The WF10 Phase 3 Protocol
This protocol was discussed extensively during the Investigators' Meeting held in San Diego, CA on September 21-23, 1998.
WF10-97-US-004 Clinical Protocol Synopsis
Name of Company:
OXO Chemie
Name of Finished Product:
WF10
Name of Active Substance:
Chemically stabilized chlorite matrix
Title of Study:
A multicenter, randomized, double-blind, placebo-controlled, pivotal clinical study evaluating the safety and efficacy of WF10 (TCDO) intravenous solution in the management of patients with late-stage HIV disease
Objectives:
The primary objective is to evaluate the effect of intravenous (IV) administration of WF10 on clinical progression, defined as any occurrence of a new AIDS-defining event or death, in adults with late-stage HIV disease. The secondary objectives are to evaluate the effect of IV WF10 administration on number, duration, and cause of hospitalizations; quality of life; and density of CD38 antigen on CD8+ T cells and to evaluate long-term safety and tolerance of WF10.
Number of Patients:
Two hundred forty HIV-infected adults with CD4+ T cell counts less than or equal to 50cells/mm3 who have received or are receiving combination antiretroviral therapy with approved agents will be enrolled.
Study Design:
This is a pivotal, multicenter, randomized, placebo-controlled, double-blind clinical trial to evaluate the safety and clinical effect of four treatment cycles of 0.5 mL/kg WF10 or physiological saline solution (placebo) in the treatment of adult patients with late-stage HIV disease. After patients are screened and successfully meet the study criteria, they will be randomized to one of the two treatment groups as follows:
WF10 (four treatment cycles of 0.5 mL/kg WF10): 120 patients
Control (four treatment cycles of physiological saline solution): 120 patients
Patients will be assigned to each of the two treatment groups using a 1:1 (treatment: placebo) randomization scheme.
Patients will be monitored throughout the study for clinical progression (primary endpoint) and number, duration, and cause of hospitalizations; quality of life; and density of CD38 antigen on CD8+ T cells (secondary endpoints).
The duration of the treatment period will be 11 weeks. During the follow-up period, patients will be evaluated initially at Week 18, then at Weeks 24, 36, and 48. If the study is continued beyond Week 48, follow-up visits will be conducted at Weeks 72 and 96.
The statistical power of this study is based upon current information regarding survival rates and incidence of AIDS-defining events, which have declined dramatically since the recent introduction of combination antiretroviral drug therapy. In fact, the rate of mortality and clinical progression of HIV disease may continue to decline during the course of the trial. Therefore, the present study is designed to accommodate the possibility that a decrease in frequency of death and AIDS-defining events may reduce statistical power.
The study will be terminated and the endpoints will be assessed when the final surviving patient to receive treatment has completed the Week48 follow-up evaluation. Evaluations after the 48-week time point will be used to assess continued safety and efficacy of WF10. If less than 25% of the total patient population (60 patients) has reached a clinical endpoint (i.e., occurrence of a new AIDS-defining event or death), the study may be extended to the Week 96 follow-up evaluation of the last patient receiving treatment.
Inclusion Criteria:
Patients who meet the following inclusion criteria will be eligible to participate in the study:
Patient (male or female) is at least 18 years of age.
Female patients must have a negative serum ß-HCG test within 14 days before the first study drug infusion.
Patient is HIV-infected, as documented by a positive enzyme-linked immunosorbant assay (ELISA) confirmed by a positive Western Blot.
Patient has a CD4+ T cell count less than or equal to 50 cells/mm3, determined within 14 days before the first study drug infusion.
Patient is currently receiving no treatment or stable HIV treatment with antiretroviral agents approved by the Food and Drug Administration (FDA). Stable treatment is defined as no change in treatment within 30days before the first study drug infusion. Change in the antiretroviral medication regimen will be permitted during the follow-up period (after Day 71).
The patient has the following laboratory values within 14 days before first drug infusion:
Hemoglobin >9.0 g/dL for women and >10.0 g/dL for men
Platelet count >75,000/mm3
Absolute neutrophil count >750/mm3
Serum glutamic oxaloacetic transaminase (SGOT) less than 5 times the central laboratory's upper limit of normal (ULN) and serum glutamic pyruvic transaminase (SGPT) less than 5 times the central laboratory's ULN.
Creatinine less than 2 times the central laboratory's ULN.
Patient provides written informed consent to participate in this study and is willing to comply with all procedures and scheduled visits.
Exclusion Criteria:
Patients who meet any of the following exclusion criteria will be ineligible for the study:
Female patient is pregnant or nursing.
Patient is not employing adequate contraception (e.g., condom plus foam, surgical sterilization, oral contraceptives).
Patient has never received treatment with antiretroviral agents.
Patient is receiving treatment other than stable treatment for an active opportunistic infection or AIDS-defining clinical condition on Day 1 (i.e., treatment has been initiated or changed within 14 days before first study drug infusion). Initiation or change of treatment for an active opportunistic infection or AIDS-defining clinical condition will be permitted after the first day of drug infusion.
Patient has any malignancy other than HIV-associated lymphoma, basal cell or squamous cell carcinoma of the skin, nonsystemic Kaposi's sarcoma, or carcinoma in situ of the cervix.
Patient is receiving, or has received within 30 days before first drug infusion, cytotoxic therapy for treatment of any malignancy.
Treatment with cytotoxic chemotherapeutic agents after the treatment period (which ends on Day 71) will be permitted.
Patient has a condition (such as abuse of nonprescription opiates, cocaine, or phencyclidine) that, in the opinion of the Investigator, would interfere with patient compliance or safety.
Patient has participated in a previous WF10 study.
Patient is receiving, or has received within 30 days before first drug infusion, treatment with an investigational agent (drug, device, biologic). Receiving investigational antiretroviral agents through FDA approved Expanded Access Programs will be permitted if the patient meets the eligibility criteria for the Program.
Patient has received an HIV vaccine at any time before or during the treatment period. Prior use of the gp120 or gp160 vaccines greater than 6 months before first drug infusion will be permitted.
Patient has any condition or history of any illness that, in the opinion of the Investigator, might confound the results of the study or pose additional risk to study drug administration.
Patient is receiving, or has received within 30 days before first drug infusion, steroids (except testosterone, which is allowed throughout the trial). During the follow-up period, use of less than 10mg/day prednisolone or less than 2 mg/day dexamethasone for fewer than 7 days, inhaled steroids, and testosterone for maintenance of body mass will be permitted.
Patient has received a blood transfusion within 45 days before first study drug infusion.
Patient is receiving, or has received within 60 days before first drug infusion, immune modulating medications, specifically IL-2, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF) intravenous immunoglobulin, cytokines, plasmapheresis, steroidal antirheumatic compounds, leukotriene antagonists, cyclosporin, methotrexate, interferon alpha, or agents that stimulate macrophage activity.
Patient's Karnofsky score is less than 50 at screening.
Test Product(s), Dose, and Mode of Administration, Batch Number(s):
WF10 and placebo (0.9% sodium chloride solution) will be supplied by OXO Chemie as sterile solutions for IV infusion in 20-mL glass vials. Each patient will receive treatment with 0.5 mL/kg WF10 or placebo, diluted into 250 mL physiological saline. The test product will be administered intravenously via an infusion pump over a period of at least 90 minutes.
Duration of Treatment:
Patients will be administered WF10 or placebo by IV infusion for four treatment cycles of five consecutive days per cycle, each cycle separated by a sixteen-day interval. The treatment cycles will be administered from Days 1 to 5, Days 22 to 26, Days 43 to 47, and Days 64 to 68.
Criteria for Evaluation:
This study will evaluate the effects of WF10 on clinical progression, defined as any new occurrence of an AIDS-defining event or death; number, duration, and cause of hospitalizations; quality of life; and density of CD38 antigen on CD8+ T cells. The safety and tolerance of WF10 will be evaluated by analysis of adverse events and standard clinical laboratory tests.
Statistical Methods:
Demographic and background information will be summarized and presented as means, standard deviations, medians, and ranges for continuous variables and as counts and percentages for categorical variables. In general, all demographic and analytic data will be summarized using traditional statistical methods. The frequency distribution of the age data will be presented. Categorical data will be summarized using frequency tables. Confidence intervals will be calculated using standard formulae. All demographic and analytical between-group differences will be analyzed parametrically and nonparametrically.
Patient randomization to each of the two treatment groups (WF10 and Control) will be stratified by investigator. As a result, the Investigator will be included as a factor in each of the analyses performed. Where appropriate, treatment by investigator interaction will be tested. If the interaction should prove to be statistically significant, results may be summarized by treatment group within each investigator. If interaction is not found, investigators will be treated as blocking factors in the analyses.
All patients who receive at least one-half of the total intended dose will be included in all evaluations of clinical effect. All patients who receive any drug will be included in safety analyses.
An overall p-value of 0.05 or less will be considered to be statistically significant. The p-values of all tests will be reported without any correction for the multiplicity of tests performed. An intent-to-treat approach will be followed in all data summaries, using all available data in the analyses. Consequently, no adjustments to the data are intended for dealing with missing values or patients who withdraw prior to completing the study. A final statistical plan will be developed before locking the CRF database and opening the randomization for the final analysis at the conclusion of the study.
Please refer to the AIDS Clinical Trials Information Service (ACTIS) for more information or call 1-800-TRIALS-A.
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