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Immuno-modulation in Amyotrophic Lateral Sclerosis- a Phase II Study of Safety and Activity of Low Dose Interleukin-2 (IMODALS)

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ClinicalTrials.gov Identifier: NCT02059759
Recruitment Status : Completed
First Posted : February 11, 2014
Last Update Posted : June 1, 2016
Sponsor:
Information provided by (Responsible Party):
Centre Hospitalier Universitaire de Nīmes

Brief Summary:
The primary objective is to evaluate in ALS patients the regulatory T cell early response to two low-doses of IL-2 at 1 and 2 MIU per day after one course of 5 consecutive days comparatively to placebo.

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis Drug: Placebo Drug: 1.0 MIU IL-2 per day Drug: 2.0 MIU IL-2 per day Phase 2

Detailed Description:

This is a phase II study on ld-IL-2 as a therapeutic agent for ALS which aims at defining the activity and safety of a range a doses for subsequent use of the best dose in a phase II/III trial. For ethical reasons, ld-IL-2 must be tested as an add-on therapy to riluzole hence all patients will need to be treated with riluzole for at least three months prior to entry. A randomized (1:1:1), placebo-controlled, double-blind, parallel group trial will be carried out to assess ld-IL-2 activity on regulatory T cells and immuno-inflammatory markers in ALS patients treated for 3 months (5 days every four weeks repeated three times).

The secondary objectives of this study are:

A. To evaluate maintenance of Tcell response after three repeated 5-day courses at one course every four weeks for 12 weeks.

B. To evaluate the safety of ld-IL-2 therapy in an ALS population, with an overall follow-up of 6 months (up to 15 weeks after last administration); C. To evaluate functional changes throughout the study; D. To evaluate changes in other pre-defined blood cytology parameters, and a blood biomarker for axonal damage.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 36 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Immuno-modulation in Amyotrophic Lateral Sclerosis- a Phase II Study of Safety and Activity of Low Dose Interleukin-2
Study Start Date : September 2015
Actual Primary Completion Date : December 2015
Actual Study Completion Date : May 2016


Arm Intervention/treatment
Placebo Comparator: Placebo

Patients in this arm will receive sub-cutaneous injections of placebo (same vehicle as for experimental arms, and same volume) for 5 consecutive days at the beginning of three consecutive months (a total of 15 injections, 5 per month for 3 months).

Intervention: Placebo

Drug: Placebo
Patients in this arm will receive sub-cutaneous injections of placebo (same vehicle as for experimental arms, and same volume) for 5 consecutive days at the beginning of three consecutive months (a total of 15 injections, 5 per month for 3 months).

Experimental: 1.0 IL-2

Patients in this arm will receive sub-cutaneous injections corresponding to 1.0 MIU of IL-2 per injection for 5 consecutive days at the beginning of three consecutive months (a total of 15 injections, 5 per month for 3 months).

Intervention: 1.0 MIU IL-2 per day

Drug: 1.0 MIU IL-2 per day
Patients in this arm will receive sub-cutaneous injections corresponding to 1.0 MIU of IL-2 per injection for 5 consecutive days at the beginning of three consecutive months (a total of 15 injections, 5 per month for 3 months).
Other Names:
  • Aldesleukine
  • Proleukin

Experimental: 2.0 IL-2

Patients in this arm will receive sub-cutaneous injections corresponding to 2.0 MIU of IL-2 per injection for 5 consecutive days at the beginning of three consecutive months (a total of 15 injections, 5 per month for 3 months).

Intervention: 2.0 MIU IL-2 per day

Drug: 2.0 MIU IL-2 per day
Patients in this arm will receive sub-cutaneous injections corresponding to 2.0 MIU of IL-2 per injection for 5 consecutive days at the beginning of three consecutive months (a total of 15 injections, 5 per month for 3 months).
Other Names:
  • Aldesleukine
  • Proleukin




Primary Outcome Measures :
  1. CD4+ CD25+ CD127- FoxP3+(Treg) cells: change in percentage of total lymphocytes [ Time Frame: Day 8 ]
    Treg refers to regulatory T cells


Secondary Outcome Measures :
  1. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 1 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.

  2. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 2 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.

  3. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 3 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.

  4. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 4 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.

  5. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 5 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.

  6. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 6 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.

  7. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 7 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.

  8. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 8 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.

  9. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 29 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.

  10. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 30 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.

  11. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 31 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.

  12. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 32 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.

  13. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 33 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.

  14. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 34 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.

  15. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 35 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.

  16. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 36 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.

  17. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 57 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.

  18. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 58 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.

  19. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 59 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.

  20. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 60 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.

  21. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 61 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.

  22. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 62 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.

  23. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 63 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.

  24. Presence/absence of specific, pre-defined adverse events. [ Time Frame: Day 64 ]
    The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.

  25. Presence/absence of abnormal vital signs [ Time Frame: Day 1 ]
    (based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)

  26. Presence/absence of abnormal vital signs [ Time Frame: Day 8 ]
    (based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)

  27. Presence/absence of abnormal vital signs [ Time Frame: Day 29 ]
    (based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)

  28. Presence/absence of abnormal vital signs [ Time Frame: Day 57 ]
    (based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)

  29. Presence/absence of abnormal vital signs [ Time Frame: Day 64 ]
    (based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)

  30. Presence/absence of abnormal vital signs [ Time Frame: Week 13 ]
    (based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)

  31. Presence/absence of abnormal vital signs [ Time Frame: Week 25 ]
    (based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)

  32. MedDRA classification of all adverse events throughout the study [ Time Frame: Week 25 ]
    MedDRA refers to "Medical Dictionary for Regulatory Activities"

  33. Thyroid function: blood T4 [ Time Frame: Baseline (day 0 to day -15) ]
  34. Thyroid function: blood T4 [ Time Frame: Week 13 ]
  35. Thyroid function: blood TSH [ Time Frame: Baseline (day 0 to day -15) ]
  36. Thyroid function: blood TSH [ Time Frame: Week 13 ]
  37. Presence/absence of clinically significant abnormality on a lung x-ray [ Time Frame: Baseline (day 0 to day -15) ]
  38. Presence/absence of clinically significant abnormality on a lung x-ray [ Time Frame: Week 13 ]
  39. Presence/absence of clinically significant abnormality on an electrocardiogram [ Time Frame: Baseline (day 0 to day -15) ]
  40. Presence/absence of clinically significant abnormality on an electrocardiogram [ Time Frame: Week 13 ]
  41. Presence/absence of a clinically significant abnormality among routine laboratory tests [ Time Frame: Day 1 ]

    The routine blood tests considered are:

    • haemogram (hemoglobin, hematocrit, red blood cell count, white blood cell count, leukocyte formula, platelets, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration )
    • blood biochemistry (ionogram, urea, creatinine, glucose, C reactive protein, procalcitonin, protein, albumin)
    • liver function panel (aspartate transaminase, alanine transaminase, gamma-glutamyl transpeptidase, bilirubin)
    • iron metabolism (iron, ferritin, transferrin)

  42. Presence/absence of a clinically significant abnormality among routine laboratory tests [ Time Frame: Day 8 ]

    The routine blood tests considered are:

    • haemogram (hemoglobin, hematocrit, red blood cell count, white blood cell count, leukocyte formula, platelets, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration)
    • blood biochemistry (ionogram, urea, creatinine, glucose, C reactive protein, procalcitonin, protein, albumin)
    • liver function panel (aspartate transaminase, alanine transaminase, gamma-glutamyl transpeptidase, bilirubin)
    • iron metabolism (iron, ferritin, transferrin)

  43. Presence/absence of a clinically significant abnormality among routine laboratory tests [ Time Frame: Day 29 ]

    The routine blood tests considered are:

    • haemogram (hemoglobin, hematocrit, red blood cell count, white blood cell count, leukocyte formula, platelets, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration)
    • blood biochemistry (ionogram, urea, creatinine, glucose, C reactive protein, procalcitonin, protein, albumin)
    • liver function panel (aspartate transaminase, alanine transaminase, gamma-glutamyl transpeptidase, bilirubin)
    • iron metabolism (iron, ferritin, transferrin)

  44. Presence/absence of a clinically significant abnormality among routine laboratory tests [ Time Frame: Day 57 ]

    The routine blood tests considered are:

    • haemogram (hemoglobin, hematocrit, red blood cell count, white blood cell count, leukocyte formula, platelets, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration)
    • blood biochemistry (ionogram, urea, creatinine, glucose, C reactive protein, procalcitonin, protein, albumin)
    • liver function panel (aspartate transaminase, alanine transaminase, gamma-glutamyl transpeptidase, bilirubin)
    • iron metabolism (iron, ferritin, transferrin)

  45. Presence/absence of a clinically significant abnormality among routine laboratory tests [ Time Frame: Day 64 ]

    The routine blood tests considered are:

    • haemogram (hemoglobin, hematocrit, red blood cell count, white blood cell count, leukocyte formula, platelets, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration)
    • blood biochemistry (ionogram, urea, creatinine, glucose, C reactive protein, procalcitonin, protein, albumin)
    • liver function panel (aspartate transaminase, alanine transaminase, gamma-glutamyl transpeptidase, bilirubin)
    • iron metabolism (iron, ferritin, transferrin)

  46. Presence/absence of a clinically significant abnormality among routine laboratory tests [ Time Frame: Week 13 ]

    The routine blood tests considered are:

    • haemogram (hemoglobin, hematocrit, red blood cell count, white blood cell count, leukocyte formula, platelets, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration)
    • blood biochemistry (ionogram, urea, creatinine, glucose, C reactive protein, procalcitonin, protein, albumin)
    • liver function panel (aspartate transaminase, alanine transaminase, gamma-glutamyl transpeptidase, bilirubin)
    • iron metabolism (iron, ferritin, transferrin)

  47. Presence/absence of a clinically significant abnormality among routine laboratory tests [ Time Frame: Week 25 ]

    The routine blood tests considered are:

    • haemogram (hemoglobin, hematocrit, red blood cell count, white blood cell count, leukocyte formula, platelets, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration)
    • blood biochemistry (ionogram, urea, creatinine, glucose, C reactive protein, procalcitonin, protein, albumin)
    • liver function panel (aspartate transaminase, alanine transaminase, gamma-glutamyl transpeptidase, bilirubin)
    • iron metabolism (iron, ferritin, transferrin)

  48. Vital capacity (% of normal) [ Time Frame: Baseline (day 0 to day -15) ]
    This is a measure of respiratory function.

  49. Vital capacity (% of normal) [ Time Frame: Day 1 ]
    This is a measure of respiratory function.

  50. Vital capacity (% of normal) [ Time Frame: Week 13 ]
    This is a measure of respiratory function.

  51. Vital capacity (% of normal) [ Time Frame: Week 25 ]
    This is a measure of respiratory function.

  52. The ALSFRS Questionnaire [ Time Frame: Day 1 ]
  53. The ALSFRS Questionnaire [ Time Frame: Day 29 ]
  54. The ALSFRS Questionnaire [ Time Frame: Day 57 ]
  55. The ALSFRS Questionnaire [ Time Frame: Week 13 ]
  56. The ALSFRS Questionnaire [ Time Frame: Week 25 ]
  57. Tregs (absolute number and % CF4+ cells) [ Time Frame: Day 1 ]
  58. Tregs (absolute number and % CF4+ cells) [ Time Frame: Day 8 ]
  59. Tregs (absolute number and % CF4+ cells) [ Time Frame: Day 57 ]
  60. Tregs (absolute number and % CF4+ cells) [ Time Frame: Day 64 ]
  61. Tregs (absolute number and % CF4+ cells) [ Time Frame: Week 13 ]
  62. Tregs (absolute number and % CF4+ cells) [ Time Frame: Week 25 ]
  63. Total lymphocyte number [ Time Frame: Day 1 ]
  64. Total lymphocyte number [ Time Frame: Day 8 ]
  65. Total lymphocyte number [ Time Frame: Day 57 ]
  66. Total lymphocyte number [ Time Frame: Day 64 ]
  67. Total lymphocyte number [ Time Frame: Week 13 ]
  68. Total lymphocyte number [ Time Frame: Week 25 ]
  69. CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes [ Time Frame: Day 1 ]
  70. CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes [ Time Frame: Day 8 ]
  71. CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes [ Time Frame: Day 57 ]
  72. CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes [ Time Frame: Day 64 ]
  73. CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes [ Time Frame: Week 13 ]
  74. CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes [ Time Frame: week 25 ]
  75. effector T cells: number and % of CD4 cells [ Time Frame: Day 1 ]
    This is measured as CD4+ lymphocytes minus regulatory T cells

  76. effector T cells: number and % of CD4 cells [ Time Frame: Day 8 ]
    This is measured as CD4+ lymphocytes minus regulatory T cells

  77. effector T cells: number and % of CD4 cells [ Time Frame: Day 57 ]
    This is measured as CD4+ lymphocytes minus regulatory T cells

  78. effector T cells: number and % of CD4 cells [ Time Frame: Day 64 ]
    This is measured as CD4+ lymphocytes minus regulatory T cells

  79. effector T cells: number and % of CD4 cells [ Time Frame: Week 13 ]
    This is measured as CD4+ lymphocytes minus regulatory T cells

  80. effector T cells: number and % of CD4 cells [ Time Frame: Week 25 ]
    This is measured as CD4+ lymphocytes minus regulatory T cells

  81. Phosphorylated neurofilament heavy protein (pNfH) levels in serum [ Time Frame: day 1 ]
  82. Light chain neurofilament levels in serum [ Time Frame: Day 1 ]
  83. Light chain neurofilament levels in serum [ Time Frame: Week 13 ]

Other Outcome Measures:
  1. Age (years) [ Time Frame: Baseline ]
  2. Sex (male/female) [ Time Frame: Baseline ]
  3. Body mass index (kg/m^2) [ Time Frame: Baseline ]
  4. Disease duration from date of first symptoms (fatigue, weakness) [ Time Frame: Baseline ]
  5. The patient's current Riluzole posology [ Time Frame: Baseline to week 25 ]
  6. The patient's currentposology for other concomitant treatments [ Time Frame: Baseline to week 25 ]
  7. Description of concomitant treatments, if any [ Time Frame: Throughout study, up to 25 weeks ]
  8. Routine serology results dating to within the last 30 days: HIV-1 (positive/negative ?) [ Time Frame: Baseline ]
  9. Routine serology results dating to within the last 30 days: Epstein Barr Virus (positive/negative ?) [ Time Frame: Baseline ]
  10. Routine serology results dating to within the last 30 days: cytomegalovirus (positive/negative ?) [ Time Frame: Baseline ]


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 to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • The patient has been correctly informed
  • The patient must have given his/her informed and signed consent.
  • The patient must be insured or beneficiary of a health insurance plan.
  • The patient is at least 18 years old and less than 75 years old
  • Probable, or laboratory-supported probable or definite ALS as defined by El Escorial Revised ALS diagnostic criteria (according to Airlie House Conference 1988)
  • Stable on riluzole treatment for more than 3 months with liver function test results < 2ULN
  • Disease duration ≤ 5 years
  • Vital capacity ≥ 70% of normal
  • Ability to swallow without the requirement for nasogastric or PEG feeding
  • Agreement for patient to use an adequate method of contraception throughout the study and for 2 weeks after post study visit
  • The patient is available and willing to participate in seven study visits occurring at the CHU within the next six months

Exclusion Criteria:

  • The patient is participating in another interventional study
  • Within the past three months, the patient has participated in another interventional
  • The patient is in an exclusion period determined by a previous study
  • The patient is under judicial protection
  • The patient is an adult under guardianship
  • The patient refuses to sign the consent
  • It is impossible to correctly inform the patient
  • Other life threatening disease
  • Presence of contra-indicated concomitant treatments or with potential neuroprotective benefit (see section 11.2 of the protocol)
  • Presence of tracheostomy or non-invasive ventilation
  • Use of Percutaneous endoscopic gastrostomy (PEG) or nasogastric tube
  • Presence of clinical infection (treated or untreated)
  • Positive serology for CMV, EBV (confirmed by viral load), or HIV
  • Vaccination within 8 weeks prior to first experimental dosing
  • Other disease precluding functional assessments
  • Cancer within the past 5 years (except stable non-metastatic basal cell skin carcinoma or in situ carcinoma of the cervix)
  • Severe cardiac or pulmonary disease
  • Documented auto-immune disorders except asymptomatic Hashimoto thyroiditis
  • Women of child bearing age without contraception or pregnant or breast feeding
  • Any clinically significant laboratory abnormality (excepting cholesterol, triglyceride and glucose)

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): NCT02059759


Locations
France
CHRU de Montpellier - Hôpital Gui de Chauliac
Montpellier, France, 34295
Sponsors and Collaborators
Centre Hospitalier Universitaire de Nīmes
Investigators
Study Director: Raul Juntas-Morales, MD CHRU de Montpellier

Responsible Party: Centre Hospitalier Universitaire de Nīmes
ClinicalTrials.gov Identifier: NCT02059759     History of Changes
Other Study ID Numbers: LOCAL/2014/WC-01
2014-001327-71 ( EudraCT Number )
First Posted: February 11, 2014    Key Record Dates
Last Update Posted: June 1, 2016
Last Verified: May 2016

Keywords provided by Centre Hospitalier Universitaire de Nīmes:
low-dose interleukin 2

Additional relevant MeSH terms:
Sclerosis
Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Aldesleukin
Interleukin-2
Antineoplastic Agents
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents