Preventive Treatment Of Latent Tuberculosis Infection In People With Diabetes Mellitus (PROTID)

• ClinicalTrials.gov Identifier: NCT04600167
• Recruitment Status: Not yet recruiting
• First Posted: October 23, 2020
• Last Update Posted: October 23, 2020
• Sponsor: Dr. Nyanda Elias Ntinginya
• Collaborators: Stichting Katholieke Universiteit- Radboudumc (RUMC), Netherlands; Otago University, New Zealand; Makerere University; St George's, University of London, United Kingdom; Kilimanjaro Christian Medical University College (KCMUCo), Tanzania; Uganda Martyrs Hospital Lubaga, Uganda; King's College London
• Information provided by (Responsible Party): Dr. Nyanda Elias Ntinginya, National Institute for Medical Research, Tanzania

Study Description

Brief Summary:

Diabetes mellitus (DM) increases susceptibility to Tuberculosis (TB) and worsens TB patient outcomes. The number of patients with combined TB and DM now outnumbers that of combined TB and HIV and it has been estimated that 15-30% of TB disease may be attributable to diabetes globally. This may be expected to rise substantially as DM prevalence increases. Treatment of Latent TB Infection (LTBI) in this population will likely have a significant clinical benefit. Similar to HIV-infected individuals, those with DM might benefit from therapy to prevent the development of TB disease. Current international guidelines do not recommend LTBI management in people with DM, but this is because no studies have examined the risk-benefit ratio of such an intervention. To date, no RCTs have been conducted to investigate the efficacy and safety of preventive treatment of LTBI in DM patients. Based on evidence on effectiveness, safety, and treatment completion rates, 3HP has been selected as the regimen of choice for this study of African people living with DM. People living with DM will be randomized to 3HP or placebo to determine the efficacy of 3HP in the prevention of TB disease in this population. PROTID's preventive treatment of LTBI among people with DM will generate the first solid evidence to support or refute the use of preventive treatment against TB in people with DM.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus; Tuberculosis	Drug: Isoniazid and Rifapentine (INH-RPT); Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 3000 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: A Randomized Double Blind Placebo Controlled Trial of Rifapentine and Isoniazid for Prevention of Tuberculosis in People With Diabetes
• Estimated Study Start Date: January 2021
• Estimated Primary Completion Date: May 2024
• Estimated Study Completion Date: May 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Isoniazid and Rifapentine (INH-RPT); Participants in intervention arm will receive an oral combination of rifapentine (RPT, 900 mg) and isoniazid (INH, 900 mg), once-weekly for 12 weeks.	Drug: Isoniazid and Rifapentine (INH-RPT); Oral combination of rifapentine (RPT, 900 mg) and isoniazid (INH, 900 mg), once-weekly for 12 weeks.; Other Name: 3HP
Placebo Comparator: Control; Participants in the control arm will receive placebo once weekly for 12 weeks.	Drug: Placebo; Participants in the control group will receive placebo once weekly for 12 weeks

Outcome Measures

Primary Outcome Measures :

1. First diagnosis of TB [ Time Frame: Through study completion, median of 33 months follow-up ]
   The primary outcome will compare the rate of occurrence of TB disease (defined as definite or probable TB) in treatment and control groups. Definite TB disease will be confirmed by a culture or Xpert positive result for M. tuberculosis. Probable TB will be diagnosed according to an algorithm that takes into account symptoms, chest x-ray reading, sputum smear, histology and verbal autopsy results.

Secondary Outcome Measures :

1. Occurrence of possible, probable or definite TB disease [ Time Frame: At least 24 months post randomisation ]
2. Occurrence of an adverse event [ Time Frame: From randomisation to 60 days after end of study treatment ]
3. Treatment completion [ Time Frame: Defined as > 11 of 12 doses of treatment over no more than 16 weeks. ]
4. All-cause mortality [ Time Frame: At least 24 months post randomisation ]
5. Occurrence of possible, probable, or definite TB, or death [ Time Frame: At least 24 months post randomisation ]
   Occurrence of possible, probable, or definite TB, or death, noting that a proportion of deaths are likely to be due to TB but not possible to confirm through verbal autopsy and clinical notes review.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Enrolled in diabetes care with a history of DM and current use of anti-diabetic medication ('known DM'); OR in the absence of anti-diabetic medication an HbA1c of =6.5% (48 mmol/mol) or a fasting venous plasma glucose of =7.0 mmol (126 mg/dl). For those with no previously known DM a repeat test above the diagnostic cut-point is required to confirm the diagnosis ('new DM')
2. Adult (18 years or older)
3. Diagnosed with LTBI, defined as a positive IGRA test or TST reactivity =10 mm
4. Voluntarily signed Informed Consent Form
5. If sexually active, willing to use an effective contraceptive method for the duration of preventive therapy.

Exclusion Criteria:

1. Weight <45 kg
2. Previous TB disease, defined as either bacteriologically confirmed or clinically diagnosed and treated
3. Treatment with a rifamycin medication or isoniazid in the previous 2 years.
4. Diagnosis of probable or definite TB during screening
5. Confirmed HIV-infection or receiving antiretroviral treatment
6. Liver dysfunction, defined as serum aspartate aminotransferase (AST) level 5 times the upper limit of normal
7. Pregnant or planning to become pregnant in the next 3 months, or lactating
8. Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation
9. Other conditions inapplicable for participation in this study, such as likely to fail to adhere to study commitment or to complete the whole study, at the discretion of the site investigator

Contacts and Locations

Contacts

Contact: Issa Sabi, MD.; +255 25 250 3364; isabi@nimr-mmrc.org

Contact: Nyanda E Ntinginya, MD., MSc., PhD.; +255 25 250 3364; nelias@nimr-mmrc.org

Sponsors and Collaborators

Dr. Nyanda Elias Ntinginya

Stichting Katholieke Universiteit- Radboudumc (RUMC), Netherlands

Otago University, New Zealand

Makerere University

St George's, University of London, United Kingdom

Kilimanjaro Christian Medical University College (KCMUCo), Tanzania

Uganda Martyrs Hospital Lubaga, Uganda

King's College London

Investigators

• Study Chair: Nyanda E Ntinginya, MD, MSc., Ph.D; Mbeya Medical Research Center, National Institute for Medical Research, Tanzania
• Principal Investigator: Nyasatu Chamba, MD.; Kilimanjaro Christian Medical Centre,Moshi,Tanzania
• Principal Investigator: Irene Andia- Biraro, MD., Ph.D.; Makerere University, Makerere, Uganda
• Principal Investigator: Davis Kibirige, MD, Ph.D.; Martyrs Hospital Lubaga, Makerere, Uganda

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Ntinginya NE, Te Brake L, Sabi I, Chamba N, Kilonzo K, Laizer S, Andia-Biraro I, Kibirige D, Kyazze AP, Ninsiima S, Critchley JA, Romeo R, van de Maat J, Olomi W, Mrema L, Magombola D, Mwayula IH, Sharples K, Hill PC, van Crevel R; PROTID Consortium. Rifapentine and isoniazid for prevention of tuberculosis in people with diabetes (PROTID): protocol for a randomised controlled trial. Trials. 2022 Jun 10;23(1):480. doi: 10.1186/s13063-022-06296-8.

Olomi W, Andia Biraro I, Kilonzo K, Te Brake L, Kibirige D, Chamba N, Elias Ntinginya N, Sabi I, Critchley J, Sharples K, Hill PC, Van Crevel R. Tuberculosis Preventive Therapy for People With Diabetes Mellitus. Clin Infect Dis. 2022 Apr 28;74(8):1506-1507. doi: 10.1093/cid/ciab755.

• Responsible Party: Dr. Nyanda Elias Ntinginya, Director, NIMR - Mbeya Medical Research Centre, National Institute for Medical Research, Tanzania
• ClinicalTrials.gov Identifier: NCT04600167
• Other Study ID Numbers: NIMR-MB-002
• First Posted: October 23, 2020
• Last Update Posted: October 23, 2020
• Last Verified: October 2020

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Dr. Nyanda Elias Ntinginya, National Institute for Medical Research, Tanzania:

Tuberculosis; Drugs; Social science; Health systems; Epidemiology; Diabetes

Additional relevant MeSH terms:

Tuberculosis; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Isoniazid; Rifapentine; Antitubercular Agents; Anti-Bacterial Agents; Anti-Infective Agents; Fatty Acid Synthesis Inhibitors; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Antibiotics, Antitubercular; Leprostatic Agents