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Treg Therapy in Subclinical Inflammation in Kidney Transplantation (TASK)

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ClinicalTrials.gov Identifier: NCT02711826
Recruitment Status : Recruiting
First Posted : March 17, 2016
Last Update Posted : January 30, 2018
Sponsor:
Collaborator:
Clinical Trials in Organ Transplantation
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:

The purpose of this study is:

  • To see if polyTregs and/or "donor reactive" darTregs can reduce inflammation in a transplanted kidney.
  • To find out what effects, good or bad, polyTregs or darTregs will have in the kidney recipient.
  • To find out what effects, good or bad, taking everolimus after polyTregs or darTregs will have in the kidney recipient.

Condition or disease Intervention/treatment Phase
Kidney Transplant Adult Living Donor Kidney Transplant Recipients Renal Transplant Living Kidney Donor Biological: Polyclonal Regulatory T Cells Biological: Donor-Alloantigen-Reactive Regulatory T Cells Drug: Everolimus Drug: Tacrolimus Drug: Mycophenolate mofetil Drug: Mycophenolic acid Drug: Acetaminophen Drug: Diphenhydramine Procedure: Biopsy, Kidney Procedure: Blood Draw Procedure: Leukapheresis Procedure: IS regimen conversion Phase 1 Phase 2

Detailed Description:

Inflammation occurs when the body's defense system recognizes a foreign object (such as a transplanted kidney), and responds by sending white blood cells to attack the foreign object. These cells and the substances they produce can damage the transplanted kidney. There is currently no standard treatment for inflammation in the kidney; some transplant centers do not treat inflammation at all. Rejection is a more severe form of inflammation and injury. Both inflammation and rejection are diagnosed by looking at a piece of kidney (a kidney biopsy) under a microscope. Kidneys that have inflammation and/or rejection do not work as well or last as long as kidneys without injury.

People who have a transplant take immunosuppressive drugs (IS) to prevent inflammation and rejection. Although kidney transplant recipients usually do well in the first five years after transplant, transplant researchers are interested in finding ways to prevent inflammation and rejection without IS, or with lower doses of IS in order to avoid side effects.

While some white blood cells cause inflammation, other types of white blood cells, called T regulatory cells (Tregs), can control inflammation. Tregs may have an important role in controlling or preventing inflammation and rejection. A person's Tregs can be grown in the laboratory to increase their number (polyTreg). These Tregs can be given back through a needle placed in a vein (IV). Researchers can expose a transplant recipient's Tregs to the donor's cells, which results in Tregs that recognize the donor. These are called donor reactive Tregs (darTreg). Both polyTregs and darTreg, when given to the recipient, might reduce inflammation in the transplanted kidney. However, this effect has not yet been shown. The darTregs are thought to be more effective because they might be able to help the body specifically recognize and accept the donated kidney. This is one of the first clinical trials using darTregs.

One of the IS drugs used in kidney transplant is Everolimus. Everolimus has been shown to help Tregs survive better than other types of IS drugs.

This is a randomized open‐label trial to determine the safety and efficacy of a single dose of autologous polyTregs or darTregs in renal transplant recipients with subclinical inflammation (SCI) in the 6 month post‐transplant allograft protocol biopsy compared to control patients treated with CNI‐based immunosuppression. The efficacy of the Treg therapy will be assessed by the reduction of graft inflammation on biopsies performed at 7 months after study group allocation compared to the eligibility biopsy.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Treg Adoptive Therapy in Subclinical Inflammation in Kidney Transplantation (CTOT-21)
Study Start Date : May 2016
Estimated Primary Completion Date : October 1, 2021
Estimated Study Completion Date : October 1, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Maintenance CNI based immunosuppression therapy group
Standard of care
Drug: Tacrolimus
Other Names:
  • FK-506
  • FR-900506
  • Prograf

Drug: Mycophenolate mofetil
All enrolled participants will be on MMF (or MPA below) at the time of study entry at a minimum dose of 1000mg per day.
Other Names:
  • Cellcept
  • MMF

Drug: Mycophenolic acid
All enrolled participants will be on MPA (or MMF above) at the time of study entry at a minimum dose of 720mg per day.
Other Names:
  • Myfortic
  • MPA

Procedure: Biopsy, Kidney
Other Name: Kidney Biopsy

Procedure: Blood Draw
Other Names:
  • Phlebotomy
  • Venipuncture

Experimental: Polyclonal Regulatory T Cells group

Subjects to receive polyTregs (400 ± 100 x 10^6). After polyTreg infusion, eligible subjects will start Mammalian Target of Rapamycin (mTOR) inhibitor.

Target tacrolimus trough levels prior to conversion to everolimus are 4-11 μg/dl, which falls within standard of care. For eligible participants in polyTregs and darTregs groups, the tacrolimus dose will be reduced by 50% when everolimus is initiated. Tacrolimus will be discontinued 4 weeks after initiation of everolimus therapy.

Everolimus, a mTOR inhibitor immunosuppressant, will be initiated at a dose of 1.5 mg orally twice daily and titrated, as needed. Participants will begin everolimus with target trough levels of 3-8μg/L for 4 weeks while still taking tacrolimus. Everolimus target trough levels will be 6-10 μg/L when tacrolimus is discontinued.

Biological: Polyclonal Regulatory T Cells
Participants randomized to polyTregs group will receive a single infusion of 400 ±100 x 10^6 polyTregs.
Other Names:
  • Polyclonal Tregs
  • polyTregs

Drug: Everolimus
Other Name: Zortress

Drug: Tacrolimus
Other Names:
  • FK-506
  • FR-900506
  • Prograf

Drug: Mycophenolate mofetil
All enrolled participants will be on MMF (or MPA below) at the time of study entry at a minimum dose of 1000mg per day.
Other Names:
  • Cellcept
  • MMF

Drug: Mycophenolic acid
All enrolled participants will be on MPA (or MMF above) at the time of study entry at a minimum dose of 720mg per day.
Other Names:
  • Myfortic
  • MPA

Drug: Acetaminophen
650 mg acetaminophen, administered 30-60 minutes prior to infusion as pre-medication.
Other Name: Tylenol

Drug: Diphenhydramine
25-50 mg diphenhydramine intravenously or by mouth, administered 30-60 minutes prior to infusion as pre-medication.
Other Name: Benadryl

Procedure: Biopsy, Kidney
Other Name: Kidney Biopsy

Procedure: Blood Draw
Other Names:
  • Phlebotomy
  • Venipuncture

Procedure: Leukapheresis
Other Name: leukocytapheresis

Procedure: IS regimen conversion
Conversion from Tacrolimus, a calcineurin inhibitors (CNI), to Everolimus, an mTOR inhibitor.
Other Name: Everolimus Conversion

Experimental: Donor-Alloantigen-Reactive Regulatory T Cells group

Subjects to receive darTregs (400 ± 100 x 10^6). After darTregs infusion, eligible subjects will start Mammalian Target of Rapamycin (mTOR) inhibitor.

Target tacrolimus trough levels prior to conversion to everolimus are 4-11 μg/dl, which falls within standard of care. For eligible participants in polyTregs and darTregs groups, the tacrolimus dose will be reduced by 50% when everolimus is initiated. Tacrolimus will be discontinued 4 weeks after initiation of everolimus therapy.

Everolimus, a mTOR inhibitor immunosuppressant, will be initiated at a dose of 1.5 mg orally twice daily and titrated, as needed. Participants will begin everolimus with target trough levels of 3-8μg/L for 4 weeks while still taking tacrolimus. Everolimus target trough levels will be 6-10 μg/L when tacrolimus is discontinued.

Biological: Donor-Alloantigen-Reactive Regulatory T Cells
Participants randomized to darTregs group will receive a single infusion of 400 ±100 x 10^6 darTregs.
Other Names:
  • darTregs
  • DRTreg

Drug: Everolimus
Other Name: Zortress

Drug: Tacrolimus
Other Names:
  • FK-506
  • FR-900506
  • Prograf

Drug: Mycophenolate mofetil
All enrolled participants will be on MMF (or MPA below) at the time of study entry at a minimum dose of 1000mg per day.
Other Names:
  • Cellcept
  • MMF

Drug: Mycophenolic acid
All enrolled participants will be on MPA (or MMF above) at the time of study entry at a minimum dose of 720mg per day.
Other Names:
  • Myfortic
  • MPA

Drug: Acetaminophen
650 mg acetaminophen, administered 30-60 minutes prior to infusion as pre-medication.
Other Name: Tylenol

Drug: Diphenhydramine
25-50 mg diphenhydramine intravenously or by mouth, administered 30-60 minutes prior to infusion as pre-medication.
Other Name: Benadryl

Procedure: Biopsy, Kidney
Other Name: Kidney Biopsy

Procedure: Blood Draw
Other Names:
  • Phlebotomy
  • Venipuncture

Procedure: Leukapheresis
Other Name: leukocytapheresis

Procedure: IS regimen conversion
Conversion from Tacrolimus, a calcineurin inhibitors (CNI), to Everolimus, an mTOR inhibitor.
Other Name: Everolimus Conversion




Primary Outcome Measures :
  1. Timing of Banff 2A or higher acute cell-mediated rejection and/or acute antibody mediated rejection [ Time Frame: Baseline (Day 0) to Day 405 ]
    The safety of polyTregs and/or darTregs will be described in comparison with CNI-based maintenance IS therapy.

  2. Incidence of Banff 2A or higher acute cell-mediated rejection and/or acute antibody mediated rejection [ Time Frame: Baseline (Day 0) to Day 405 ]
    The safety of polyTregs and/or darTregs will be described in comparison with CNI-based maintenance IS therapy.

  3. Timing of study defined Grade 3 or higher infection [ Time Frame: Baseline (Day 0) to Day 405 ]
    The safety of polyTregs and/or darTregs will be described in comparison with CNI-based maintenance IS therapy.

  4. Incidence of study defined Grade 3 or higher infection [ Time Frame: Baseline (Day 0) to Day 405 ]
    The safety of polyTregs and/or darTregs will be described in comparison with CNI-based maintenance IS therapy.

  5. Percent change in inflammation [ Time Frame: Baseline and 7 months after study group allocation. ]
    As measured by the percentage area of cortex occupied by inflammatory cells using computer-assisted quantitative image analysis on the biopsy, expressed as the percent change relative to the baseline biopsy.

  6. Immunologic profiles of kidney transplant recipients [ Time Frame: At 2 weeks after infusion (PolyTregs and darTregs groups) and 7 months after group allocation. ]
    Immunologic profiles using the common response module (CRM) graft gene expression of rejection and/or histologic evidence of inflammation in biopsies.


Secondary Outcome Measures :
  1. Timing of polyTregs and/or darTreg infusion reactions [ Time Frame: Baseline (Day 0) to Day 405 ]
    To assess safety of PolyTregs and darTregs in all groups

  2. Incidence of polyTregs and/or darTreg infusion reactions [ Time Frame: Baseline (Day 0) to Day 405 ]
    To assess safety of PolyTregs and darTregs in all groups

  3. Severity of polyTregs and/or darTreg infusion reactions [ Time Frame: Baseline (Day 0) to Day 405 ]
    To assess safety of PolyTregs and darTregs in all groups

  4. Timing of culture-proven and clinically diagnosed infection [ Time Frame: Baseline (Day 0) to Day 405 ]
    To assess safety of PolyTregs and darTregs in all groups

  5. Incidence of culture-proven and clinically diagnosed infection. [ Time Frame: Baseline (Day 0) to Day 405 ]
    To assess safety of PolyTregs and darTregs in all groups

  6. Severity of culture-proven and clinically diagnosed infection [ Time Frame: Baseline (Day 0) to Day 405 ]
    To assess safety of PolyTregs and darTregs in all groups

  7. Timing of acute rejection using Banff grading [ Time Frame: Baseline (Day 0) to Day 405 ]

    To assess safety of PolyTregs and darTregs in all groups

    Banff 2007 Type 1A or higher and clinical treatment for acute rejection. Central reading will be utilized when accounting for study stopping rule and for safety endpoint.


  8. Incidence of acute rejection using Banff grading [ Time Frame: Baseline (Day 0) to Day 405 ]
    To assess safety of PolyTregs and darTregs in all groups. Banff 2007 Type 1A or higher and clinical treatment for acute rejection. Central reading will be utilized when accounting for study stopping rule and for safety endpoint.

  9. Severity of acute rejection using Banff grading [ Time Frame: Baseline (Day 0) to Day 405 ]

    To assess safety of PolyTregs and darTregs in all groups

    Banff 2007 Type 2A or higher and clinical treatment for acute rejection. Central reading will be utilized when accounting for study stopping rule and for safety endpoint.


  10. Timing of BK viremia and cytomegalovirus (CMV) reactivation [ Time Frame: Baseline (Day 0) to Day 405 ]
    To assess safety of PolyTregs and darTregs in all groups

  11. Incidence of BK viremia and CMV reactivation [ Time Frame: Baseline (Day 0) to Day 405 ]
    To assess safety of PolyTregs and darTregs in all groups

  12. Timing of > 10% decrease in estimated Glomerular Filtration Rate (eGFR ) compared to baseline [ Time Frame: Baseline (Day 0) to Day 405 ]
    To assess safety of PolyTregs and darTregs in all groups

  13. Incidence of > 10% decrease in eGFR compared to baseline [ Time Frame: Baseline (Day 0) to Day 405 ]
    To assess safety of PolyTregs and darTregs in all groups

  14. Timing of acute rejection in PolyTregs and darTregs groups [ Time Frame: Day 69 to Day 405 ]
    To assess safety of mTOR therapy after Treg infusion. Subjects who receive Tregs in either group who convert to mTOR therapy will be compared to subjects who did not convert to mTOR therapy; as well as subjects in CNI Maintenance group.

  15. Incidence of acute rejection in PolyTregs and darTregs groups [ Time Frame: Day 69 to Day 405 ]
    To assess safety of mTOR therapy after Treg infusion. Subjects who receive Tregs in either group who convert to mTOR therapy will be compared to subjects who did not convert to mTOR therapy; as well as subjects in CNI Maintenance group.

  16. Proportion of subjects exhibiting a relative decrease of 25% or more inflammation on kidney biopsy [ Time Frame: Baseline to 2 weeks after polyTregs and/or darTregs ]
    Measured as the percentage area of cortex occupied by inflammatory cells using computer-assisted quantitative image analysis on the baseline kidney biopsy and the biopsy 2 weeks after polyTregs and/or darTregs.

  17. Proportion of subjects who exhibit a relative decrease of 50% or more inflammation on kidney biopsy [ Time Frame: Baseline to 2 weeks after polyTregs and/or darTregs ]
  18. Proportion of subjects who exhibit a relative decrease of 25% or more inflammation on kidney biopsy [ Time Frame: Baseline to 7 months after group allocation ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

Individuals who meet all of the following criteria are eligible for enrollment as study participants:

  1. Subject must be able to understand and provide informed consent;
  2. Age ≥18 years of age at the time of study entry
  3. Recipients of non- Human Leukocyte Antigen (HLA) identical living renal transplants;
  4. Living donor able and willing to have 100 ml blood draw for Treg manufacture (darTreg group only);
  5. Protocol renal allograft biopsy at 5 months (± 8 weeks) after transplantation with Banff i1 and/or ti1 with concomitant t scores t0, t1,t2 or t3; Banff i2 and/or ti2 with concomitant t scores t0 or t1; and without v > 0, [ptc + g] ≥2, C4d >1 (by immunofluorescence, IF), or C4d > 0 (by immunohistochemistry, IHC); confirmed by central pathologist. Subjects must not be treated for pathologic criteria (e.g. steroids).
  6. Estimated glomerular filtration rate (eGFR) ≥35 ml/min at the time of study entry;
  7. Maintenance immunosuppression consisting of tacrolimus, MMF/MPA (≥1000 mg/720 mg daily) ± prednisone (≤10 mg/day);
  8. Positive Epstein-Barr Virus (EBV) serology at the time of study entry;
  9. Current immunizations including TdAP, hepatitis B, pneumococcal and seasonal influenza vaccines at the time of study entry, completed prior to enrollment and no less than 14 days prior to planned manufacturing collection.
  10. Documented Hepatitis B (HB) serologies must be:

    1. Positive HB surface antibody, negative HB core antibody and negative HB surface antigen for recipients immune to hepatitis B
    2. Negative HB surface antibody, negative HB core antibody and negative HB surface antigen for non-immune/ HBV naïve recipients provided donor had negative HB core antibody and negative HB surface antigen at the time of donation.
  11. Negative TB test (PPD, interferon-gamma release assay, ELISPOT testing) within 1 year prior to enrollment. Subjects with a history of TB (positive TB test without active infection) must have completed one of the latent TB infection treatment regimens endorsed by the CDC (Division of TB Elimination, 2016). Alternative regimens for latent TB infection eradication will be adjudicated by the site's infectious disease specialist.
  12. Women subjects of childbearing potential must have reviewed the Mycophenolate Mycophenolate Risk Evaluation and Mitigation Strategy (REMS) and have a negative pregnancy test upon study entry (Reference:https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm318880.htm);
  13. Female subjects with child-bearing potential, must agree to use FDA approved methods of birth control for the duration of the study; subjects must consult with their physician and determine the most suitable method(s) that are greater than 80% effective (http://www.fda.gov/birthcontrol).

Treg Infusion Inclusion Criteria:

1. Individuals randomized to the polyTreg and darTreg groups who continue to meet all of the enrollment criteria.

mTOR Conversion Inclusion Criteria:

Individuals who meet all of these criteria are eligible for mTOR conversion:

  1. Received either polyTreg or darTregs infusion;
  2. Inflammatory load on 2 week post-infusion biopsy has decreased by ≥50% relative to the baseline biopsy, confirmed by central pathologist.

Exclusion Criteria:

Individuals who meet any of these criteria are not eligible for enrollment as study participants:

  1. Inability or unwillingness of a participant to give written informed consent or comply with study protocol;
  2. History of malignancy; except adequately treated basal cell carcinoma;
  3. History of graft loss from acute rejection within 1 year after any previous transplant;
  4. History of transplant renal artery stenosis;
  5. History of cellular rejection prior to enrollment that did not respond to steroids and/or subsequent creatinine after treatment for rejection greater than 15% above baseline;
  6. Known hypersensitivity to mTOR inhibitors or contraindication to everolimus (including history of wound healing complications);
  7. Any chronic illness requiring uninterrupted anti-coagulation after kidney transplantation;
  8. HLA-DR matched to donor at both loci;
  9. Post-transplant DSA >5000 MFI or post-transplant treatment with IVIg for DSA. Enrolled subjects with post-transplant DSA >2000 MFI will not be eligible for mTOR conversion.
  10. Positive HIV 1 or HIV 2 serology prior to transplantation;
  11. Positive Hepatitis C virus (HCV) Ab serology or positive HBSAg prior to transplantation;
  12. Proteinuria with urine pr/cr > 0.5 g/g;
  13. Any condition requiring chronic use of corticosteroids >10mg/day at the time of study entry;
  14. Subjects requiring treatment for pathologic findings on study eligibility biopsy (see inclusion 5).
  15. Active infection at the time of study entry;
  16. History of active TB or latent TB without adequate treatment (see inclusion 11).
  17. Serum BK virus >1,000 copies/ml by Polymerase Chain Reaction (PCR) at the time of study entry;
  18. Hematocrit <27%; White Blood Cell (WBC) count < 3,000/μL; Absolute Neutrophil Count (ANC) < 1,500/μL; lymphocyte count <800/μL; platelet count <100,000/μL at the time of study entry;
  19. Participation in any other studies with investigational drugs or regimens in the preceding year;
  20. Any condition or prior treatment which, in the opinion of the investigator, precludes study participation.
  21. Unable to provide adequate biopsy specimen (paraffin embedded formalin fixed) from eligibility biopsy (3-7 months post -transplant) for quantitative analysis.

Treg Infusion Exclusion Criteria:

Individuals randomized to polyTreg and darTreg groups who meet any of these criteria are not eligible for Treg infusion:

  1. Received any vaccination within 14 days prior to blood collection for Treg manufacture;
  2. Unacceptable Treg product;
  3. Positive pregnancy test for women of child bearing potential.

mTOR Conversion Exclusion Criteria:

1. Post-transplant Donor-Specific Antibodies (DSA) >2000 mean florescence intensity (MFI).


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02711826


Locations
United States, Alabama
University of Alabama, Birmingham Recruiting
Birmingham, Alabama, United States, 35294
Contact: Jill Andringa    205-934-0035    jillrn@uab.edu   
Principal Investigator: Rosyln Mannon, MD         
United States, California
University of California at San Francisco Recruiting
San Francisco, California, United States, 94118
Contact: Erica Tavares    415-353-8380    erica.tavares@ucsf.edu   
Principal Investigator: Flavio Vincenti, MD         
United States, Michigan
University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Jennifer Mawby    734-936-4811    jlmawby@med.umich.edu   
Principal Investigator: Abhijit Naik, MBBS         
United States, Minnesota
Mayo Clinic, Department of Surgery Not yet recruiting
Rochester, Minnesota, United States, 55905
Contact: Nong Yowe Braaten    507-538-9617    Braaten.Nong@mayo.edu   
Contact: Leah Majerus    507-255-3940    Majerus.Leah@mayo.edu   
Principal Investigator: Mark Stegall, MD         
United States, Ohio
Cleveland Clinic Recruiting
Cleveland, Ohio, United States, 44195
Contact: Jennifer Czerr    216-444-3256    czerrj@ccf.org   
Principal Investigator: Emilio Poggio, MD         
United States, Pennsylvania
University of Pittsburgh Medical Center Not yet recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Mindi A. Styn, PhD    412-383-8884    stynma@upmc.edu   
Principal Investigator: Rajil Mehta, MD         
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Clinical Trials in Organ Transplantation
Investigators
Principal Investigator: Flavio Vincenti, MD University of California at San Francisco
Study Chair: Sindhu Chandran, MD University of California at San Francisco

Additional Information:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT02711826     History of Changes
Other Study ID Numbers: DAIT CTOT-21
First Posted: March 17, 2016    Key Record Dates
Last Update Posted: January 30, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The plan is to share data in ImmPort [https://immport.niaid.nih.gov/ ], a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts, upon completion of the study.

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
graft inflammation
Treg
polyclonally expanded Tregs (polyTregs)
darTregs
calcineurin inhibitors (CNIs)
mTOR inhibitors

Additional relevant MeSH terms:
Inflammation
Pathologic Processes
Tacrolimus
Everolimus
Sirolimus
Calcineurin Inhibitors
Mycophenolic Acid
Acetaminophen
Diphenhydramine
Promethazine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Antipyretics
Antibiotics, Antitubercular
Antitubercular Agents
Anesthetics, Local
Anesthetics
Central Nervous System Depressants