Prophylaxis of Visceral Leishmaniasis Relapses in HIV Co-infected Patients With Pentamidine: a Cohort Study

• Sponsor: Institute of Tropical Medicine, Belgium (Other)
• Overall Status: Completed
• CT.gov ID: NCT01360762
• Collaborator: Addis Ababa University (Other), University of Gondar (Other), Tigray Regional Health Bureau, Tigray Region (Other), Amhara Regional Health Bureau, Amhara Region (Other), Medecins Sans Frontieres, Netherlands (Other), Leishmania East Africa Platform (LEAP) (Other), Drugs for Neglected Diseases (Other)
• Enrollment: 74
• Locations: 3
• Arm: 1
• Duration (Months): 48
• Patients Per Site: 24.7
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

Visceral leishmaniosis (VL) is widely reported in Ethiopia, with about 30% of cases being associated with human immunodeficiency virus (HIV). In absence of antiretroviral treatment (ART), poor prognosis, high mortality and high relapse rates are characteristic of Ethiopian VL patients with HIV co-infection. Conversely, co-infection can be successfully managed via a combination of effective treatment of the initial episode, timely ART and prevention of relapses.

Actually, until cellular immunity returns with ART, the patient is at risk of VL relapses, which can result in death, severe illness, reduced ART efficacy, drug-resistance and possibly transmission of drug-resistant Leishmania donovani. Patients most vulnerable to relapses are those with high levels of immunosuppression, with previous VL episodes, or with opportunistic infections (OIs). The most important factor to prevent relapses seems to be the clearance of visible parasites.

Limited studies in Europe show that HIV co-infected patients may benefit from secondary prevention with antimonials (part of mainstay treatment for VL in Ethiopia) and pentamidine (PM), not used for VL treatment in Africa. Such maintenance treatment has not been studied in African VL, but the poor outcomes without secondary prevention highlight a need of better care to patients at risk of relapse.

This prospective cohort study aims at documenting the patient's outcomes of secondary prophylaxis with PM in VL-HIV co-infection, in terms of time to relapse or death, safety and feasibility, before it can be considered for general use in Ethiopia. A placebo group is not included, due to the clear advantages of the intervention to the patient population.

Condition or Disease	Intervention/Treatment	Phase
Visceral Leishmaniosis; HIV-infection/Aids	Drug: Pentamidine	Phase 3

Detailed Description

Visceral leishmaniosis (VL) in Ethiopia has been reported in different parts of the country, with approximately 30% of cases being associated with human immunodeficiency virus (HIV). The ruralisation of HIV epidemic in VL endemic areas will hamper efforts to control VL. Clinical experience in Ethiopia has shown that anti-leishmanial treatment in the absence of anti-retroviral therapy (ART) does not result in favourable outcomes: poor prognosis, high mortality and relapse rates are characteristic of Ethiopian VL patients with HIV co-infection. The effective management of the initial VL episode, timely ART, and prevention of relapses should be the cornerstones of effective management of HIV/VL co-infection.

However, parasitological cure of VL in HIV co-infected patients cannot easily be established, and until cellular immunity returns with ART, the patient is at risk of relapses of VL, which can result in death, severe illness, negative effect on ART efficacy leading to other opportunistic infections (OIs), emergence of drug-resistant parasites, and possibly to transmission of drug-resistant Leishmania donovani. Patients most vulnerable to relapses are

1. those with high levels of immunosuppression, 2) patients with previous VL episodes, and 3) patients with OIs.

ART reduces the risk of VL relapse/recurrence by ~50%, while the type of anti-leishmanial primary treatment has little effect on relapses; the most important factor seems to be clearance of visible parasites (if residual parasites are seen at the end of treatment, the relapse rate is 100%).

Limited studies in Europe show that HIV co-infected patients may benefit from secondary prevention, by significantly prolonging the relapse-free period. The drugs studied for secondary prophylaxis in Europe have been meglumine antimoniate and AmBisome, which are part of mainstay treatment for VL in Ethiopia, and pentamidine (PM), which is not used for VL treatment in Africa. The effect of such maintenance treatment has not been studied in African VL, but the poor outcomes without secondary prevention highlight a clear need to offer better care to patients at high risk of relapse.

Indeed, secondary prophylaxis is generally recommended in Europe and the United States (see the 2009 Center for Disease Control guidelines). PM 4 mg/kg intravenous (IV) every 3-4 weeks has been proposed as secondary prophylaxis, and it is already used in countries like United Kingdom and Spain.

Consequently, this prospective cohort study aims at documenting the patient's outcomes of secondary prophylaxis with PM in VL-HIV co-infection, in terms of time to relapse or death, safety and feasibility, before it can be considered for more general use in Ethiopia. A placebo group is not included, due to the clear advantages of the intervention to the patient population targeted herewith. Furthermore as other available VL treatments are used as main line treatments, they cannot be considered as alternative comparators, given the potential risk of rapid emergence of drug resistance and subsequent spread in areas of anthroponotic VL.

Study Design

• Study Type: Interventional
• Actual Enrollment: 74 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Secondary Prophylaxis of Visceral Leishmaniasis Relapses in HIV Co-infected Patients Using Pentamidine as a Prophylactic Agent: a Prospective Cohort Study
• Study Start Date: Nov 1, 2011
• Actual Primary Completion Date: Nov 1, 2015
• Actual Study Completion Date: Nov 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Pentamidine Secondary Prophylaxis (PSP) Patients with co-infection of human immunodeficiency virus (HIV)and visceral leishmaniosis (VL), having being treated for VL, are allocated to pentamidine secondary prophylaxis, to prevent VL relapses. The treatment period is of 12 months, plus an "extended treatment period" of 0 to 6 months depending on the immunosuppression status, plus 12 months follow-up after the extended treatment period.

Drug: Pentamidine; Pentamidine isethionate 300 mg for one vial for intramuscular or intravenous route(1 mg of pentamidine isethionate is equivalent to 0.57 mg of pentamidine base); Other Names: PENTACARINAT 300 mg, by Sanofi-Aventis

Outcome Measures

Primary Outcome Measures

1. Probability of Relapse-free Survival [up to 1 year after the start of the intervention (PSP)]

   Probability of relapse-free survival up to one year after the start of the intervention (PSP) (at month 6 and month 12)

2. Number of Participants With Serious Adverse Events (SAEs) [1 year]

   Number of patients with SAEs which are possibly, probably or definitely drug-related following clinician's assessment or that lead to permanent drug discontinuations during the first year of pentamidine administration

Secondary Outcome Measures

1. Number of Participants With Adverse Events [1 year]

   During the first year of pentamidine administration for prophylaxis: participants with any drug-related non-serious adverse events (with drug-related defined as possibly, probably or definitely related to primary therapy following physicians assessment) as well as any serious adverse events (drug-related or not)

2. Number of Treatment Discontinuations and Interruptions [30 months]

   Number of treatment discontinuations and interruptions/missed doses.

3. Number of Required Additional Interventions [30 months]

   The number of required additional clinical interventions/therapeutic procedures

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients diagnosed with Visceral Leishmaniosis (VL) during the recruitment period that are EITHER treated for VL relapse and have a documented negative test of cure (TOC), OR are treated for primary VL and have a documented CD4 <200 or WHO stage 4 disease during the recruitment period and have a documented negative TOC

• Patients treated for VL in the past with documented CD4 <200 or WHO stage 4 disease during the recruitment period AND documented negative TOC after the latest VL treatment and currently asymptomatic OR currently negative diagnostic test (microscopy)

• Patients agreeing to start or continue antiretroviral treatment (first or second line)

• Patients willing to provide written informed consent

Exclusion Criteria:

• Patients with known hypersensitivity to pentamidine

• Patients with known renal failure

• Patients with diabetes mellitus (type I or II)

• Patients unlikely to attend follow-up visits/comply with study requirements

• Pregnant and lactating women

• Any other condition that could increase the risk of toxicity of pentamidine to such an extent outweighing the expected benefit (eg severe cardiac dysfunction).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Abdurafi Health Center/Médecins Sans Frontières	Abdurafi	Amhara	Ethiopia
2	Kahsay Abera Hospital	Humera	Tigray	Ethiopia
3	Leismania Research and Treatment Centre, University of Gondar Hospital	Gondar		Ethiopia

Sponsors and Collaborators

• Institute of Tropical Medicine, Belgium
• Addis Ababa University
• University of Gondar
• Tigray Regional Health Bureau, Tigray Region
• Amhara Regional Health Bureau, Amhara Region
• Medecins Sans Frontieres, Netherlands
• Leishmania East Africa Platform (LEAP)
• Drugs for Neglected Diseases

Investigators

• Study Director: Ermias Diro, MD, University of Gondar, Ethiopia
• Study Director: Johan Van Griensven, MD, PhD, ITM

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Institute of Tropical Medicine, Belgium
• ClinicalTrials.gov Identifier: NCT01360762
• Other Study ID Numbers: ITMC0109
• First Posted: May 26, 2011
• Last Update Posted: Feb 15, 2019
• Last Verified: Oct 1, 2018

• Keywords provided by Institute of Tropical Medicine, Belgium: Secondary prophylaxis; Visceral leishmaniasis; Relapses; HIV co-infection; Pentamidine; Ethiopia
• Additional relevant MeSH terms: HIV Infections; Leishmaniasis; Leishmaniasis, Visceral; Acquired Immunodeficiency Syndrome; Recurrence; Pentamidine

Study Results

Participant Flow

Arm/Group Title	Pentamidine Secondary Prophylaxis (PSP)
Arm/Group Description	Patients with co-infection of human immunodeficiency virus (HIV) and visceral leishmaniosis (VL), having being treated for VL.
Period Title: Main Study Period (12-month Treatment)
STARTED	74
COMPLETED	45
NOT COMPLETED	29
Period Title: Main Study Period (12-month Treatment)
STARTED	74
COMPLETED	38
NOT COMPLETED	36

Baseline Characteristics

Arm/Group Title	Pentamidine Secondary Prophylaxis (PSP)
Arm/Group Description	Patients with co-infection of human immunodeficiency virus (HIV) and visceral leishmaniosis (VL), having being treated for VL.
Overall Participants	74
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	32
Sex: Female, Male (Count of Participants)
Female	3 4.1%
Male	71 95.9%
Weight (kg) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg]	50
Body Mass Index (BMI) (Count of Participants)
BMI < 18.5 kg/m^2	56 75.7%
BMI > 18.5 kg/m^2	18 24.3%
Functional status (Count of Participants)
Working	46 62.2%
Ambulatory	25 33.8%
Bed ridden	2 2.7%
Spleen size (Count of Participants)
not palpable	30 40.5%
Palpable < 5 cm	14 18.9%
Palpable 5 cm or > 5 cm	29 39.2%
Total liver span (cm) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [cm]	11
Total WBC count (cells/µL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [cells/µL]	3000
Neutrophil percent (percentage of neutrophils) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [percentage of neutrophils]	62.3
Lymphocyte percent (percentage of lymphocytes) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [percentage of lymphocytes]	27.8
Haemoglobin (g/dL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [g/dL]	9.2
Platelet count (platelets x10^3 / µL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [platelets x10^3 / µL]	192
Current CD4 count (cells/µL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [cells/µL]	127
Current CD4 count (Count of Participants)
50 or less	7 9.5%
51-100	15 20.3%
101-200	37 50%
201-350	7 9.5%
more than 350	5 6.8%
Missing	3 4.1%
VL status (Count of Participants)
Primary	31 41.9%
Relapse	43 58.1%
Number of VL episodes before inclusion (Count of Participants)
1 episode	27 36.5%
2 episodes	12 16.2%
3 episodes	3 4.1%
4 episodes	1 1.4%

Outcome Measures

1. Primary Outcome

Title	Probability of Relapse-free Survival
Description	Probability of relapse-free survival up to one year after the start of the intervention (PSP) (at month 6 and month 12)
Time Frame	up to 1 year after the start of the intervention (PSP)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pentamidine Secondary Prophylaxis (PSP)
Arm/Group Description	Patients with co-infection of human immunodeficiency virus (HIV) and visceral leishmaniosis (VL), having being treated for VL.
Measure Participants	74
Probability of relapse-free survival at 6 months	79
Probability of relapse-free survival at 12 months	71

2. Primary Outcome

Title	Number of Participants With Serious Adverse Events (SAEs)
Description	Number of patients with SAEs which are possibly, probably or definitely drug-related following clinician's assessment or that lead to permanent drug discontinuations during the first year of pentamidine administration
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pentamidine Secondary Prophylaxis (PSP)
Arm/Group Description	Patients with co-infection of human immunodeficiency virus (HIV) and visceral leishmaniosis (VL), having being treated for VL.
Measure Participants	74
Count of Participants [Participants]	3 4.1%

3. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	During the first year of pentamidine administration for prophylaxis: participants with any drug-related non-serious adverse events (with drug-related defined as possibly, probably or definitely related to primary therapy following physicians assessment) as well as any serious adverse events (drug-related or not)
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pentamidine Secondary Prophylaxis (PSP)
Arm/Group Description	Patients with co-infection of human immunodeficiency virus (HIV) and visceral leishmaniosis (VL), having being treated for VL.
Measure Participants	74
Drug-related non-serious adverse events	30 40.5%
Any serious adverse event	17 23%

4. Secondary Outcome

Title	Number of Treatment Discontinuations and Interruptions
Description	Number of treatment discontinuations and interruptions/missed doses.
Time Frame	30 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pentamidine Secondary Prophylaxis (PSP)
Arm/Group Description	Patients with co-infection of human immunodeficiency virus (HIV) and visceral leishmaniosis (VL), having being treated for VL.
Measure Participants	74
Permanent discontinuation	2
Missed more than 1 dose	4
Treatment interruption	0

5. Secondary Outcome

Title	Number of Required Additional Interventions
Description	The number of required additional clinical interventions/therapeutic procedures
Time Frame	30 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pentamidine Secondary Prophylaxis (PSP)
Arm/Group Description	Patients with co-infection of human immunodeficiency virus (HIV) and visceral leishmaniosis (VL), having being treated for VL.
Measure Participants	74
Additional IV fluid during PM administration	10
Prolonged hospital observation	2
additional medication during PM infusion	2
Additional IV or oral glucose	1

Adverse Events

Time Frame	Adverse event data were collected over the whole study period of 30 months (primary study period (12 months), extended study period (6 months) and 12 months follow-up period).
Arm/Group Title	Pentamidine Secondary Prophylaxis (PSP)
Arm/Group Description	Patients with co-infection of human immunodeficiency virus (HIV) and visceral leishmaniosis (VL), having being treated for VL.
All Cause Mortality
	Pentamidine Secondary Prophylaxis (PSP)
	Affected / at Risk (%)	# Events
Total	7/74 (9.5%)
Serious Adverse Events
	Pentamidine Secondary Prophylaxis (PSP)
	Affected / at Risk (%)	# Events
Total	33/74 (44.6%)
Blood and lymphatic system disorders
Hypovolemic shock	2/74 (2.7%)
Eye disorders
Uveitis	1/74 (1.4%)
Gastrointestinal disorders
Diarrhoea	1/74 (1.4%)
Upper gastro-intestinal haemorrhage	1/74 (1.4%)
Infections and infestations
Disseminated tuberculosis	1/74 (1.4%)
Herpes Zoster	1/74 (1.4%)
Bacterial Lymphadenitis	1/74 (1.4%)
Meningitis	1/74 (1.4%)
Appendicitis	1/74 (1.4%)
Cellulitis	1/74 (1.4%)
Giardiasis	1/74 (1.4%)
Tuberculosis	1/74 (1.4%)
Tuberculosis of central nervous system	1/74 (1.4%)
Typhoid fever	1/74 (1.4%)
Visceral Leishmaniasis	20/74 (27%)
Injury, poisoning and procedural complications
Limb injury	1/74 (1.4%)
Metabolism and nutrition disorders
Hypoglycaemia	1/74 (1.4%)
Nervous system disorders
Demyelinating polyneuropathy	1/74 (1.4%)
Renal and urinary disorders
Renal failure	2/74 (2.7%)
Acute renal failure	1/74 (1.4%)
Respiratory, thoracic and mediastinal disorders
Pneumonia	16/74 (21.6%)
Skin and subcutaneous tissue disorders
Stevens-Johnson syndrome	1/74 (1.4%)
Other (Not Including Serious) Adverse Events
	Pentamidine Secondary Prophylaxis (PSP)
	Affected / at Risk (%)	# Events
Total	71/74 (95.9%)
Blood and lymphatic system disorders
Anaemia	9/74 (12.2%)
Iron deficiency anaemia	1/74 (1.4%)
Lymphadenopathy	1/74 (1.4%)
Thrombocytosis	1/74 (1.4%)
Eye disorders
Cataract	1/74 (1.4%)
Allergic conjunctivitis	1/74 (1.4%)
Eye allergy	2/74 (2.7%)
Eye degenerative disorder	1/74 (1.4%)
Iridocyclitis	3/74 (4.1%)
Night blindness	2/74 (2.7%)
Ocular hyperaemia	2/74 (2.7%)
Refraction disorder	1/74 (1.4%)
Uveitis	1/74 (1.4%)
Gastrointestinal disorders
Abdominal pain	4/74 (5.4%)
Diarrhoea	13/74 (17.6%)
Dyspepsia	11/74 (14.9%)
Gastritis	9/74 (12.2%)
Hemorrhoids	4/74 (5.4%)
Peptic ulcer	4/74 (5.4%)
Vomiting	5/74 (6.8%)
Abdominal distention	1/74 (1.4%)
Upper abdominal pain	1/74 (1.4%)
Anal fistula	1/74 (1.4%)
Ascites	1/74 (1.4%)
Constipation	2/74 (2.7%)
Haemorrhagic diarrhoea	1/74 (1.4%)
Nausea	3/74 (4.1%)
Pancreatitis	1/74 (1.4%)
Proctalgia	1/74 (1.4%)
Proctitis	1/74 (1.4%)
Toothache	4/74 (5.4%)
Upper gastrointestinal haemorrhagues	2/74 (2.7%)
General disorders
Application site hypersensitivity	2/74 (2.7%)
Asthenia	1/74 (1.4%)
Chest pain	10/74 (13.5%)
Chills	1/74 (1.4%)
Injection site hypersensitivity	2/74 (2.7%)
Local swelling	1/74 (1.4%)
Pain	1/74 (1.4%)
Pyrexia	10/74 (13.5%)
Hepatobiliary disorders
Cholecystitis acute	1/74 (1.4%)
Immune system disorders
Hypersensitivity	2/74 (2.7%)
Infections and infestations
Abscess limb	1/74 (1.4%)
Abscess neck	1/74 (1.4%)
Acarodermatitis	1/74 (1.4%)
Acute tonsillitis	1/74 (1.4%)
Amoebiasis	6/74 (8.1%)
Amoebic dysentery	2/74 (2.7%)
Anal abscess	1/74 (1.4%)
Appendicitis	1/74 (1.4%)
Ascariasis	2/74 (2.7%)
Atypical pneumonia	7/74 (9.5%)
Body tinea	2/74 (2.7%)
Bronchitis	4/74 (5.4%)
Bronchopneumonia	1/74 (1.4%)
Carbuncle	3/74 (4.1%)
Cellulitis	4/74 (5.4%)
Cerebral toxoplasmosis	2/74 (2.7%)
Cestode infection	4/74 (5.4%)
Chlamydial infection	1/74 (1.4%)
Cystitis	1/74 (1.4%)
Disseminated tuberculosis	1/74 (1.4%)
Dysentery	9/74 (12.2%)
Eye infection	2/74 (2.7%)
Bacterial eye infection	7/74 (9.5%)
Folliculitis	2/74 (2.7%)
Fungal skin infection	1/74 (1.4%)
Furuncle	1/74 (1.4%)
Gastroenteritis	16/74 (21.6%)
Giardiasis	14/74 (18.9%)
Helminthic infection	7/74 (9.5%)
Viral hepatitis	1/74 (1.4%)
Herpes Zoster	6/74 (8.1%)
Hookworm infection	1/74 (1.4%)
Hordeolum	1/74 (1.4%)
Impetigo	3/74 (4.1%)
Influenza	1/74 (1.4%)
Intertrigo candida	2/74 (2.7%)
Isopsoriasis	1/74 (1.4%)
Lower respiratory tract infection	2/74 (2.7%)
Lymph node tuberculosis	1/74 (1.4%)
Bacterial lymphadenitis	1/74 (1.4%)
Malaria	19/74 (25.7%)
Meningitis	1/74 (1.4%)
Nasopharingitis	1/74 (1.4%)
Oesophageal candidiasis	1/74 (1.4%)
Oral candidiasis	3/74 (4.1%)
Oral herpes	1/74 (1.4%)
Otitis media	1/74 (1.4%)
Acute otitis media	1/74 (1.4%)
Periorbital cellulitis	1/74 (1.4%)
Bacterial peritonitis	1/74 (1.4%)
Plasmodium falciparum infection	3/74 (4.1%)
Plasmodium vivax infection	8/74 (10.8%)
Pneumonia	32/74 (43.2%)
Pulmonary tuberculosis	1/74 (1.4%)
Pulpitis dental	1/74 (1.4%)
Pyomyositis	1/74 (1.4%)
Respiratory tract infection	1/74 (1.4%)
Sepsis	1/74 (1.4%)
Sinusitis	1/74 (1.4%)
Skin infection	2/74 (2.7%)
Strongyloidiasis	3/74 (4.1%)
Subcutaneous abscess	1/74 (1.4%)
Syphilis	1/74 (1.4%)
Taeniasis	1/74 (1.4%)
Tonsillitis	1/74 (1.4%)
Tuberculosis	3/74 (4.1%)
Tuberculosis of central nervous system	1/74 (1.4%)
Typhoid fever	2/74 (2.7%)
Upper respiratory tract infection	7/74 (9.5%)
Urinary tract infection	10/74 (13.5%)
Visceral leishmaniasis	21/74 (28.4%)
Wound infection	2/74 (2.7%)
Injury, poisoning and procedural complications
Accident at work	1/74 (1.4%)
Animal bite	2/74 (2.7%)
Chest injury	1/74 (1.4%)
Excoriation	2/74 (2.7%)
Laceration	1/74 (1.4%)
Limb injury	1/74 (1.4%)
Muscle strain	2/74 (2.7%)
Soft tissue injury	4/74 (5.4%)
Wound	1/74 (1.4%)
Investigations
Blood albumin decreased	1/74 (1.4%)
Blood alkaline phosphatase increased	2/74 (2.7%)
Blood creatinine increased	2/74 (2.7%)
Creatinine renal clearance decreased	1/74 (1.4%)
Platelet count decreased	1/74 (1.4%)
Weight decreased	1/74 (1.4%)
Metabolism and nutrition disorders
Decreased appetite	11/74 (14.9%)
Dehydration	1/74 (1.4%)
Hyperglycemia	1/74 (1.4%)
Hypoglycaemia	4/74 (5.4%)
Hypokalaemia	1/74 (1.4%)
Hypovitaminosis	3/74 (4.1%)
Tetany	1/74 (1.4%)
Arthralgia	14/74 (18.9%)
Back pain	4/74 (5.4%)
Myalgia	2/74 (2.7%)
Pain in extremity	3/74 (4.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Anogenital warts	1/74 (1.4%)
Nervous system disorders
Convulsion	1/74 (1.4%)
Demyelinating polyneuropathy	1/74 (1.4%)
Dizziness	1/74 (1.4%)
Headache	8/74 (10.8%)
Migraine	2/74 (2.7%)
Myelopathy	1/74 (1.4%)
Neuralgia	1/74 (1.4%)
Peripheral neuropathy	8/74 (10.8%)
Polyneuropathy	1/74 (1.4%)
Post herpetic neuropathy	1/74 (1.4%)
Psychiatric disorders
Anxiety	1/74 (1.4%)
Somatoform disorder	1/74 (1.4%)
Renal and urinary disorders
Renal failure	2/74 (2.7%)
Acute renal failure	2/74 (2.7%)
Renal impairment	1/74 (1.4%)
Urethral discharge	3/74 (4.1%)
Reproductive system and breast disorders
Genital ulceration	1/74 (1.4%)
Gynaecomastia	1/74 (1.4%)
Scrotal swelling	2/74 (2.7%)
Testicular swelling	1/74 (1.4%)
Respiratory, thoracic and mediastinal disorders
Bronchial hyperreactivity	2/74 (2.7%)
Cough	4/74 (5.4%)
Epistaxis	1/74 (1.4%)
Haemoptysis	1/74 (1.4%)
Nasal congestion	16/74 (21.6%)
Skin and subcutaneous tissue disorders
Acne	1/74 (1.4%)
Cold urticaria	1/74 (1.4%)
Dandruff	1/74 (1.4%)
Allergic dermatitis	3/74 (4.1%)
Contact dermatitis	1/74 (1.4%)
Eczema	1/74 (1.4%)
Pruritus	5/74 (6.8%)
Psoriasis	2/74 (2.7%)
Rash	4/74 (5.4%)
Skin hypopigmentation	1/74 (1.4%)
Skin lesion	1/74 (1.4%)
Skin reaction	1/74 (1.4%)
Stevens-Johnson syndrome	1/74 (1.4%)
Subcutaneous emphysema	1/74 (1.4%)
Vascular disorders
Hypotension	13/74 (17.6%)
Hypovolaemic shock	2/74 (2.7%)
Shock	1/74 (1.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.