Phase II trials

Samples of blood and excreta are taken for laboratory analysis. It is expected that, at the end of this phase, you will have a preliminary estimate of the maximum dose that may be safely tolerated in humans, and also a basic profile of the drug s pharmacokinetic behaviour. Depending on the availability of appropriate analytical indicators, pharmacodynamic and indicative efficacy data may also be generated. The data acquired must be carefully analysed and assessed so that, based on the findings, appropriate Phase II trials can be planned. 

Phase I trials are relatively short, and are usually completed within a year. 

The primary objective of Phase II trials is to explore therapeutic efficacy in patients. The number of subj ects may range from 50 to 5 00, and patients may be selected based on specific restrictive criteria for example, those suffering only from the condition under study, disease stage, age, and so on. An important goal for this phase is to 

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Aniracetam (6), launched in 1993 in both Japan and Italy for the treatment of cognition disorders, is in Phase II trials in the United States as of this writing. In clinical studies it has been shown to cause some improvement in elderly patients with mild to moderate mental deterioration (63), and in geriatric patients with cerebral insufficiency (64). In a multicenter double-blind placebo-controUed trial involving 109 patients with probable AD, positive effects were observed in 36% of patients after six months of treatment (65), a result repeated in a separate study of 115 patients (66). A review of the biological and pharmacokinetic properties, and clinical results of aniracetam treatment in cognitively impaired individuals is available (49). 

Although no PPARS-specific ligands are currently FDA-approved, GW501516 is a compound being developed jointly by GlaxoSmithKline and Ligand Pharmaceuticals. This compound is currently in Phase II trials for the treatment of dyslipidemia. 

On the other hand, 5-HT2C agonists are being investigated in obesity, depression, and schizophrenia, and SCA-136, has entered phase II trials in schizophrenia. 

Lalezari JP, DeJesus E, Northfelt DW, Richmond G, Wolfe P, Haubrich R, Henry D, Powderly W, Becker S, Thompson M, Valentine E, Wright D, Carlson M, Riddler S, Haas FF, DeMasi R, Sista PR, Salgo M, Delehanty J (2003a) A controlled Phase II trial assessing three doses of enfuvirtide (T-20) in combination with abacavir, amprenavir, ritonavir and efavirenz in nonnucleoside reverse transcriptase inhibitor-naive HIV-infected adults. Antivir Ther 8 279-287... 

In a clinical phase II trial, the efficacy of varions doses of pegylated IFN-a2a (90-270 pg weekly) administered for 24 weeks was studied in treatment-naive patients, by comparison with standard IFN-a2a at a dose of 4.5 MU three times a week... 

Figure 22.2 Three different clinical phase II trials, each with slightly different end points, are compared on an eqnal footing. This comparison is made possible by nsing these diverse data to derive a single model with a nniform end point. It is clear that the maximum effect was approached in only one trial. Modeling and analysis of the data would likely have suggested phase II trials that included more data at higher doses.

Martin C, Solders G et al (2000) Antiretroviral therapy may improve sensory function in HIV-infected patients a pilot study. Neurology 54(11) 2120-2127 Masjuan J, Corral I et al (1997) Mycobacterial acute lumbosacral polyradiculopathy as the initial manifestation of AIDS. J Acquir Immune Defic Syndr Hum Retrovirol 15(2) 175 McArthur JC, Yiannoutsos C et al (2000) A phase II trial of nerve growth factor for sensory neuropathy associated with HIV infection. AIDS Clinical Trials Group Team 291. Neurology 54(5) 1080-1088... 

Hacke W. The results of the joint analysis of two phase II trials on desmoteplase in acute ischemic stroke with treatment 3 to 9 hours after stroke onset. 14th European Stroke Conference. Bologna, Italy, May 2005. 

Anakinra/Kineret, an IL-1 receptor antagonist approved for use in rheumatoid arthritis, was recently evaluated in a small phase II trial. When initiated within 6 hours after stroke onset, Anakinra treatment yielded promising preliminary results it was deemed safe with demonstrable biologic activity and likely favorable clinical outcome." ... 

FIGURE 5.3 The Albumin in Acute Stroke (ALIAS) Phase II Trial. Data represent mean SEM. p-Value according to multiple regression analysis. Dead patients have been censored, (a) Mean change in NIH Stroke Scale score over time since treatment in rt-PA and non-rt-PA cohorts receiving the three lowest doses (Tiers I, 0.34 mg/kg II, 0.68 mg/kg III, 1.03 mg/kg) and three highest doses of albumin (Tiers IV, 1.37 mg/kg V, 1.71 mg/kg VI, 2.03 mg/kg). 

Phase II trial of copper zinc superoxide dismutase (CuZnSOD) in treatment of Crohn s disease. Free Rad. Biol. Med. 7, 145-149. 

Nearly all the clinical data comes from the use of atosiban (see Peptide Antagonists), a peptide oxytocin antagonist that is licensed in Europe for acute (48 h) treatment of preterm labour. Early clinical studies demonstrated the ability of atosiban to inhibit uterine contractions associated with labour [14]. Following these successful phase II trials, full phase III trials were... 

Fig. 5. Structures of (A) CP-481,715, (B) BX 471, and (C) T487. CP-481,715 and BX 471 are specific CCR1 antagonists from Pfizer and Berlex/Schering AG, and both failed to exhibit efficacy for rheumatoid arthritis and multiple sclerosis, respectively, in phase II trials. T487 is a specific CXCR3 antagonist from Amgen/Turalik that failed in phase Ha psoriasis clinical trials due to lack of efficacy.

Phase II investigates the compound s efficacy and safety in controlled clinical trials for a specific therapeutic indication. To eliminate as many competing factors as possible, Phase II trials are narrowly controlled. They are characterized as small—several hundred subjects with the indicated disease or symptoms—and are closely monitored. The control may be either a placebo study arm or an active control arm. The endpoint measured may be the clinical outcome of interest or a surrogate. Phase II trials may last for several months or even several years. Early pilot trials to evaluate safety and efficacy are called Phase Ila. Later trials, called Phase lib, are important tests of the compound s efficacy. These trials may constitute the pivotal trials used to establish the drug s safety and efficacy. At least one pivotal trial (most frequently a large, randomized Phase III study) is done. Only about one third of compounds entered into Phase II will begin Phase III studies [61],... 

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