Efficacy Of Compound X In Treating Fungal Infections Biology Essay

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The development of a new drug is a really very complicated and long-lasting challenge with numerous researchers involved in it. From the first concept up to the available treatment it takes approximately twelve years.

At the very beginning of the development of a drug so-called targets have to be detected. A target for example may be a protein from which researchers suspect, that it might be involved in the emergence of a certain illness. If such molecules can successfully be stimulated or blocked, it might be possible to soothe or even heal a disease. Concerning this matter pharmaceutical companies have developed gigantic libraries which contain several millions of substances. These substances usually are one by one brought together with the target of interest. This process is called "High Throughput screening".

For being accepted as an active agent, a substance has to fulfill numerous requirements: healing or at least soothing a sickness, it must not affect other molecules in the human body if possible (side effects), it must reach its place of action before being eliminated and last but not least the agent should not be poisonous after multiple overdosages.

Experimental program

An experimental program for the evaluation of an antimycotic drug always consists of numerous steps.

I will introduce an experimental program, which is built up from different single studies, covering both preclinical and clinical experiments. Clinical studies are classified in different phases (I-IV).

In order not to go beyond the scope I will focus on the phase II study, which is the relevant part for evaluating a new drug. Therefore preclinical experiments and phase I, III and IV studies will be presented in terms of a short overwiev. It is important to know, that each experiment is subject to ethical approval and to financial issues (sponsors, grants).

Preclinical experiments in the laboratory: effectiveness and compatibility

Compound X is a substance which is chemically well characterized and appears to have an antimycotic effect. At first this active agent has to be tested in the laboratory on its effectiveness. Different studies concerning tolerance and distribution will be performed. Toxicologists examine with comprehensive security checks, whether Compound X is toxic or not, if it can cause embryopathy or if it is able to trigger cancer or changes of the genome. Besides cell cultures, animals are also required for all these tests, in order to imitate the complex procedure within the living body. This is important being able to recognize possible detrimental effects before applying the substance in man. If Compound X meets demands it may be applied for patent.

Phase I Study:

Now Compound X can be tested for the first time in people. Tolerance of this new drug has to be evaluated. In healthy volunteers it will be checked how small application rates of Compound X behave in the body, and at what concentration it starts to cause side effects. In phase I studies normally some dozens of healthy persons are included. Afterwards the appropriate pharmaceutical form has to be figured out.

Phase II Studien:

Clinical trials are experimental studies which involve people as study units. Clinical trials nowadays play a major role in deciding the efficacy of new substances as they become available. Early investigations of new treatments tend to focus on animal studies, but the ultimate evaluation involves a clinical trial.In modern therapy research controlled studies, in which single persons are assigned to the test arms by random are regarded as a gold standard to provide valid evidence of effectiveness2. Basic idea is to avoid systematic faults by an ideal experimental design and to create the prerequisite for a clear detection of causalities.

Compound X does not show any essential side effects in phase I, therefore it can be applied in larger group of patients (100 to 500), which receive either Compound X or a conventional treatment. In this study efficacy, compatibility and possible interactions with other drugs are being examined.

Representative for all other studies of this experimental program I will present the various steps of phase II in form of a study protocol.

Study Protocol Phase II: Compound X

Introduction / Background

Patients with HIV often present with Candida esophagitis. Drug A is regarded as a first-line treatment.

Compound X belongs to the group of echinocandine. In-vitro activity was shown against Candida spp. at similar M.I.C.

Study Title

A multicenter, randomised, double-blind, phase II study to investigate the efficacy, safety and tolerability of 1 dose Compound X 50 mg i.v. a day vs drug A 0.6 mg/kg body weight/day for the treatment of endoscopically proven esophageal candidiasis

Study Sponsor

Superpharma, Berne, Switzerland


Institute for Infectious Diseases, University of Bern (ifik) & local institutes of microbiology

Research Hypothesis

The aim of this study is to demonstrate that Compound X has a better response rate and less side effects compared to drug A

Study Objectives

To evaluate and compare the efficacy, safety and tolerability of 1 dose Compound X 50 mg vs drug A 0.6 mg/kg body weight/day for the treatment of endoscopically proven esophageal candidiasis during 14 days


esophageal candidiasis

Study design

Multicenter, double-blind, randomised, comparing 1 dose of Compound X 50 mg iv vs drug A 0.6 mg/kg body weight / day during 14 days

Study outline

The study first consists of a screening of patients presenting with symptomatic esophageal candidiasis.

The diagnosis of Candidiasis will be assessed by endoscopy and biopsy before inclusion, randomisation and treatment start.

Esophageal specimens will be collected and processed for microscopy and culture at the local Institute of Microbiology at each visit. This allows for confirmation of diagnosis, quantitative assessment and identification of the fungal species. In vitro susceptibility testing of isolates of yeast will also be conducted.

Screening (visit 1):

Evaluation of signs and symptoms of esophagal candidiasis

Physical examination and vital signs

Laboratory tests: hematology, chemistry


Biospsies will be sent to the local Institute of Microbiology for microscopy and culture.

Randomisation and treatment start

An entry culture should be positive for Candida albicans or one of the other Candida species. Testing should be performed to identify the isolates to species level. Yeast isolates collected at different visits will be specified and tested for in vitro susceptibility.

Post-treatment visit (Visit 2) (test of cure)

Physical examination and vital signs (21-30 days)

Signs and symptoms evaluation

Adverse events


Microscopic examination and culture

For an overview see Table 1

Study population

Inclusion criteria:

adults (at least 18 yrs old)

Patients who are able to understand

protocol and have given informed consent

endoscopically and microbiologically

documented Candida esophagitis

Exclusion criteria:

Patients treated with drug A during the prior 4 weeks

Pregnant or nursing women


Creatinine clearance, aminotransferase levels (3-5x upper limit), anemia

inability to undergo repeat treatment, clinical evaluations, and other diagnostic procedures required by the protocol

Number of Patients / Randomisation

Based on power analysis at least 120 patients presenting with symptomatic esophagal candidiasis randomized in 2 parallel groups. The number of patients randomised will be equal in both groups

Duration of study

Recruitment is expected to start on day X. The clinical phase of this study will take approximately 12 months

Estimated Number of study centers

The study will be conducted in 7 sites in Switzerland

Study Medication Dose/Route/Regimen

Compound X: 50 mg by intravenous infusion once daily during 7-14 days

Drug A: 0.6 mg/kg body weight / day, once daily by intravenous infusion for 7-14 days


Primary endpoint: Overall therapeutic cure rate

Therapeutic cure: A patient who is judged to be both a clinical cure and fungal eradication (day 21 to 30 of the study)

This composite endpoint is made up of the clinical cure rate and the mycological outcome (eradication or persistence) for candidiasis

Overall therapeutic cure rate at visit 2 will be analysed using one-sided Chi-Square-test (x2)

Secondary endpoints

Dose-response relationship will be modeled for each dose group using Emax-model

Clinical cure rate

Time to resolution of symptoms

Eradication or persistence for candidiasis

Secondary endpoints will be analysed using

appropriate statistical methods.

Criteria for Efficacy


Clinical outcome: Cure or improvement/failure

Assessment of efficacy on symptoms of esophagitis

Optionally supported by patient symptom assessment

Cure: resolution of all entry clinical signs and symptoms



incomplete resolution

worsening of entry signs and symptoms

new signs or symptoms of the disease

need for treatment with additional antimicrobial therapy

Mycological outcome:

Cure: Mycological eradication; negative culture (no growth) for Candida albicans (or baseline yeast pathogen)

Improvement/failure: positive culture for Candida albicans (or baseline yeast pathogen)

Overall therapeutic assessment:

Therapeutic cure: Patient who is considered both a clinical cure and mycological eradication

Therapeutic failure: Patient who anytime during the study period was considered by the investigator as a clinical failure or mycological persistence.

Criteria for Safety

The following safety assessment will be performed:

adverse events (local and systemic)

Safety laboratory tests: hematology, chemistry (Visit 1 & 2)

Statistical Plan

sample size evaluation: Coumpound X group must be statistically significantly superior to drug A (chi square test). Sample size estimation are performed by NQuery Advisor

The evolution of all (primary and secondary) endpoints will be compared to baseline. All statistical tests will be one-sided at the 5% significance level. 95% confidence intervals of the treatment difference will be presented to illustrate the precision of the study

Compliance with good clinical practice, ethical considerations & informed consent

The study must be conducted in compliance with the independent ethics committee/institutional review board (IEC/IRD)'s recommendation, informed consent regulations, ICH GCP Guidelines3 and this protocol. In addition this study will adhere to all local regulatory requirements and Declaration of Helsinki1.

A written informed consent must be obtained by the investigator for each volunteer participating in the study. This protocol and other documents will be submitted by the investigator to an independent Ethics Committee and the institutional Review Board.

Case report forms

CRF will be implemented by Contract Research Organisation

Study management & materials

The investigator is to record all data with respect to protocol procedures on the case report forms.

Source Data Verification

Source data consists of original records or certified copies necessary for the reconstruction and evaluation of the trial.

Clinical study report

A final clinical study report will be prepared according to the ICH guideline on Structure and Content of clinical study reports (ICH E3).


All measures must be taken in order to insure the patient`s anonymity.

Financing and insurance

A financial agreement will be signed between the investigator and the sponsor, outlining overall sponsor and investigator responsibilities to the study. The agreement should describe the costs for pharmacy, laboratory and other protocol required services and the remuneration needed to be paid