[Show abstract][Hide abstract] ABSTRACT: Recently, more clinical trials are being conducted in Africa and Asia, therefore, background morbidity in the respective populations is of interest. Between 2000 and 2007, the International AIDS Vaccine Initiative sponsored 19 Phase 1 or 2A preventive HIV vaccine trials in the US, Europe, Sub-Saharan Africa and India, enrolling 900 healthy HIV-1 uninfected volunteers.
To assess background morbidity as reflected by unsolicited adverse events (AEs), unrelated to study vaccine, reported in clinical trials from four continents.
All but three clinical trials were double-blind, randomized, and placebo-controlled. Study procedures and data collection methods were standardized. The frequency and severity of AEs reported during the first year of the trials were analyzed. To avoid confounding by vaccine-related events, solicited reactogenicity and other AEs occurring within 28 d after any vaccination were excluded.
In total, 2134 AEs were reported by 76% of all participants; 73% of all events were mild. The rate of AEs did not differ between placebo and vaccine recipients. Overall, the percentage of participants with any AE was higher in Africa (83%) compared with Europe (71%), US (74%) and India (65%), while the percentage of participants with AEs of moderate or greater severity was similar in all regions except India. In all regions, the most frequently reported AEs were infectious diseases, followed by gastrointestinal disorders.
Despite some regional differences, in these healthy participants selected for low risk of HIV infection, background morbidity posed no obstacle to clinical trial conduct and interpretation. Data from controlled clinical trials of preventive interventions can offer valuable insights into the health of the eligible population.
Human vaccines & immunotherapeutics. 05/2012; 8(5):630-8.
[Show abstract][Hide abstract] ABSTRACT: The recombinant vaccine, tgAAC09, based on an adeno-associated virus serotype 2 (AAV2) vector encoding HIV-1 subtype C Gag, protease, and part of reverse transcriptase, induced robust T cell and antibody responses in nonhuman primates. In a previous phase I study in 80 healthy HIV-seronegative European and Indian adults, the vaccine was generally safe, well tolerated, and modestly immunogenic when administered once at doses up to 3 x 10(11) DRP. This phase II double-blind, randomized, placebo-controlled trial tested two administrations and a higher dosage of tgAAC009. Ninety-one healthy HIV-seronegative adults from three African countries were given one of three dosage levels of tgAAC09 (3 x 10(10), 3 x 10(11), or 3 x 10(12) DRP) intramuscularly, either at a 6- or 12-month interval; follow-up was 18 months. Overall, 65% and 57% of vaccine recipients experienced local and systemic signs and symptoms, respectively, most being mild. Frequency and severity were not dose related and were similar to those in placebo recipients. No vaccine-related serious adverse events were reported. Overall, HIV-specific T cell responses were detected by IFN-gamma ELISPOT in 17/69 (25%) vaccine recipients with 38% (10/26) responders in the highest dosage group. The response rate improved significantly with boosting at 6, but not 12 months, in the 3 x 10(11) and 3 x 10(12) dosage groups only. Neutralizing antibody titers to the AAV2 did not alter the frequency of immune responses to HIV. Two doses of tgAAC09 were well tolerated at the dosage levels given. Fewer than half the recipients of the highest vaccine dosage, 3 x 10(12) DRP, had T cell responses to HIV.
AIDS research and human retroviruses 08/2010; 26(8):933-42. · 2.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess safety and clinical outcomes in patients with inflammatory arthritis after intraarticular (IA) injection of rAAV2-TNFR:Fc, a recombinant adeno-associated viral vector containing the human tumor necrosis factor (TNF) receptor-immunoglobulin (IgG1) Fc fusion (TNFR:Fc) gene.
In this phase 1/2 randomized study, adults with persistent moderate or severe inflammation in a target joint, being treated with or without systemic anti-TNF therapy, received a single IA injection of either rAAV2-TNFR:Fc (1 x 10(11), 1 x 10(12), or 1 x 10(13) DNase-resistant particles/ml joint volume) or placebo, followed by open-label rAAV2-TNFR:Fc 12-30 weeks later, depending on when the target joint met predetermined criteria for reinjection.
127 subjects received the first injection of blinded study drug; 95 subjects received open-label rAAV2-TNFR:Fc. Administration site reactions, consisting of transient mild to moderate increases in tenderness and swelling of the injected joint, occurred after 23/191 (12%) rAAV2-TNFR:Fc injections and were dose-dependent. Rates of other adverse events were not dose-dependent. Notable serious adverse events (SAE) included culture-negative septic arthritis in a subject receiving leflunomide and fatal disseminated histoplasmosis considered unrelated to rAAV2-TNFR:Fc in a subject receiving adalimumab. In the phase 2 portion of the study, a 30% decrease in target joint global visual analog scale was observed in 21/50 (42%) rAAV2-TNFR:Fc subjects and 3/16 (19%) placebo subjects 12 weeks after first injection (p = 0.14).
IA rAAV2-TNFR:Fc resulted in administration site reactions after 12% of injections. A fatal SAE, disseminated histoplasmosis, was considered not related to study agent. Patient-reported outcome measures of clinical response showed greater improvement in treated patients than placebo patients.
The Journal of Rheumatology 04/2010; 37(4):692-703. · 3.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess the validity, responsiveness, and reliability of single-joint outcome measures for determining target joint (TJ) response in patients with inflammatory arthritis.
Patient-reported outcomes (PRO), consisting of responses to single questions about TJ global status on a 100-mm visual analog scale (VAS; TJ global score), function on a 100-mm VAS (TJ function score), and pain on a 5-point Likert scale (TJ pain score) were piloted in 66 inflammatory arthritis subjects in a phase 1/2 clinical study of an intraarticular gene transfer agent and compared to physical examination measures (TJ swelling, TJ tenderness) and validated function questionnaires (Disabilities of the Arm, Shoulder and Hand scale, Rheumatoid Arthritis Outcome Score, and the Health Assessment Questionnaire). Construct validity was assessed by evaluating the correlation between the single-joint outcome measures and validated function questionnaires using Spearman's rank correlation. Responsiveness or sensitivity to change was assessed through calculating effect size and standardized response means (SRM). Reliability of physical examination measures was assessed by determining interobserver agreement.
The single-joint PRO were highly correlated with each other and correlated well with validated functional measures. The TJ global score exhibited modest effect size and modest SRM that correlated well with the patient's assessment of response on a 100-mm VAS. Physical examination measures exhibited high interrater reliability, but correlated less well with validated functional measures and the patient's assessment of response.
Single-joint PRO, particularly the TJ global score, are simple to administer and demonstrate construct validity and responsiveness in patients with inflammatory arthritis. (ClinicalTrials.gov identifier NCT00126724).
The Journal of Rheumatology 03/2010; 37(5):1042-8. · 3.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The need to develop validated outcome measures to assess response to therapies in single joints has been recognized. In 2004, a task force was established to assess established and novel outcome measures in accordance with the OMERACT filter (truth, discrimination, and feasibility) for single joint assessment. This report describes the proceedings of the single joint assessment special interest group (SIG) at OMERACT 9, including an updated literature review of imaging of the knee joints, with a focus on the extent to which these modalities fulfill the OMERACT filter. A series of studies are reported that examine patient reported, clinical examination, and imaging outcomes in therapeutic studies in knee arthritis. A summary of discussions from the meeting are presented that raise many of the ongoing challenges in establishing appropriate domains to evaluate a range of conditions and potential therapeutic interventions. Because of emerging drug candidates and modalities targeting individual joints, the ongoing work of this SIG is providing the evidence base that can be used to establish a core domain set to incorporate as outcomes in future studies.
The Journal of Rheumatology 10/2009; 36(9):2092-6. · 3.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To examine the safety and tolerability of a single intra-articular injection of rAAV2-TNFR:Fc, an adenoassociated virus serotype 2 vector containing the cDNA for the human tumour necrosis factor-immunoglobulin Fc fusion gene (tgAAC94), in subjects with inflammatory arthritis.
In a double-blind, placebo-controlled, phase 1, dose-escalation study, 15 subjects with inflammatory arthritis (14 with rheumatoid arthritis and 1 with ankylosing spondylitis) not receiving tumour necrosis factor alpha (TNFalpha) inhibitors with persistent moderate (grade 2) or severe (grade 3) swelling in a target joint due to inflammatory arthritis received a single intra-articular injection of rAAV2-TNFR:Fc at 1 x 10(10) (n = 5) or 1 x 10(11) (n = 6) DNase resistant particles per ml joint volume or placebo (n = 4) into a knee (n = 14) or ankle (n = 1). Safety was assessed through adverse event monitoring. As a secondary objective, changes in injected joint tenderness and swelling scores, each measured on a four-point scale, were evaluated.
Intra-articular injections of rAAV2-TNFR:Fc were well tolerated with no major safety issues. One event, mild knee pruritus, was considered probably related. Synovial fluid TNFR:Fc protein was not detected (nor expected) at the doses used. At 12 weeks after injection, a two-point decrease in swelling was noted in 2/11 and 2/4 subjects injected with rAAV2-TNFR:Fc and placebo, respectively.
A single dose of intra-articular rAAV2-TNFR:Fc appears to be safe and well tolerated in subjects without concurrent systemic TNFalpha antagonist use. It is thus feasible to proceed with larger trials to further test the safety and efficacy of local TNFR:Fc gene transfer as a therapeutic modality for patients with inflammatory arthritis.
Annals of the rheumatic diseases 09/2008; 68(8):1247-54. · 8.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A novel prophylactic AIDS vaccine candidate, consisting of single-stranded DNA for HIV-1 subtype C gag, protease, and part of reverse transcriptase genes, enclosed within a recombinant adeno-associated virus serotype-2 protein capsid (tgAAC09) induced T cell responses and antibodies in nonhuman primates. In this randomized, dose escalation phase I trial, HIV-uninfected healthy volunteers (50 in Europe, 30 in India) received a single intramuscular injection of tgAAC09 at 3 x 10(9) DNase resistant particles (DRP) (n = 16), 3 x 10(10) DRP (n = 23), 3 x 10(11) DRP (n = 25), or placebo (n = 16). Twenty-one participants in Europe received a second (boost) dose of 3 x 10(11) DRP tgAAC09 or placebo at least 24 weeks after the first injection. The vaccine was safe and well-tolerated after initial and boost vaccination. Local and systemic reactogenicity was experienced by 13-25% of participants and was not dose related. No vaccine-related serious adverse events were reported. Modest HIV-specific T cell responses were detected in 7/64 vaccinees (40-385 SFC/10(6) PBMC), with 16% (4/25) responders in the highest dose group. All responses were to Gag epitopes. tgAAC09 appears to be safe, well-tolerated, and modestly immunogenic. Further evaluation of higher doses of tgAAC09 and boost injections is ongoing in Africa.
AIDS research and human retroviruses 07/2008; 24(6):873-80. · 2.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Previous studies have demonstrated that delivery of a recombinant adeno-associated virus (AAV) vector encoding the complete human cystic fibrosis transmembrane regulator (CFTR) cDNA (tgAAVCF) to the nose, sinus, and lungs of subjects with cystic fibrosis (CF) was safe and well tolerated. In a small randomized, double-blind study of three doses of aerosolized tgAAVCF or placebo at 30-day intervals, encouraging but non-significant trends in pulmonary function and induced sputum interleukin 8 (IL-8) levels were seen at early time points. This larger study was conducted to verify these trends. One hundred and two subjects aged 12 years and older with mild-to-moderate cystic fibrosis (forced expiratory flow in 1 sec [FEV1]:60% predicted) were randomized to two aerosolized doses of 1x10(13)DNase-resistant particles of tgAAVCF (n=51) or matching placebo (n=51) administered 30 days apart. Although tgAAVCF was well tolerated, the study did not meet its primary efficacy end point of statistically significant improvement in FEV1 30 days after initial administration of tgAAVCF compared with placebo. There were no significant differences in spirometric lung function over time, induced sputum biologic markers, or days of antibiotic use in either treatment group. Thus repeated doses of aerosolized tgAAVCF were safe and well tolerated, but did not result in significant improvement in lung function over time. Because gene transfer is the simplest, most basic way to correct the underlying genetic defect that leads to disease in CF, further research is warranted to develop an effective gene transfer agent for the treatment of CF.
Human Gene Therapy 09/2007; 18(8):726-32. · 4.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Endpoints and outcome measurements to detect changes in joint structure for the assessment of single joints are needed to enable rheumatology clinical trials of therapies targeting preservation of joint structure, especially via locally applied therapies. While the assessment of certain aspects of single joint inflammation and function is accepted in the evaluation of osteoarthritis (OA) using the WOMAC, it tends to be limited to the knee and hip. The advent of therapies that are directed toward a single joint in inflammatory arthritis, including intraarticular cytokine antagonists and gene therapeutics, requires reliable measures to assess change over time in single joints and the clinical meaningfulness of such change. Traditionally, clinical trials for inflammatory arthritis have used composite response indices such as American College of Rheumatology response or improvement in Disease Activity Score as outcomes based on multiple joint clinical measures, acute phase reactants, and functional status. However, it is not known whether these will appropriately detect changes referable to single joint intervention. This Special Interest Group was developed to bring together interested individuals to identify and evaluate outcome measurements for single joints. The knee was the initial focus, as clinical, radiographic, and functional assessments have been well developed for knee OA. A PubMed English language review was conducted before OMERACT 8, evaluating existing clinical instruments in the context of the OMERACT filter. At OMERACT 8, the group developed a research agenda to perform additional validation studies of clinical and functional indices, imaging, synovial histopathology, and soluble biomarkers.
The Journal of Rheumatology 04/2007; 34(3):641-7. · 3.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A study was conducted to assess health care worker exposure to tgAAVCF during the aerosolized administration of this experimental gene transfer agent in clinical trials for the treatment of cystic fibrosis (CF). tgAAVCF is a recombinant adeno-associated virus (AAV) genetically engineered to contain the human CF transmembrane conductance regulator cDNA. Study subjects included eight health care workers involved in the administration of tgAAVCF in a phase II study and 12 control health care workers who were involved with the treatment of CF patients, but not administration of the study drug. The exposure assessment entailed the determination of personal and area airborne tgAAVCF concentrations. In addition, serologic status of the health care workers was evaluated throughout the study for the presence of antibodies to AAV. A symptom survey was also completed by both the active and control health care workers. Air samples were analyzed by an infectivity assay (active vector) and a DNA polymerase chain reaction amplification procedure (vector DNA). Air monitoring was conducted during 13 tgAAVCF and seven placebo administrations. Active vector and vector particles were detected in four of 51 and 48 of 51 air samples collected during the administration of tgAAVCF, respectively. Based on the airborne vector particle concentration, the workers' exposure was estimated to be 0.0006% of the administered dose. At this level of exposure, the prevalence of symptoms was very low, the spectrum was similar in both study groups and did not result in any reported negative health effects.
Annals of Occupational Hygiene 12/2004; 48(8):673-81. · 2.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The primary objective was to determine the safety and tolerability of repeated doses of aerosolized adeno-associated serotype 2 vector containing cystic fibrosis transmembrane conductance regulator (CFTR) complementary DNA (cDNA) [tgAAVCF], an adeno-associated virus (AAV) vector encoding the complete human CFTR cDNA. Secondary objectives included evaluation of pulmonary function assessed by spirometry, lung abnormalities by high-resolution CT (HRCT), airway cytokines, vector shedding, serum neutralizing antibody to AAV serotype 2 (AAV2), and gene transfer and expression in a subset of subjects undergoing bronchoscopy with bronchial brushings.
Randomized, double-blind, placebo-controlled, phase II trial.
Eight cystic fibrosis (CF) centers in the United States.
CF patients with mild lung disease, defined as FEV(1) > or =60% predicted.
Subjects were randomized to inhale three aerosolized doses of 1 x 10(13) deoxyribonuclease-resistant particles of tgAAVCF or matching placebo at 30-day intervals using the Pari LC Plus nebulizer (PARI; Richmond, VA). Measurements and results: Of 42 subjects randomized, 20 subjects received at least one dose of tgAAVCF and 17 subjects received placebo. No difference in the pattern of adverse events or laboratory abnormalities was noted between the two treatment groups. Improvements in induced-sputum interleukin-8 (p = 0.03) and FEV(1) (p = 0.04) were observed at day 14 and day 30, respectively, in the group receiving tgAAVCF when compared to those receiving placebo. No significant differences in HRCT scans were noted. Vector shedding in sputum was observed at low levels up to 90 days after the third dose of vector. All subjects receiving tgAAVCF exhibited an increase (by at least fourfold) in serum AAV2-neutralizing antibodies and detectable levels in BAL fluid from five of six treated subjects undergoing BAL. Gene transfer but not gene expression was detected in a subset of six tgAAVCF subjects who underwent bronchoscopy.
Repeat doses of aerosolized tgAAVCF were safe and well tolerated, and resulted in encouraging trends in improvement in pulmonary function in patients with CF and mild lung disease.
[Show abstract][Hide abstract] ABSTRACT: Recombinant adeno-associated serotype 2-based vectors (rAAV2) possess a number of theoretical advantages for cystic fibrosis (CF) gene therapy because they elicit little or no inflammatory response and generally result in stable expression. rAAV2 vectors expressing the cystic fibrosis transmembrane conductance regulator (CFTR) gene have previously been shown to mediate stable correction of the CF defect in CF bronchial epithelial cells and stable expression of CFTR in rabbit and nonhuman primate models. Here we report the results of the first trial initiated with rAAV in humans, a phase I study in 25 adult and adolescent CF patients with mild to moderate lung disease. Doses of the rAAV-CFTR vector (tgAAVCF) ranging from 3 x 10(1) to 1 x 10(9) replication units (RU), which is equivalent to approximately 6 x 10(4) to 2 x 10(12) DNase resistant particles (DRP), were administered to one side of the nose and to the superior segment of the lower lobe of the right lung. Several adverse events were noted prior to and/or after vector delivery, but most of them appeared to be related to the endogenous CF lung disease or a result of the bronchoscopic procedures. Only one of the serious events was judged to be possibly vector-related (based on temporal association), and this event was a pulmonary exacerbation very similar to several others experienced by the same subject in the three months preceding vector delivery. Vector shedding was minimal throughout the study, and serum-neutralizing antibodies were detected after vector delivery to subjects in the highest dosage cohorts. Gene transfer as measured by DNA polymerase chain reaction (PCR) was not observed until cohort 10 in nasal and bronchial epithelia. Sporadic low-level copy numbers suggested gene transfer of anywhere from 0.002 copies per cell up to 0.5 copies per cell was possible; however, DNA PCR was positive in lungs prior to direct dosing suggesting aspiration from the nasal dosing. These data indicate the need for continued evaluation of rAAV-CFTR vectors in additional clinical trials.
Human Gene Therapy 08/2003; 14(11):1079-88. · 4.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The anti-cancer gene, E1A, can be complexed to a lipid carrier, DC-Cholesterol:DOPE, to form tgDCC-E1A, which can be injected directly into tumors.
Twenty-four patients with recurrent, unresectable, head and neck cancer were treated with intratumoral injections of tgDCC-E1A over 8 weeks. Tumor response was assessed using CT scans. Time to progression and overall survival were calculated.
Intratumoral tgDCC-E1A was well tolerated in all patients. No significant toxicities related to tgDCC-E1A were reported. One patient (4.2%) had a complete response, two patients (8.3%) had minor response, and seven patients (29.2%) had stable disease by two-dimensional cross-products on blinded CT scans. The median time to progression was 8.6 weeks (range, 3.3-43.7 weeks), and median survival was 4.6 months (range, 1.3-15.6 months).
Intratumoral injections of tgDCC-E1A were safe and well tolerated. Modest tumor response was observed. Further development of tgDCC-E1A is warranted in combination with other treatment modalities.
Head & Neck 08/2002; 24(7):661-9. · 2.83 Impact Factor