Phase I trial

The primary objective of a Phase I trial is to assess the safety of the drug in humans. Studies are normally conducted in healthy male volunteers, although specific categories of subject may be used in certain cases. For example, to avoid the risk of low blood pressure, subjects with mild hypertension would be more appropriate for the evaluation of antihypertensive drugs, while patients are likely to be used in the case of drugs that are expected to produce significant toxic effects (e.g. anti-cancer cytotoxic drugs). Remuneration may be offered for participation in the study. The number of subjects is normally between 10 and 100 people. 

The study will commence with the administration of low doses, as judged from the non-clinical data. As the study progresses - and provided that there are no indications that it is unsafe to do so - the dosage levels may be increased past the anticipated therapeutic range. Subjects are closely monitored for changes in vital signs (blood pressure, heart rate, body temperature, etc.) and the emergence of any adverse side effects (nausea, drowsiness, pain, headache, irritability, hair loss, etc.). 

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A.n log ue Synthesis. Two notable examples, in which analogues have greater therapeutic indexes than the parent dmgs, have been identified in Phase I trials. These are carboplatin (29) and ado2elesin (37) (35). Carboplatin s approval was based on its comparable efficacy to cis-platinum (28) and its more favorable toxicity profile, ie, reduced and delayed episodes of emesis, reduced ototoxicity, etc. On the other hand, ado2elesin, a totally synthetic analogue of natural product CC1065, has demonstrated a similar potency and antitumor activity profile as its natural prototype but is devoid of the delayed death UabiUty associated with the parent dmg in animals (36). 

Most recently, a phase-I-study defined a dose of 13-ris-retinoic acid that was tolerable in patients after myeloablative therapy, and a phase-III-trial showed that postconsolidation therapy with 13-cis-retinoic acid improved EFS for patients with high-risk neuroblastoma [7]. Preclinical studies in neuroblastoma indicate that ATRA or 13-cw-RA can antagonize cytotoxic chemotherapy and radiation, such that use of 13-cis-RA in neuroblastoma is limited to maintenance after completion of cytotoxic chemotherapy and radiation. It is likely that recurrent disease seen during or after 13-cis-RA therapy in neuroblastoma is due to tumor cell resistance to retinoid-mediated differentiation induction. Studies in neuroblastoma cell lines resistant to 13-cw-RA and ATRA have shown that they can be sensitive, and in some cases collaterally hypersensitive, to the cytotoxic retinoid fenretinide. Here, fenretinide induces tumor cell cytotoxicity rather than differentiation, acts independently from RA receptors, and in initial phase-I-trials has been well tolerated. Clinical trials of fenretinide, alone and in combination with ceramide modulators, are in development. 

In infectious disease compounds such as ANA975 (phase I trials) and Resiquimod (phase II trails) have been developed to target Hepatitis C and genital herpes, respectively. DRS954 is a TLR-7 and 9 antagonist in pre-clinical trials for Systemic Lupus Erythematosus (SLE). 

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

A phase I trial of an antisense inhibitor of hepatitis C virus (ISIS 14803), administered to chronic hepatitis C patients, J Hepatol 44 88-96... 

In pharmaceutical and medical device development, clinical trials are classified into four main phases designated with Roman numerals 1,11, III and lY The various phases of development trials differ in purpose, length and number of subjects involved. Phase I trials are conducted to determine safe dose levels of a medication, treatment or product (National Institutes of Health, 2002). The main purpose is often to determine an acceptable single dosage - how much can be given without causing serious side-effects. Phase I trials will also involve studies of metabolism and bioavailabity (Pocock, 1983). The sample size of a Phase 1 clinical trial is usually small, ranging from 10-80 subjects (National Institutes of Health, 2002 Pocock, 1983). 

The definitive identifieation of a therapeutie raison d etre for H3 antagonists will happen in the elinie. A handful of H3 ligands are reported to have entered elinieal testing. ABT-834 entered Phase-I trials for the indieation of cognitive disorders in May 2003 but no news has been reported since that time. GT-2331 (11) was approved for Phase-II clinical trials in 1999 but no news has been reported since then [4]. At this point, there are no data available to assess the therapeutic potential in human disease (See Table 5.1). 

Investigation of the differences in crystal packing between (431) and (426) from comparison of their respective X-ray structures, revealed that (431) was more tightly packed than (442), reflected in their respective melting points of 235 and 170 °C. It was postulated that the absence of in vivo activity for (431) may be explained by the resultant reduction in water solubility and dissolution rate compared with (426). The comparatively high calculated polar surface area of (431) (122.5A ) compared with (426) (89.3 A ) was also proposed as a factor influencing the marked difference in bioavailability between the two related compounds. Compound (426) (SLV-319) is currently being developed with Bristol-Myers Squibb for the potential treatment of obesity and other metabolic disorders. Phase I trials for obesity were started in April 2004. Earlier Phase I clinical trials for the treatment of schizophrenia and psychosis, which commenced in April 2002, appear to have been abandoned. 

In phase I clinical trials 47 patients, all of whom had previously failed standard treatments for solid tumors, received the drug in the UK, Italy, and Switzerland on three different schedules.123,124 Dose-limiting toxicities have been defined as bone marrow depression and diarrhea. The latter is treatable with loperamide. Signs of biological activity were seen. Notably one patient with metastatic pancreatic cancer showed a partial response (for 4 months) and two further patients, one with metastatic melanoma and one with bronchoalveolar carcinoma, also showed partial responses. In a phase I trial in combination with 5-FU, a partial response in breast cancer was observed.125 Furthermore, a reduction in tumor marker levels was observed in two patients, one with ovarian cancer, and one with colon cancer. Phase II studies have shown partial responses in cisplatin-resistant ovarian and nonsmall-cell lung cancer.126,127 The indications are that the profile of clinical activity is different and complementary to the mononuclear platinum agents. 

Clinical trials may be divided into three consecutive phases (Table 4.4). During phase I trials, the drug is normally administered to a small group of healthy volunteers. The aims of these studies are largely to establish ... 

Trump DL, Smith DC, Ellis PG, Rogers MP, Schold SC, Winer EP, Panella TJ, Jordan VC, Fine RL (1992) High-dose oral tamoxifen, a potential multidrug-resistance-reversal agent Phase I trial in combination with vinblastine. J Natl Cancer Inst 84 1811-1816... 

Addo S, Yates RA, Laight A (2002) A phase I trial to assess the pharmacology of the new oestrogen receptor antagonist fulvestrant on the endometrium in healthy postmenopausal volunteers. Br J Cancer 87 1354-1359... 

Pisters, K.M. et al., Phase I trial of oral green tea extract in adult patients with solid tumors, J Clin Oncol, 19, 1830, 2001. 

Regulatory guidance for the conduct of clinical trials on vaccines is specific. Traditional phase I trials in normal volunteers are not conducted. Rather, all trials assess not only safety but also efficacy (or at least immunogenicity). Trials may well be challenge trials, that is, after immunization subjects are purposely challenged with exposure to the infective agent of concern. 

Sometimes investigators say that Phase I studies are not clinical trials because there is no treatment comparison being made (except that frequently a placebo is employed). Such treatment comparisons are not a prerequisite for experiments. Because Phase I trials rely on investigator controlled treatment administration and subsequent structured observations, they are clinical trials. 

Phase I. Initial safety trials on a new medicine, usually conducted in normal male volunteers. An attempt is made to establish the dose range tolerated by volunteers for single and for multiple doses. Phase I trials are sometimes conducted in severely ill patients (e.g., in the field of cancer) or in less ill patients when pharmacokinetic issues are addressed (e.g., metabolism of a new antiepileptic medicine in stable epileptic patients whose microsomal liver enzymes have been induced by other antiepileptic medicines). Pharmacokinetic trials are usually considered Phase I trials regardless of when they are conducted during a medicine s development. 

Campbell, K.J. et al., A phase I trial of ABI-007 administered weekly for three doses every 4 weeks in patients with advanced non-hematologic malignancies, Proc. Am. Assoc. Can. Res., 44, 1059, Abstr. R5337, 2003. 

This is provided for reference only, as healthy children will rarely be volunteers for Phase I trials. 

Normally, healthy volunteers are recruited for the Phase I trial. In many cases, volunteers are compensated financially for participation in the Phase I trial. However, in some situations, patients who are critically ill or have terminal disease are presented with the option to be included in the trial after due consideration of the risk-benefit ratio. Phase I trials are usually conducted... 

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