Clinical trial NCT00128193: Leprosy Skin Test Antigens Trial
Official title: Two New Leprosy Skin Test Antigens: MLSA-LAM and MLCwA Phase II Study in a Leprosy-Endemic Region
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leprosy
Keywords: leprosy, Mycobacterium leprae, Hansen's Disease, skin test, Nepal
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2005-08-09
Enrollment: 260
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

Brief summary: The purpose of this study is to see how healthy people and leprosy patients react to 2 new skin tests for detecting leprosy. The study will evaluate the new skin tests that may aid in measuring the number of people exposed to leprosy and enable its diagnosis and treatment at an earlier stage. Participant's ages 18-60 living in Kathmandu, Nepal will be enrolled. Stages A and B of the study will use the skin test in healthy volunteers. Stage C will use the skin test in high risk volunteers (including individuals with leprosy), healthy individuals in contact with leprosy patients and individuals with tuberculosis (TB, lung disease). Study procedures will include injections, physical exam, and blood testing. Injection sites will be checked several times during the participant's study involvement (5 hours of time spread over approximately 1 month). Volunteers screened for the study, which have leprosy or tuberculosis will be treated or referred for treatment.

Detailed description: This double-blind Phase II clinical trial will be conducted in 3 stages to evaluate 2 new leprosy skin test antigens, Mycobacterium (M.) leprae Soluble Antigen (MLSA)-Lipoarabinomannan (LAM) and M. leprae Cell Wall Antigen (MLCwA), as diagnostic-epidemiological tools designed to measure incidence of leprosy infection in Kathmandu, Nepal, a leprosy endemic area. Stage A will provide an initial indication of safety of the 2 new test antigens in 10 healthy members of the leprosy endemic population (5 subjects per antigen at 2 dosages each). Stage B will expand this analysis by an additional 90 healthy subjects (45 subjects per antigen). If any subjects in Stage A or B show ulcerations at the 1.0 mcg dose of MLSA-LAM or MLCwA test sites, then only the 0.1 mcg dose will be used for Stage C. The final stage, Stage C, is divided into 2 parts. The first part, Stage C-1, will assess safety of both antigens at the high dose (1.0 mcg) in populations at a higher risk of developing ulcerations at skin test sites. Eighty subjects will be recruited: 20 household contacts of Borderline Lepromatous Leprosy (BL) / Lepromatous Leprosy (LL) leprosy patients, 20 BL/LL leprosy patients, 20 Borderline Tuberculoid Leprosy (BT) / Tuberculoid Leprosy (TT) patients and 20 tuberculosis (TB) patients. The second part, Stage C-1b, is a continuation of Stage C-1 with the same number of subjects recruited from the same groups to assess the reactivity of both antigens at the low dose (0.1 mcg). This study will define a positive skin test reaction for MLSA-LAM and MLCwA, and this definition will be used in estimating sensitivity and specificity for each skin test antigen and dosage. It is expected that the BT/TT leprosy patients and healthy contacts of leprosy patients will have larger indurations at both M. leprae-derived antigen sites and a variable reaction at the tuberculin/Purified Protein Derivative (PPD) site. The non-contacts, BL/LL leprosy patients, and TB patients will have smaller indurations at all leprosy skin test sites and a variable reaction at the tuberculin/PPD site. Finally, the TB patients will react with a large induration at the tuberculin/PPD site. Primary study objectives are to evaluate safety of these 2 new leprosy skin test antigens and to estimate specificity and sensitivity of these skin test antigens in detecting M. leprae infection by: selecting a dosage of the MLSA-LAM and MLCwA antigens that causes minimal induration in healthy non-exposed subjects; selecting a size of induration that will serve as a definition of a positive skin test reaction for MLSA-LAM and MLCwA in leprosy patients; and comparing proportion of positive skin test reactors in healthy subjects to proportion in BT/TT and BL/LL leprosy patients, contacts of leprosy patients, and TB patients. Secondary study objectives are to compare mean size of induration in response to each test antigen in healthy subjects versus BT/TT and BL/LL leprosy patients, contacts of leprosy patients, and TB patients as a measure of specificity and sensitivity; to compare the specificity and sensitivity of the 2 new antigens with tuberculin/PPD in patients with clinical leprosy, contacts of leprosy patients, and healthy unexposed subjects (non-patient contacts); to quantify release of IFN-gamma from lymphocytes in whole blood from leprosy patients, leprosy patient contacts, TB patients, and healthy nonexposed subjects, following in vitro stimulation with leprosy skin test antigens and PPD, using the QuantiFERON-CMI (Cellestis Limited, Valentia California) kit. Results will be compared to the magnitude of the skin test response; and to determine if antibodies against a M. leprae specific anti

Eligibility criteria: Inclusion Criteria:

All Subjects

* Between the ages of 18 and 60 years old
* Male or female; not less than 30 percent for one gender
* Agree to participate in the study after verbal explanation by the physician and nurses, as indicated by signing an informed consent form
* Weight greater than 30 Kg (female) and 38 Kg (male)
* Available for skin test readings
* Nepali residents, including expatriates from India

Healthy, Non-Contacts

* Healthy (determined by history and physical examination)
* No household or working contact with tuberculosis or leprosy patients

Contacts of Leprosy Patients

* Healthy (determined by history and physical examination)
* Household contact of a person with leprosy for at least 6 months duration, and within 6 months of this study, or a person professionally exposed to leprosy for at least 5 years duration, and within 6 months of this study

Persons with Leprosy

* Having one or more of the following symptoms:

  1. Hypopigmented or erythematous skin lesion(s) with definite loss of sensation
  2. Damage to the peripheral nerves as demonstrated by palpable thickening with or without impairment of sensation and/or weakness of the muscles of hands, feet or face
  3. Presence of acid-fast bacilli in slit skin smears
  4. Histological changes diagnostic of leprosy in skin biopsy
* Receiving standard multi drug treatment for leprosy or completed treatment for leprosy no more than 4 years prior to study enrollment

Persons with Tuberculosis

* Having active tuberculosis as defined by one of the following:

  1. Extra-pulmonary tuberculosis if confirmed by culture
  2. Pulmonary tuberculosis, defined as:
* Having a history of a productive cough of more than 3 weeks duration that may be accompanied by night sweats, loss of appetite, haemoptysis, weight loss, chest pain, or shortness of breath, and
* Having one or more of the following diagnostic criteria:
* Sputum smear-positive, defined as one or more of the following: at least 2 of 3 successive sputum samples positive for acid-fast bacilli by microscopy; or at least one sputum specimen positive and x-ray abnormalities consistent with pulmonary tuberculosis; or at least one positive sputum specimen that is culture positive for Mycobacterium tuberculosis
* Sputum smear-negative, defined as three sputum specimens negative for acid-fast bacilli but with x-ray evidence consistent with pulmonary tuberculosis and that does not clear with non-tuberculosis antibiotics; or three sputum samples negative for acid-fast bacilli by microscopy but culture positive for Mycobacterium tuberculosis
* Completed the intensive phase of chemotherapy for tuberculosis, but still undergoing the continuation phase of therapy

Exclusion Criteria:

All subjects

* Pregnant (as determined by a urine pregnancy test performed on females of child-bearing age on Day 0, prior to admission into the study) or lactating females
* Currently on oral corticosteroid or other immunosuppressive treatment
* Cancer, diabetes, or other chronic illness
* Extra-pulmonary tuberculosis not confirmed by culture
* Known hypersensitivities or allergies
* Expatriates other than those from India
* Participation in an earlier stage of this study
* Concurrent participation in another clinical trial

Healthy, Non-Contacts

* History of treated tuberculosis or leprosy
* Clinical signs of leprosy or tuberculosis
* Known contact with persons with leprosy or tuberculosis

Healthy Contacts of Leprosy Patients

* History of treated tuberculosis or leprosy
* Clinical signs of leprosy or tuberculosis

Persons with Leprosy

* Leprosy patients in reversal reaction or erythema nodosum leprosum (ENL) reaction or those being treated with corticosteroids or thalidomide for these conditions
* History of treated tuberculosis
* Clinical signs of tuberculosis
* Completed full course of standard multidrug treatment (MDT) for leprosy more than 4 years prior to study enrollment

Persons with Tuberculosis

* History of treated leprosy
* Clinical signs of leprosy
* Completed full course of standard tuberculosis treatment
* Known contact with leprosy patients

Primary outcomes:
measure: Number of Participants With Reactions to the Antigen Mycobacterium (M.) Leprae Soluble Antigen (MLSA)-Lipoarabinomannan (LAM) at Doses of 0.1 Microgram
timeFrame: Up to 28 Days
measure: Number of Participants With the Reaction of Itching to the Antigen Mycobacterium (M.) Leprae Soluble Antigen (MLSA)-Lipoarabinomannan (LAM) at Doses of 0.1 Microgram
timeFrame: Up to 28 Days
measure: Number of Participants With Reactions to the Antigen Mycobacterium (M.) Leprae Soluble Antigen (MLSA)-Lipoarabinomannan (LAM) at Doses of 1.0 Microgram
timeFrame: Up to 28 Days
measure: Number of Participants With the Reaction of Itching to the Antigen Mycobacterium (M.) Leprae Soluble Antigen (MLSA)-Lipoarabinomannan (LAM) at Doses of 1.0 Microgram
timeFrame: Up to 28 Days
measure: Number of Participants With Reactions to the Antigen M. Leprae Cell Wall Antigen (MLCwA) at Doses of 0.1 Microgram
timeFrame: Up to 28 Days
measure: Number of Participants With Reaction of Itching to the Antigen M. Leprae Cell Wall Antigen (MLCwA) at Doses of 0.1 Microgram
timeFrame: Up to 28 Days
measure: Number of Participants With Reactions to the Antigen M. Leprae Cell Wall Antigen (MLCwA) at Doses of 1.0 Microgram
timeFrame: Up to 28 Days
measure: Number of Participants With the Reaction of Itching to the Antigen M. Leprae Cell Wall Antigen (MLCwA) at Doses of 1.0 Microgram
timeFrame: Up to 28 Days
measure: Number of Participants With Reactions to the Antigen Purified Protein Derivative (PPD)
timeFrame: Up to 28 Days
measure: Number of Participants With the Reaction of Itching to the Antigen Purified Protein Derivative (PPD)
timeFrame: Up to 28 Days
measure: Mean Diameter of Erythema at Site of Injection With the Antigen Mycobacterium (M.) Leprae Soluble Antigen (MLSA)-Lipoarabinomannan (LAM) at Doses of 0.1 Micrograms
timeFrame: Day 3
measure: Mean Diameter of Erythema at Site of Injection With the Antigen Mycobacterium (M.) Leprae Soluble Antigen (MLSA)-Lipoarabinomannan (LAM) at Doses of 0.1 Micrograms
timeFrame: Day 7
measure: Mean Diameter of Erythema at Site of Injection With the Antigen Mycobacterium (M.) Leprae Soluble Antigen (MLSA)-Lipoarabinomannan (LAM) at Doses of 1.0 Micrograms
timeFrame: Day 3
measure: Mean Diameter of Erythema at Site of Injection With the Antigen Mycobacterium (M.) Leprae Soluble Antigen (MLSA)-Lipoarabinomannan (LAM) at Doses of 1.0 Micrograms
timeFrame: Day 7
measure: Mean Diameter of Erythema at Site of Injection With the Antigen M. Leprae Cell Wall Antigen (MLCwA) at Doses of 0.1 Micrograms
timeFrame: Day 3
measure: Mean Diameter of Erythema at Site of Injection With the Antigen M. Leprae Cell Wall Antigen (MLCwA) at Doses of 0.1 Micrograms
timeFrame: Day 7
measure: Mean Diameter of Erythema at Site of Injection With the Antigen M. Leprae Cell Wall Antigen (MLCwA) at Doses of 1.0 Micrograms
timeFrame: Day 3
measure: Mean Diameter of Erythema at Site of Injection With the Antigen M. Leprae Cell Wall Antigen (MLCwA) at Doses of 1.0 Micrograms
timeFrame: Day 7
measure: Mean Diameter of Erythema at Site of Injection With the Antigen Purified Protein Derivative (PPD)
timeFrame: Day 3
measure: Mean Diameter of Erythema at Site of Injection With the Antigen Purified Protein Derivative (PPD)
timeFrame: Day 7
measure: Mean Diameter of Induration at Site of Injection With the Antigen Mycobacterium (M.) Leprae Soluble Antigen (MLSA)-Lipoarabinomannan (LAM) at Doses of 0.1 Micrograms
timeFrame: Day 3
measure: Mean Diameter of Induration at Site of Injection With the Antigen Mycobacterium (M.) Leprae Soluble Antigen (MLSA)-Lipoarabinomannan (LAM) at Doses of 0.1 Micrograms
timeFrame: Day 7
measure: Mean Diameter of Induration at Site of Injection With the Antigen Mycobacterium (M.) Leprae Soluble Antigen (MLSA)-Lipoarabinomannan (LAM) at Doses of 1.0 Micrograms
timeFrame: Day 2
measure: Mean Diameter of Induration at Site of Injection With the Antigen Mycobacterium (M.) Leprae Soluble Antigen (MLSA)-Lipoarabinomannan (LAM) at Doses of 1.0 Micrograms
timeFrame: Day 3
measure: Mean Diameter of Induration at Site of Injection With the Antigen Mycobacterium (M.) Leprae Soluble Antigen (MLSA)-Lipoarabinomannan (LAM) at Doses of 1.0 Micrograms
timeFrame: Day 7
measure: Mean Diameter of Induration at Site of Injection With the Antigen M. Leprae Cell Wall Antigen (MLCwA) at Doses of 0.1 Micrograms
timeFrame: Day 3
measure: Mean Diameter of Induration at Site of Injection With the Antigen M. Leprae Cell Wall Antigen (MLCwA) at Doses of 0.1 Micrograms
timeFrame: Day 7
measure: Mean Diameter of Induration at Site of Injection With the Antigen M. Leprae Cell Wall Antigen (MLCwA) at Doses of 1.0 Micrograms
timeFrame: Day 2
measure: Mean Diameter of Induration at Site of Injection With the Antigen M. Leprae Cell Wall Antigen (MLCwA) at Doses of 1.0 Micrograms
timeFrame: Day 3
measure: Mean Diameter of Induration at Site of Injection With the Antigen M. Leprae Cell Wall Antigen (MLCwA) at Doses of 1.0 Micrograms
timeFrame: Day 7
measure: Mean Diameter of Induration at Site of Injection With the Antigen Purified Protein Derivative (PPD)
timeFrame: Day 2
measure: Mean Diameter of Induration at Site of Injection With the Antigen Purified Protein Derivative (PPD)
timeFrame: Day 3
measure: Mean Diameter of Induration at Site of Injection With the Antigen Purified Protein Derivative (PPD)
timeFrame: Day 7
measure: Mean Diameter of Induration at Site of Injection With the Antigen Purified Protein Derivative (PPD)
timeFrame: Day 28
measure: Number of Participants With QuantiFERON Responses Based on the Presence or Absence of Induration at the Injection Site for the Antigen MLSA-LAM at Doses of 0.1 Microgram.
timeFrame: Day 0 for QuantiFERON; Days 3, 7, and 28 for induration
measure: Number of Participants With QuantiFERON Responses Based on the Presence or Absence of Induration at the Injection Site for the Antigen MLSA-LAM at Doses of 1.0 Microgram.
timeFrame: Day 0 for QuantiFERON; Days 3, 7, and 28 for induration
measure: Number of Participants With QuantiFERON Responses Based on the Presence or Absence of Induration at the Injection Site for the Antigen MLCwA at Doses of 0.1 Microgram.
timeFrame: Day 0 for QuantiFERON; Days 3, 7, and 28 for induration
measure: Number of Participants With QuantiFERON Responses Based on the Presence or Absence of Induration at the Injection Site for the Antigen MLCwA at Doses of 1.0 Microgram.
timeFrame: Day 0 for QuantiFERON; Days 3, 7, and 28 for induration
measure: Number of Participants With QuantiFERON Responses Based on the Presence or Absence of Induration at the Injection Site for the Antigen PPD.
timeFrame: Day 0 for QuantiFERON; Days 3, 7, and 28 for induration
measure: Number of Participants Positive for Phenolic Glycolipid-1 (PGL-1) by QuantiFERON Results and the Presence or Absence of Induration at the Injection Site for the Antigen MLSA-LAM at Doses of 0.1 Microgram
timeFrame: Day 0 for PGL-1 and QuantiFERON; Days 3, 7, and 28 for induration
measure: Number of Participants Positive for Phenolic Glycolipid-1 (PGL-1) by QuantiFERON Results and the Presence or Absence of Induration at the Injection Site for the Antigen MLSA-LAM at Doses of 1.0 Microgram
timeFrame: Day 0 for PGL-1 and QuantiFERON; Days 3, 7, and 28 for induration
measure: Number of Participants Positive for Phenolic Glycolipid-1 (PGL-1) by QuantiFERON Results and the Presence or Absence of Induration at the Injection Site for the Antigen MLCwA at Doses of 0.1 Microgram
timeFrame: Day 0 for PGL-1 and QuantiFERON; Days 3, 7, and 28 for induration
measure: Number of Participants Positive for Phenolic Glycolipid-1 (PGL-1) by QuantiFERON Results and the Presence or Absence of Induration at the Injection Site for the Antigen MLCwA at Doses of 1.0 Microgram
timeFrame: Day 0 for PGL-1 and QuantiFERON; Days 3, 7, and 28 for induration
measure: Number of Participants Positive for Phenolic Glycolipid-1 (PGL-1) by QuantiFERON Results and the Presence or Absence of Induration at the Injection Site for the Antigen PPD
timeFrame: Day 0 for PGL-1 and QuantiFERON; Days 3, 7, and 28 for induration
Secondary outcomes:
Other outcomes:
Locations:
city: Fort Collins
country: United States
facility: Colorado State University - Microbiology, Immunology & Pathology
state: Colorado
city: Kathmandu
country: Nepal
facility: Anandaban Hospital
city: Kathmandu
country: Nepal
facility: Green Pastures Hospitals
city: Kathmandu
country: Nepal
facility: Lalitpur Nursing Campus
city: Kathmandu
country: Nepal
facility: Patan Hospital
city: Kathmandu
country: Nepal
facility: Tribhuvan University - Anandaban Hospital
Study officials:
References:
citation: Rivoire BL, Groathouse NA, TerLouw S, Neupane KD, Ranjit C, Sapkota BR, Khadge S, Kunwar CB, Macdonald M, Hawksworth R, Thapa MB, Hagge DA, Tibbals M, Smith C, Dube T, She D, Wolff M, Zhou E, Makhene M, Mason R, Sizemore C, Brennan PJ. Safety and efficacy assessment of two new leprosy skin test antigens: randomized double blind clinical study. PLoS Negl Trop Dis. 2014 May 29;8(5):e2811. doi: 10.1371/journal.pntd.0002811. eCollection 2014.