09/30/2008

Clinical Trial - Phase I

 

 Safety in humans

 

A placebo-controlled, Phase I, pilot clinical trial 

 

 Objectives

 

 Primary

 

To determine the toxicity and side effects, if any, of P-MAPA imunomodulator in HIV + individuals

 

Secondary

 

To determine the local and systemic effect, if any, of P-MAPA in the individuals.

 

To determine the effect, if any, in the white blood cell count

 

Study Design : Treatment, double blind, randomized, phase I, pilot clinical trial

 

Number of patients enrolled:

 

26 individuals (18 male, 18 female)

 

Condition	Intervention	Phase
HIV +	Drug: P-MAPA  Procedure: Adjuvant therapy  Procedure : Biological therapy	Phase I

 

Dosage schedule:

 

13 individuals received 5 mg per square meter per day of P-MAPA by i.m. route four 45 days.

 

13 individuals received placebo.

 

This dosage schedule was followed for 6 weeks. 

 

Ethical criteria

 

The trial was done in compliance with the Helsinki Declaration. The protocol was approved by the Hospital Ethics Committee (Instituto de Infectologia Emilio Ribas-São Paulo- Brazil) and all of the patients signed an informed consent form approved by that committee.

 

Protocol inclusion criteria : 

 

Age 18 to 65 years old

 

Serology positive for HIV-I

 

Karnofsky performance scale (KPS) ≥ 60

 

Counting CD4 cells (300 ≤CD4 ≤500) cells/mm

 

Serum creatinine ≤1.5 mg/dL

 

Serum bilirubin ≤1.5 mg/dL

 

SGOT and SGPT ≤ 3  times the upper normal level

 

Leukocytes ≥ 2000/mm

 

Platelets ≥50000/mm

 

Hemoglobin ≥10 mg/dL, without blood transfusion

 

Women must be using a contraception method and/or have a negative response to pregnancy test

 

Protocol exclusion criteria:

 

Pregnancy or lactation 

 

Concomitant use of one or more of the following :  antiretroviral therapy, corticosteroids, antineoplastic chemotherapy, investigational new drug. 

 

Nosocomial infection 

 

Unable to follow protocol procedures

 

Groups under evaluation and participant codes:

 

Group A (using P-MAPA): AOS, ABP, AMF, CTC, EG, FCN, JBC, JER, JFS, JSF, MRM, PLL, TMB.

 

Group B (using Placebo): CS, DDF, DDM, ERM, IBL, IBS, JTG, MAA, MC, MRD, RAS, SBS, WFS.

 

Clinical evaluation :

 

Physical examination 

Blood pressure 

Temperature 

Body mass index 

Performance Status Scale (KPS)

Electrocardiogram (ECG) 

Respiratory rate 

Neurological evaluation

 

Laboratory tests:

 

HIV-1 serum test 

Cutaneous tests

 

Hematology

 

Hemoglobin 

Hematocrit  

Total lymphocyte count 

CD4 lymphocyte count 

CD8 lymphocyte count 

Neutrophil count 

Monocyte count 

Platelets 

 

Hepatic function tests  

 

Serum glutamic oxaloacetic transaminase (SGOT)

Glutamic pyruvic transaminase (SGPT) 

Serum alkaline phosfatase (ALP) 

Serum bilirubin 

 

Kidney function tests 

 

Serum creatinine 

Blood urea  

 

Results - Clinical evaluation

  

Clinical evaluation did not reveal any adverse events  that could be attributed to use of P-MAPA. 

 

 Body temperature and respiratory rate were within normal ranges for both groups. 

 

Results of neurological and cardiological evaluation of both groups were within normal ranges. 

 

No significant differences were found between groups for body weight and body mass index.

 

The Karnofsky  performance index (KPS) exhibited no difference between groups.

 

Results - Laboratory  Tests 

 

Hematology 

 

Total lymphocyte count 

 

In 12 out of the 13 patients treated with P-MAPA, total lymphocytes increased significantly in comparison to initial values, but remained within the normal range. 

 

This stimulating effect of P-MAPA on lymphocyte population has been observed previously during the pre-clinical phase in animal models.

 

In the group treated with placebo, only 1 out of 13 patients had an increase in total lymphocytes. 

 

CD4 lymphocyte count 

 

In 8 out of 13 patients treated with P-MAPA, an increase of CD4 lymphocytes was observed. 

 

In the group receiving placebo, 4 out 13 patients showed a positive variation in the values of CD4 lymphocytes. 

 

CD8 lymphocyte count

 

In 7 out of 13 patients treated with P-MAPA, an increase in CD8 lymphocytes was observed

 

In the group receiving placebo, 6 out 13 patients showed a positive variation in the values of CD8 lymphocytes.  

 

Segmented neutrophil count 

 

In 8 out of the 13 patients treated with P-MAPA, an increase in segmented neutrophil count was observed. 

 

In the group treated with placebo, 3 out of 13 patients had an increase in segmented neutrophil count. 

 

Eosinophil count 

 

In 7 out of 13 patients treated with P-MAPA, an increase in eosinophil count was observed. 

 

In 2 out of 13 patients treated with P-MAPA, a wide variation in eosinophil count among analyses was observed, but values remained within the normal range. 

 

In the placebo group, none of the 13 patients exhibited eosinophil count increase. 

 

Monocyte count 

 

In 8 out of 13 patients treated with P-MAPA an increase in monocyte count was observed. 

 

In 1 out of the 13 patients, a wide variation in monocyte count among analyses was observed, but values remained within the normal range. 

 

In the placebo group, only 3 out of 13 patients displayed an increase in monocyte count.

 

In 4 out of 13 patients a wide variation in monocyte count among analyses was observed, but values remained within the normal range 

 

Platelets 

 

Both in the P-MAPA group and in the placebo group, no significant qualitative or quantitative changes were observed in platelets. 

 

Hemoglobin 

 

No significant differences were observed in hemoglobin between the P-MAPA group and the placebo group.  

 

Hematocrit

 

No significant differences were observed between hematocrit values of the P-MAPA group and the placebo group group. 

 

Hepatic function tests

 

 Serum glutamic oxaloacetic transaminase (SGOT)

 

No significant diferences wre observed betwen SGOT values of the P-MAPA group and the placebo group 

 

Serum glutamic pyruvic transaminase (SGPT)

 

No significant differences were observed between SGPT values of the P-MAPA group and the placebo group. 

 

Serum Alkaline Phosfatase (ALP)

 

No significant differences were observed between ALP values of the P-MAPA group and the placebo group. 

 

Serum bilirubin 

 

No significant differences were observed between bilirubin values of the P-MAPA group and the placebo group. 

 

Kidney function tests 

 

Serum creatinne 

 

No significant differences were observed between serum creatinine values of the P-MAPA group and the placebo group. 

 

Blood urea 

 

No significant differences were observed between blood urea values of the P-MAPA group and the placebo group. 

 

 

Conclusions

 

• Comparison between the group using P-MAPA and the placebo group showed that P-MAPA was able to induce an increase in granulocyte and lymphocyte populations. 

 

• This result had been previously observed in animal models, and is indicative of the ability of the product to stimulate the haematopoietic system. However, this is not a sign of toxicity. 

 

• In this protocol, no clinical evaluation or laboratory test brought to light any adverse events that could be attributed to the use of P-MAPA.   

 

• In the 5 mg/square meter/day dosage, the use of P-MAPA does not display any sign of adverse drug reaction or adverse event.