHO HIV stage 2, 3, or 4 illness | 32-66 months |
| Bacterial Infections and Malaria | Incidence of bacterial infections and malaria | 32-66 months |
| Adverse Events Greater Than or Equal to Grade 3 That Are Related to the Study Product | Occurrence of adverse events that are greater than or equal to Grade 3 that require discontinuation of TS or CQ prophylaxis | 32-66 months |
Clinical and parasitological response to antimalarial therapy in cases of uncomplicated malaria
| 32-66 months |
| Zomba |
| Malawi |
| 27431995 | Derived | Laurens MB, Mungwira RG, Nyirenda OM, Divala TH, Kanjala M, Muwalo F, Mkandawire FA, Tsirizani L, Nyangulu W, Mwinjiwa E, Taylor TE, Mallewa J, Blackwelder WC, Plowe CV, Laufer MK, van Oosterhout JJ. TSCQ study: a randomized, controlled, open-label trial of daily trimethoprim-sulfamethoxazole or weekly chloroquine among adults on antiretroviral therapy in Malawi: study protocol for a randomized controlled trial. Trials. 2016 Jul 18;17(1):322. doi: 10.1186/s13063-016-1392-3. |
| Death |
|
| Withdrawal by Subject |
|
| Non-compliant participant |
|
| Physician Decision |
|
Participants will discontinue standard of care trimethoprim sulfamethoxazol prophylaxis and start weekly CQ prophylaxis at 300 mg.. |
| BG002 | Discontinuation of Standard of Care (Control Arm) | Participants will discontinue standard of care trimethoprim sulfamethoxazol prophylaxis and receive no prophylaxis. |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG002 |
| Discontinuation of Standard of Care (Control Arm) |
Participants will discontinue standard of care trimethoprim sulfamethoxazol prophylaxis and receive no prophylaxis. |
|
|
|
| Secondary | Number of Participants With at Least One Detectable HIV Viral Load | Number of participants who ever have a detectable viral load (>400 copies/ml). | Posted | Count of Participants | Participants | Throughout study participation, measured every six months (2-5.5 years). |
|
|
|
|
| Secondary | CD4 Cell Count | Number of Participants with at Least One CD4 Count <200 | Posted | Count of Participants | Participants | Every 6 months for 22-66 months |
|
|
|
|
| Secondary | WHO HIV Stage 2, 3, 4 Illness | Incidence of any WHO HIV stage 2, 3, or 4 illness | Posted | Number | Events per 100 participant-years | 32-66 months |
|
|
|
|
| Secondary | Bacterial Infections and Malaria | Incidence of bacterial infections and malaria | Posted | Number | Events per 100 participant-years | 32-66 months |
|
|
|
|
| Secondary | Adverse Events Greater Than or Equal to Grade 3 That Are Related to the Study Product | Occurrence of adverse events that are greater than or equal to Grade 3 that require discontinuation of TS or CQ prophylaxis | Posted | Number | Events per 100 participant-years | 32-66 months |
|
|
|
| Other Pre-specified | Bacterial or Malaria Infection With CQ or TS Resistant Organism | Occurrence of bacterial or malaria infection with CQ or TS resistant organism | Not Posted | 32-66 months | Participants |
| Other Pre-specified | Clinical and Parasitological Response to Antimalarial Therapy | Clinical and parasitological response to antimalarial therapy in cases of uncomplicated malaria | Not Posted | 32-66 months | Participants |
| 10 |
| 500 |
| 72 |
| 500 |
| 488 |
| 500 |
| EG001 | Chloroquine (CQ) Prophylaxis | Participants will discontinue standard of care trimethoprim sulfamethoxazol prophylaxis and start weekly CQ prophylaxis at 300 mg. | 6 | 500 | 99 | 500 | 483 | 500 |
| EG002 | Discontinuation of Standard of Care (Control Arm) | Participants will discontinue standard of care trimethoprim sulfamethoxazol prophylaxis and receive no prophylaxis. | 8 | 499 | 116 | 499 | 488 | 499 |
| Pregnancy, puerperium and perinatal | Pregnancy, puerperium and perinatal conditions | MedDRA | Systematic Assessment |
|
| Nervous | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Injuries | Injury, poisoning and procedural complications | MedDRA | Systematic Assessment |
|
| Gastrointestinal | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Neoplasms | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA | Systematic Assessment |
|
| Surgical and medical | Surgical and medical procedures | MedDRA | Systematic Assessment |
|
| General | General disorders | MedDRA | Systematic Assessment |
|
| Reproductive system | Reproductive system and breast disorders | MedDRA | Systematic Assessment |
|
| Respiratory | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Blood | Blood and lymphatic system disorders | MedDRA | Systematic Assessment |
|
| Psychiatric | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Eye | Eye disorders | MedDRA | Systematic Assessment |
|
| Vascular | Vascular disorders | MedDRA | Systematic Assessment |
|
| Metabolism | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
|
| Cardiac | Cardiac disorders | MedDRA | Systematic Assessment |
|
| Endocrine | Endocrine disorders | MedDRA | Systematic Assessment |
|
| Hepatobiliary | Hepatobiliary disorders | MedDRA | Systematic Assessment |
|
| Musculoskeletal | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Renal | Renal and urinary disorders | MedDRA | Systematic Assessment |
|
| General | General disorders | MedDRA | Systematic Assessment |
|
| Investigations | Investigations | MedDRA | Systematic Assessment |
|
| Gastrointestinal | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Musculoskeletal | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Blood | Blood and lymphatic system disorders | MedDRA | Systematic Assessment |
|
| Nervous | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Skin | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
| Eye | Eye disorders | MedDRA | Systematic Assessment |
|
| Reproductive system | Reproductive system and breast disorders | MedDRA | Systematic Assessment |
|
| Injuries | Injury, poisoning and procedural complications | MedDRA | Systematic Assessment |
|
| Respiratory | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Vascular | Vascular disorders | MedDRA | Systematic Assessment |
|
| Pregnancy, puerperium and perinatal | Pregnancy, puerperium and perinatal conditions | MedDRA | Systematic Assessment |
|
| Metabolism | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
|
| Ear and labyrinth | Ear and labyrinth disorders | MedDRA | Systematic Assessment |
|
| Neoplasms | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA | Systematic Assessment |
|
| Cardiac | Cardiac disorders | MedDRA | Systematic Assessment |
|
| Renal | Renal and urinary disorders | MedDRA | Systematic Assessment |
|
| Psychiatric | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Surgical and medical | Surgical and medical procedures | MedDRA | Systematic Assessment |
|
| Hepatobiliary | Hepatobiliary disorders | MedDRA | Systematic Assessment |
|
| Endocrine | Endocrine disorders | MedDRA | Systematic Assessment |
|
| Congenital, familial and genetic | Congenital, familial and genetic disorders | MedDRA | Systematic Assessment |
|
Not provided
Not provided
| D000079426 |
| Vector Borne Diseases |
| D009930 |
| Organic Chemicals |
| D013424 | Sulfanilamides |
| D000814 | Aniline Compounds |
| D000588 | Amines |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D013450 | Sulfones |
| D013457 | Sulfur Compounds |
| D014295 | Trimethoprim |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D004338 | Drug Combinations |
| D004364 | Pharmaceutical Preparations |
| D000634 | Aminoquinolines |
| D011804 | Quinolines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| Fisher Exact | <=0.05 | No adjustment for multiple comparisons was made. | Hazard Ratio (HR) | 1.51 | 2-Sided | 95 | 0.91 | 2.49 | Non-Inferiority | Will assess performance of each experimental group relative to TS with a noninferiority margin for 1-HR of 0.35 to test the null (1-HR ≥ 0.35) and alternative (1-HR < 0.35) hypotheses. Each experimental group will be declared noninferior to TS if the upper bound of the 95% confidence interval of 1-HR is below 0.35. For ease of interpretation, the HRs have been recast with TS as the reference group, such that HRs greater than 1 indicate an increase in the experimental hazard rate relative to TS. |
| Fisher Exact | <=0.05 | No adjustments for multiple comparisons were made. | Hazard Ratio (HR) | 0.96 | 2-Sided | 95 | 0.55 | 1.68 | Non-Inferiority | Will assess performance of each experimental group relative to TS with a noninferiority margin for 1-HR of 0.35 to test the null (1-HR ≥ 0.35) and alternative (1-HR < 0.35) hypotheses. Each experimental group will be declared noninferior to TS if the upper bound of the 95% confidence interval of 1-HR is below 0.35. For ease of interpretation, the HRs have been recast with TS as the reference group, such that HRs greater than 1 indicate an increase in the experimental hazard rate relative to TS. |
| Poisson | Rate ratio confidence intervals and p-values were adjusted for overdispersion using the Pearson's chi-square scale. | <=0.05 | No adjustments for multiple comparisons were made. | Hazard Ratio (HR) | 1.43 | 2-Sided | 95 | 1.04 | 1.96 | Non-Inferiority | Will assess performance of each experimental group relative to TS with a noninferiority margin for 1-HR of 0.35 to test the null (1-HR ≥ 0.35) and alternative (1-HR < 0.35) hypotheses. Each experimental group will be declared noninferior to TS if the upper bound of the 95% confidence interval of 1-HR is below 0.35. For ease of interpretation, the HRs have been recast with TS as the reference group, such that HRs greater than 1 indicate an increase in the experimental hazard rate relative to TS. |
| Poisson | Rate ratio confidence intervals and p-values were adjusted for overdispersion using the Pearson's chi-square scale. | <=0.05 | No adjustments for multiple comparisons were made. | Hazard Ratio (HR) | 1.34 | 2-Sided | 95 | 1.14 | 1.58 | Non-Inferiority | Will assess performance of each experimental group relative to TS with a noninferiority margin for 1-HR of 0.35 to test the null (1-HR ≥ 0.35) and alternative (1-HR < 0.35) hypotheses. Each experimental group will be declared noninferior to TS if the upper bound of the 95% confidence interval of 1-HR is below 0.35. For ease of interpretation, the HRs have been recast with TS as the reference group, such that HRs greater than 1 indicate an increase in the experimental hazard rate relative to TS. |