Uncontrolled trials

Short-Term Randomized Controlled Trials of NIPPV in COPD 

There have been six randomized controlled trials(RCTs) of NIPPV for up to three months that have been published as full papers (11,18,23-26). Details of these studies are presented in Table 1. Strumpf et al. found no significant changes in any of the measured variables 

Trial Number of patients (treatment/controls) EEVi mean (range) Paco2 mean (range) Length (months) IPAP/ EPAP Outcome measures Effects 

Strumpf et al. (23) Cross-over trial Enrolled 19 Completed 7 0.54 (0.46-0.88) 49 (35-67) 3 15/2 ABG, RM, walking test, dyspnea, PFT, sleep study, NP function Significant effects for NP function 

Meecham Jones etal. (11) Cross-over trial Enrolled 18 Completed 14 0.86 (0.33-1.7) 56 (52-65) 3 18/2 ABG, 6-MWT, HRQL, PFT, sleep study Significant effects fOT ABG, sleep efficiency, HRQL 

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Pinto A, Borrutto G, Deall Anna A, Turco L, Ferried A An open, uncontrolled trial of oral rifaximin, a non-absorbable antibiotic, in inflammatory bowel disease refractory to conventional therapy. Eur J Clin Res 1997,9 217-224. 

II at least 1 well-designed clinical trial, not randomized, or a cohort or case-controlled analytical study, or from multiple time series, or from dramatic results of an uncontrolled trial III opinions of respected authorities... 

Virtually all of the above cited studies were uncontrolled and involved acute oral or intravenous ISDN/ISMN administration followed within hours by in vitro platelet activity assessment. In contrast, Sinzinger et al. showed in an uncontrolled trial that oral ISDN (100 mg daily) administered to coronary artery disease patients over four weeks inhibited ADP-induced aggregation in platelet-rich plasma in vitro and reduced the number of circulating platelet aggregates and platelet production of thromboxane... 

Dopamine-Stimulating Medications. A variety of drugs that increase the availability of dopamine have been studied in cocaine addicts including L-DOPA, bupropion, amantadine, and methylphenidate. In small uncontrolled trials, these have shown some benefit, but definitive studies have yet to be performed. In addition, some dopamine-stimulating medications (in particular, the stimulants like methylphenidate or the amphetamines) are themselves subject to abuse, though, of note, this is typically not a problem when they are prescribed to patients who do not have a history of substance abuse such as, for example, in the treatment of attention deficit-hyperactivity disorder. 

Using plasma procainamide levels as a guide to therapy, it has been demonstrated (K13), contrary to evidence derived from uncontrolled trials (E2), that procainamide is valuable for preventing as well as controlling ventricular arrhythmias which develop in the immediate post-myocardial infarct period and are one of the main causes of death at this time. 

Valproate, a simple branched-chain fatty acid, was first reported as a successful treatment for acute mania by Lambert and colleagues in 1966. Following this report, at least 16 uncontrolled trials consistently supported the observation that valproate has acute and long-term mood-stabilizing effects in patients with bipolar disorder (reviewed by Keck et al. 1992a). Recently, five double-blind controlled studies of valproate have been completed that provide definitive evidence of its efficacy in acute mania. 

Indomethacin was particularly popular for gout and ankylosing spondylitis. In addition, it has been used to accelerate closure of patent ductus arteriosus. Indomethacin has been tried in numerous small or uncontrolled trials for many other conditions, including Sweet s syndrome, juvenile rheumatoid arthritis, pleurisy, nephrotic syndrome, diabetes insipidus, urticarial vasculitis, postepisiotomy pain, and prophylaxis of heterotopic ossification in arthroplasty. 

Olschewski H, Ghofrani HA, Schmehl T, Winkler J, Wilkens H, Hoper MM, Behr J, Kleber FX, Seeger W. Inhaled iloprost to treat severe pulmonary hypertension. An uncontrolled trial. German PPH Study Group. Ann Intern Med 2000 132(6) 435 13. 

Several other classes of medications have been tried in this disorder. Examples are amantadine, a dopaminergic drug that has been reported to aid in detoxification, fluoxetine, a selective serotonin reuptake antagonist that has been reported to reduce cocaine use, and buprenorphine, a partial opioid agonist that has been found to reduce cocaine self-administration in monkeys. Thus far, all of the studies of medications to help prevent relapse to cocaine dependence have revealed modest benefits at best. Reports of success in uncontrolled trials have not been replicated in carefully controlled, double-blind studies. At present, there is general agreement that no medication is yet available that can be used reliably in the treatment of cocaine addiction. 

A number of investigators have evaluated the role of vitamin E and have reported improved sperm quality in controlled and uncontrolled trials (Geva et al., 1996 Kessopoulou et al., 1995 Suleiman et al., 1996). In a small placebo-controlled trial, Lenzi et al. (1998) have reported that glutathione... 

Shams ili S, deBeukelaar J, Gratama JW, Hooijkaas H, van den Bent M, Van t Veer M, et al. An uncontrolled trial of rituximab for antibody associated paraneoplastic neurological syndromes. J Neurol 2006 253(1) 16—20. 

Phase III Clinical Trials Consist of controlled and uncontrolled trials that are performed after preliminary evidence of effectiveness of a drug has been established. They are conducted to document the safety and efficacy of the drug, as well as to determine adequate directions (labeling) for use by the physician. A specific patient population needs to be clearly identified from the results of these studies. Trials during Phase III are conducted using a large... 

Expanded controlled and uncontrolled trials comprise the phase 3 program. They are performed after preliminary evidence suggesting a knowledge... 

In this section, a description and analysis of any additional information obtained by the applicant from any source, foreign or domestic, that is relevant to the evaluation of the efficacy and safety of the product should be included. It may include results of controlled or uncontrolled clinical trials of uses of the drug other than those claimed in the application, commercial marketing experience, and reports in the literature or otherwise obtained, other than those cited in the controlled trials and uncontrolled trials sections of the clinical data section. 

Phase III Expanded, controlled and uncontrolled trials on efficacy, safety, risk-benefit relationship, practicability usually several hundred to several thousand subjects. ... 

Figure 13-15. A simplified/generic representation of clinical trials involving Phases I (safety and tolerability in healthy participants and/or patients), II (to evalnate effectiveness of the drug in patients), and III (to perform expanded controlled and uncontrolled trials and gather benefit-risk data). About 70-90% of drugs entering Phase III studies successfully complete this phase of evaluation. For more details see the glossary at www.clinicaltrials.gov.

Adenosyl methionine is most widely used for depressive disorders, and about 40 clinical trials have been carried out. A recent meta-analysis concluded that at 200-1600 mg/day it was superior to placebo, and with a global effect size ranging from 17%i to 38%i, it was as effective as tricyclic antidepressants. A later meta-analysis reported on 16 open uncontrolled trials, 13... 

In an uncontrolled trial using dosages up to 6000 mg/day in 50 patients with refractory partial epilepsy, tiredness, dizziness, headache, and diplopia were the most common adverse effects (4). At dosages above 3600 mg/day three patients developed flatulence and diarrhea and two had myoclonic jerks. At least in some patients, gabapentin gastrointestinal absorption did not become saturated within the explored dosage range. 

In one study, there was no deleterious effect on disease progression in HIV-infected patients, and the incidence of local adverse events with imiquimod (5% three times a week) for the treatment of anogenital warts was lower than has previonsly been reported in healthy individuals (3). In an uncontrolled trial of topical imiquimod 5% for the treatment of common warts and molluscum contagio-sum in otherwise healthy patients, fever, healing with scarring, and healing with hyperpigmentation were each reported by one participant (4). 

The efficacy and tolerabihty of sublingual misoprostol has been evaluated in an uncontrolled trial in China in 50 women who requested medical abortions at up to 12 weeks of gestation (8). AH received three doses of misoprostol 600 micrograms subhnguaUy 3-hourly, and two more doses of 600 micrograms sublingually if an abortion did not occur. The overall complete abortion rate was... 

In a multicenter, open, uncontrolled trial of protease inhibitors in conjunction with NRTIs for at least 96 weeks in 32 children, the pharmacokinetics of nelfinavir showed large interindividual differences (2). In all, 17 children suffered adverse events, most of which were mild and occurred early in treatment. The rate of drug-related adverse effects was 0.16 per patient-year in those taking nelfinavir. 

Another uncontrolled trial of a 6-day desensitization procedure in 33 cases has been reported (159). The protocol started with a dose of 0.2 mg rising to 800 mg over 6 days and 32 of the subjects successfully completed the course. In addition, 12 of 14 cases were successfully re-challenged with co-trimoxazole. However, this study lacked a clear description of follow-up or the reasons for the selection of subjects for desensitization or re-chal-lenge, and cannot be used as a basis for recommending this desensitization technique. 

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